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Yue X, Wang Y, Zheng R, Li L. The coping experiences in patients with hepatocellular carcinoma and their spouses following postoperative recurrence: A dyadic qualitative study. Asia Pac J Oncol Nurs 2025; 12:100665. [PMID: 40104041 PMCID: PMC11919323 DOI: 10.1016/j.apjon.2025.100665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Accepted: 02/05/2025] [Indexed: 03/20/2025] Open
Abstract
Objective Dyadic coping practices can vary depending on cultural contexts, socioeconomic factors, and the stages of the cancer journey. This study aimed to explore the dyadic coping experiences of hepatocellular carcinoma (HCC) patients and their spouses following postoperative recurrence in the Chinese cultural context, where cancer recurrence is frequently seen as a death sentence, and family-centered care is prioritized. Methods A descriptive qualitative research design was used, involving face-to-face, in-depth semi-structured interviews with 13 pairs of hepatocellular carcinoma patients and their spouses at a tertiary cancer hospital from July to October 2023. The interview guide was designed based on the Actor-Partner Interdependence Model (APIM) framework. Data were analyzed using thematic analysis, and the study adhered to the COnsolidated criteria for REporting Qualitative research (COREQ) checklist. Results Three themes were identified: (1) active coping strategies, (2) negative coping tendencies, and (3) the need for systematic coping support. The majority of couples perceived hepatocellular carcinoma recurrence as a death sentence, which prompted them-especially the spouses-to adopt proactive strategies, such as striving to seek advanced treatments and concealing unfavorable information. In contrast, patients, particularly those with a hereditary hepatocellular carcinoma background, often exhibited passivity, withdrawal, and contemplation of treatment abandonment. Spouses frequently felt overwhelmed and unable to alleviate their partners' anxiety about recurrence and death, particularly in the absence of support from health care professionals. They expressed a strong need for professional guidance and targeted interventions to address end-of-life concerns, emphasizing the need for increased financial support, empowerment through knowledge, and access to peer support networks. Conclusions This research emphasizes the importance of recognizing the interdependent coping experiences of recurrent HCC patients and their spouses. Health care professionals are encouraged to implement culturally sensitive, dyadic interventions that foster collaborative coping, address death-related anxiety, and empower couples in managing recurrence together, thereby enhancing their coping strategies and confidence.
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Affiliation(s)
- Xian Yue
- Department of Nursing, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
- Department of Hepatobiliary, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Yanhui Wang
- Department of Hepatobiliary, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Ruishuang Zheng
- Department of Hepatobiliary, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Laiyou Li
- Department of Nursing, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
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Deng Z, Mei S, Ouyang Z, Wang R, Wang L, Zou B, Dai J, Mao K, Li Q, Guo Q, Yi C, Meng F, Xie M, Zhang X, Wang R, Deng T, Wang Z, Li X, Wang Q, Liu B, Tian X. Dysregulation of gut microbiota stimulates NETs-driven HCC intrahepatic metastasis: therapeutic implications of healthy faecal microbiota transplantation. Gut Microbes 2025; 17:2476561. [PMID: 40099491 PMCID: PMC11925110 DOI: 10.1080/19490976.2025.2476561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 12/04/2024] [Accepted: 03/03/2025] [Indexed: 03/20/2025] Open
Abstract
The stringent regulation of intrahepatic metastases is essential for improving survival outcomes in patients with hepatocellular carcinoma (HCC). This study investigated the impact of gut microbiota on intrahepatic metastasis of HCC and evaluated the therapeutic potential of healthy fecal microbiota transplantation (FMT). Dysregulation of the gut microbiota, characterized by a significant reduction in the abundance of beneficial bacteria, such as Anaerotruncus colihominis and Dysosmobacter welbionis, was observed in patients with intrahepatic metastatic HCC. A human flora-associated (HFA) intrahepatic metastatic HCC mouse model was successfully established through consecutive 4 weeks of human-mouse FMT. Dysregulation of gut microbiota promoted intrahepatic metastasis in the mouse model, primarily by enhancing neutrophil-mediated inflammatory responses and lead to excessive formation of neutrophil extracellular traps (NETs). Consequently, it promoted tumor vascular growth and tissue necrosis, resulting in intrahepatic metastasis of HCC. Notably, FMT from healthy donors mitigated these pathological processes. This study elucidated the role and mechanism of dysregulated gut microbiota in promoting intrahepatic metastasis of HCC. Healthy FMT emerges as a promising novel therapeutic strategy for preventing and treating intrahepatic metastasis of HCC.
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Affiliation(s)
- Zhe Deng
- College of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA
| | - Si Mei
- Hunan Province University Key Laboratory of Oncology of Traditional Chinese Medicine, Changsha, Hunan, China
- Key Laboratory of Traditional Chinese Medicine for Mechanism of Tumor Prevention &Treatment, Changsha, Hunan, China
- Department of Physiology, Faculty of Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Zhaoguang Ouyang
- School and Hospital of Stomatology, Tianjin Medical University, Tianjin, China
| | - Ruoyu Wang
- The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Lihuai Wang
- The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Bo Zou
- The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Jingjing Dai
- College of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Kexin Mao
- The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Qian Li
- College of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Qianqian Guo
- College of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Chun Yi
- Department of Pathology, Faculty of Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Fanying Meng
- The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Mingxia Xie
- College of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Xue Zhang
- College of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Rongrong Wang
- Hunan Province Integrated Traditional Chinese and Western Medicine Hospital, Changsha, Hunan, China
| | - Tianhao Deng
- Hunan Province Integrated Traditional Chinese and Western Medicine Hospital, Changsha, Hunan, China
| | - Zhenyu Wang
- JCY Biotech Ltd., Pingshan Translational Medicine Center, Shenzhen Bay Laboratory, Shenzhen, China
| | - Xiaozheng Li
- College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, China
- College of Biology, School of Biomedical Sciences, Hunan University, Changsha, China
| | - Qing Wang
- Shanghai OE Biotech Co. Ltd, Shanghai, China
| | - Bin Liu
- College of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Xuefei Tian
- College of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
- Hunan Province University Key Laboratory of Oncology of Traditional Chinese Medicine, Changsha, Hunan, China
- Key Laboratory of Traditional Chinese Medicine for Mechanism of Tumor Prevention &Treatment, Changsha, Hunan, China
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Peng W, Liang J, Qian X, Li M, Nie M, Chen B. IGF2BP1/AIFM2 axis regulates ferroptosis and glycolysis to drive hepatocellular carcinoma progression. Cell Signal 2025; 130:111660. [PMID: 39971223 DOI: 10.1016/j.cellsig.2025.111660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2025] [Revised: 02/12/2025] [Accepted: 02/13/2025] [Indexed: 02/21/2025]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is aggressive liver tumor that is the third leading cause of cancer death. Ferroptosis and glycolysis play key roles in HCC progression. Apoptosis-inducing factor mitochondria-associated 2 (AIFM2) in involved in regulating ferroptosis and glycolysis in cancers, but its role in HCC remains unclear. This research explored the function of AIFM2 in HCC. METHODS AIFM2 expression in HCC tissues was evaluated using the UALCAN and GEPIA databases, as well as RT-qPCR. Kaplan-Meier survival analysis analyzed the correlation between AIFM2 and the prognosis of HCC patients. EdU and transwell assays were utilized to examine HCC cell proliferation, migration, and invasion. Ferroptosis markers were analyzed by measuring iron levels, ROS production (DCFH-DA assay), and oxidative stress indicators (SOD, MDA, and GSH). Glycolytic activity was assessed through glucose uptake, lactate production, and ATP levels. m6A modification on AIFM2 mRNA was confirmed by MeRIP assay, and mRNA stability was evaluated with Actinomycin D treatment. Tumor growth and metastasis were studied in xenograft and lung metastasis models. RESULTS UALCAN analysis showed that AIFM2 was significantly upregulated in HCC tissues, which correlated with poor survival rates of HCC patients. IGF2BP1 was also highly expressed in HCC tissues and positively correlated with AIFM2 levels in HCC tissues. Functionally, AIFM2 knockdown suppressed glycolysis and enhanced ferroptosis, while its overexpression had opposite effects. IGF2BP1 was found to stabilize AIFM2 mRNA via m6A modification, promoting AIFM2 expression. IGF2BP1 knockdown reduced glycolysis, proliferation, and invasion while promoting ferroptosis, while AIFM2 overexpression could reverse this effect. In vivo, IGF2BP1 or AIFM2 silencing significantly suppressed tumor growth and metastasis. CONCLUSION IGF2BP1 stabilized AIFM2 mRNA to regulate ferroptosis and glycolysis and promoted HCC progression.
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Affiliation(s)
- Wei Peng
- Department of Gastrointestinal Surgery, Zhejiang Provincial People's Hospital Bijie Hospital, Bijie, Guizhou 551700, China
| | - Jie Liang
- Department of Gastrointestinal Surgery, Zhejiang Provincial People's Hospital Bijie Hospital, Bijie, Guizhou 551700, China
| | - Xuanlv Qian
- Department of Gastrointestinal Surgery, Zhejiang Provincial People's Hospital Bijie Hospital, Bijie, Guizhou 551700, China
| | - Mingwang Li
- Department of Gastrointestinal Surgery, Zhejiang Provincial People's Hospital Bijie Hospital, Bijie, Guizhou 551700, China
| | - Ming Nie
- Department of Gastrointestinal Surgery, Zhejiang Provincial People's Hospital Bijie Hospital, Bijie, Guizhou 551700, China
| | - Bin Chen
- Department of Gastrointestinal Surgery, Zhejiang Provincial People's Hospital Bijie Hospital, Bijie, Guizhou 551700, China.
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Li L, Li A, Wang J, Shao J, Zhou H, Peng Z, Lin H, Gao J. Visualizing enterohepatic circulation in vivo by sensitive 19F MRI with a fluorinated ferrous chelate-based small molecule probe. Biomaterials 2025; 317:123073. [PMID: 39848003 DOI: 10.1016/j.biomaterials.2024.123073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 12/10/2024] [Accepted: 12/30/2024] [Indexed: 01/25/2025]
Abstract
Enterohepatic circulation (EHC) is a critical biological process for the normal regulation of many endogenous biomolecules and the increased retention of various exogenous substances. The status of EHC is closely related to the ordinary functioning of several digestive organs. However, it remains a challenge to achieve in vivo real-time visualization of this process. Herein, we rationally design and synthesize a ferrous chelate, DO3A-Fe(II)-9F, with high fluorine content and favorable water solubility for visualizing EHC via19F magnetic resonance imaging (MRI). The assessments on imaging performance reveal an 18-time increase in signal intensity compared to the fluorinated ligand alone. This probe's capability of entering EHC via the mediation of organic anion transporting polypeptides (OATPs) is validated with ex vivo bio-distribution analysis and in vivo uptake-blocking imaging experiments, which allows short-time sensitive 19F MRI of EHC in healthy mice. Additionally, we illustrate its capacity for clearly imaging tampered EHC in the mice with inflammatory bowel diseases (IBD), drug-induced liver injury (DILI) or orthotopic hepatocellular carcinoma (HCC). These results illustrate the promising potential of this probe for in vivo visualization of EHC under different conditions, especially disease conditions, which is beneficial for the study, diagnosis, or even stratification of various diseases.
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Affiliation(s)
- Lingxuan Li
- The Key Laboratory for Chemical Biology of Fujian Province, The MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, and Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, China
| | - Ao Li
- The Key Laboratory for Chemical Biology of Fujian Province, The MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, and Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, China; State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, 361005, China
| | - Junjie Wang
- The Key Laboratory for Chemical Biology of Fujian Province, The MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, and Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, China
| | - Juan Shao
- The Key Laboratory for Chemical Biology of Fujian Province, The MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, and Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, China
| | - Huijie Zhou
- The Key Laboratory for Chemical Biology of Fujian Province, The MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, and Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, China
| | - Zixiong Peng
- The Key Laboratory for Chemical Biology of Fujian Province, The MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, and Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, China
| | - Hongyu Lin
- The Key Laboratory for Chemical Biology of Fujian Province, The MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, and Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, China; Shenzhen Research Institute of Xiamen University, Shenzhen, 518000, China.
| | - Jinhao Gao
- The Key Laboratory for Chemical Biology of Fujian Province, The MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, and Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, China; Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen Key Laboratory of Translational Medical of Digestive System Tumor, Zhongshan Hospital, Xiamen University, Xiamen 361004, China.
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Qiang N, Ao J, Nakamura M, Katayama K, Zhang J, Kogure T, Ogawa K, Kanzaki H, Kojima R, Koroki K, Kobayashi K, Inoue M, Kanogawa N, Kiyono S, Nakagawa R, Kondo T, Ogasawara S, Nakamoto S, Muroyama R, Kato J, Kato N. MEGF6 knockdown ameliorates lenvatinib-induced muscle differentiation suppression and enhances the antitumor effect of lenvatinib on hepatocellular carcinoma. Biochem Pharmacol 2025; 235:116829. [PMID: 40015652 DOI: 10.1016/j.bcp.2025.116829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 01/12/2025] [Accepted: 02/24/2025] [Indexed: 03/01/2025]
Abstract
Lenvatinib (LEN)-treated patients with hepatocellular carcinoma (HCC) are frequently accompanied by skeletal muscle loss, which is correlated with poor prognosis. Interactions between tumor and skeletal muscle may play a role in patient prognosis and tumor progression. We here demonstrated that LEN hindered proliferation and differentiation of the mouse myoblast cell line, C2C12 cells, by blocking the ERK1/2 and AKT signaling pathways. Transcriptome analysis revealed that multiple EGF-like domains 6 (Megf6) was upregulated in LEN-treated C2C12 cells. Furthermore, we observed that compared with normal adjacent tissues, MEGF6 was highly expressed in HCC tumor tissues according to the TCGA database, which suggested MEGF6-mediated interaction between tumor and skeletal muscle. The Megf6 knockdown restored the differentiation inhibition caused by LEN and ERK1/2 inhibitors; however, it had no significant impact on proliferation. Regarding mechanism, LEN increased Megf6 expression through the ERK1/2 signaling pathway, thereby resulting in myostatin expression elevation and myosin heavy chain protein expression repression. Furthermore, MEGF6 in LEN-treated C2C12 cell medium promoted tumor cell proliferation and impaired C2C12 cell differentiation when cultured with LEN-treated tumor cell medium. Clinically, patients who were accompanied by muscle mass loss and increased MEGF6 serum levels had shorter progression-free survival than those who were accompanied by muscle mass loss but no increased MEGF6 serum levels before and after LEN treatment. In conclusion, MEGF6 produced from muscle and tumor cells could impair muscle differentiation and enhance tumor proliferation. Therefore, MEGF6 is worth further investigating as a target for improving the prognosis of LEN-treated patients with HCC.
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Affiliation(s)
- Na Qiang
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, China; Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Junjie Ao
- Cancer Center, Department of Gastroenterology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China; Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Masato Nakamura
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.
| | - Keichi Katayama
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Jiaqi Zhang
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tadayoshi Kogure
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Keita Ogawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Hiroaki Kanzaki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan; Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Ryuta Kojima
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Keisuke Koroki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Kazufumi Kobayashi
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Masanori Inoue
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Naoya Kanogawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Soichiro Kiyono
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Ryo Nakagawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Takayuki Kondo
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Sadahisa Ogasawara
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Shingo Nakamoto
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Ryosuke Muroyama
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Jun Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Naoya Kato
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, China
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Fei J, Qi LW, Liu Y, Shu M, Mo WQ. Comparing transarterial chemoembolization alone to combined transarterial chemoembolization and radiofrequency ablation in primary hepatocellular carcinoma treatment. World J Gastrointest Oncol 2025; 17:102038. [DOI: 10.4251/wjgo.v17.i4.102038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Revised: 01/08/2025] [Accepted: 01/21/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Transarterial chemoembolization (TACE) combined with percutaneous radiofrequency ablation (RFA) has emerged as a promising treatment strategy for patients with unresectable HCC.
AIM To evaluate the effectiveness and safety of TACE combined with RFA compared to TACE alone in the management of primary HCC.
METHODS A comprehensive retrospective analysis was conducted at our institution from January 2020 to January 2024, involving 106 patients diagnosed with intermediate to advanced-stage HCC. Patients were divided into two groups: Those receiving TACE alone (n = 56) and those undergoing combined TACE and RFA therapy (n = 50). Treatment efficacy was assessed based on tumor response rates, serum alpha-fetoprotein (AFP) levels, and survival outcomes. Statistical analyses, including χ2 tests and Kaplan-Meier survival analysis, were performed to compare the outcomes between the two groups.
RESULTS The TACE + RFA group demonstrated significantly higher rates of complete response (15 vs 4, P < 0.01) and partial response (23 vs 15, P = 0.046) compared to the TACE group. Conversely, the TACE group exhibited higher rates of stable disease (25 vs 7, P < 0.01) and progressive disease (12 vs 5, P < 0.01). Serum AFP levels decreased over time in the TACE + RFA group, while they increased in the TACE group. Survival analysis revealed superior survival outcomes in the TACE + RFA group, with higher survival rates and a prolonged median survival time compared to the TACE group.
CONCLUSION The combination of RFA with TACE could offer enhanced treatment response and prolonged survival in patients with primary HCC compared to TACE alone. These findings might support the adoption of multimodal therapeutic approaches, emphasizing the importance of personalized treatment strategies in the management of HCC.
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Affiliation(s)
- Jing Fei
- Department of Oncology, The First Affiliated Hospital of Shihezi University, Shihezi 832008, Xinjiang Uygur Autonomous Region, China
| | - Li-Wen Qi
- Department of Oncology, The First Affiliated Hospital of Shihezi University, Shihezi 832008, Xinjiang Uygur Autonomous Region, China
| | - Yuan Liu
- Department of Oncology, The First Affiliated Hospital of Shihezi University, Shihezi 832008, Xinjiang Uygur Autonomous Region, China
| | - Min Shu
- Department of Oncology, The First Affiliated Hospital of Shihezi University, Shihezi 832008, Xinjiang Uygur Autonomous Region, China
| | - Wen-Qiang Mo
- Department of Oncology, The First Affiliated Hospital of Shihezi University, Shihezi 832008, Xinjiang Uygur Autonomous Region, China
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Li Y, Zhou L, Sun K, Guo R, Li Z, Wen Q, Fu G, Yang S. Integrated network pharmacology, proteomics, molecular docking, and experiments in vivo and in vitro to explore the efficacy and potential mechanism of bufalin against hepatocellular carcinoma angiogenesis. JOURNAL OF ETHNOPHARMACOLOGY 2025; 345:119589. [PMID: 40057142 DOI: 10.1016/j.jep.2025.119589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Revised: 02/16/2025] [Accepted: 03/05/2025] [Indexed: 03/29/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Bufalin is a potent bioactive compound extracted from the venom of toads such as Bufo gargarizans. It has rich pharmacological effects, and its traditional applications mainly include anti-cancer, anti-inflammatory and analgesic, especially in cancer treatment, which has been a hot topic of research. Prior research has suggested that bufalin may have anti-tumor angiogenic effects. However, the efficacy and mechanism of bufalin inhibiting hepatocellular carcinoma (HCC) angiogenesis have yet to be further investigated. AIM OF THE STUDY An extensive detailed strategy via network pharmacology, proteomics, histopathological analysis, molecular docking, in vitro experiments, and in vivo magnetic resonance imaging (MRI) examinations were adopted to investigate the efficacy and mechanisms of bufalin against HCC angiogenesis. MATERIALS AND METHODS Micro-vessel density (MVD) and intravoxel incoherent motion (IVIM) perfusion-related parameters based on magnetic resonance diffusion-weighted imaging were used to identify the effect of bufalin against HCC angiogenesis. Potential bufalin and HCC targets were gathered from appropriate databases. The STRING database was used to construct the target protein interaction networks. The "clusterprofiler" package (version 4.2.2) in R was applied to conduct the target-related Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and Gene Ontology (GO) analysis. Network pharmacology and proteomics were integrated to identify key targets and pathways related to bufalin against HCC angiogenesis. Molecular docking and Western Blot were utilized to validate the findings. RESULTS Analysis through IVIM and MVD showed that bufalin could inhibit HCC angiogenesis in nude mice models. A total of 159 common targets of bufalin and HCC were identified by network pharmacology. GO analysis revealed that these targets focused on multiple angiogenesis-related biological processes, including endothelial cell proliferation and migration, sprouting angiogenesis, and regulation of angiogenesis. The KEGG enrichment results suggested that bufalin could regulate multiple signaling pathways to inhibit HCC angiogenesis, including VEGF, MAPK, PI3K-Akt, mTOR, and HIF-1 signaling pathways. MAPK1, MAPK14, PRKCA, EIF4E, and APEX1 might be critical targets in regulating the above pathways. The molecular docking and Western blot analysis verified the effects of bufalin on target proteins. CONCLUSION This study demonstrated that bufalin might inhibit HCC angiogenesis by regulating multiple targets and pathways. These findings offer theoretical insights and experimental foundations for the clinical application and commercial development of bufalin in the treatment of HCC.
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Affiliation(s)
- Yuanchao Li
- Department of Radiology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 274 Middle Zhi-Jiang Road, Shanghai, 200071, People's Republic of China
| | - Lingwei Zhou
- Department of Radiology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 274 Middle Zhi-Jiang Road, Shanghai, 200071, People's Republic of China
| | - Kang Sun
- Department of Laboratory, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 274 Middle Zhi-Jiang Road, Shanghai, 200071, People's Republic of China
| | - Ran Guo
- Department of Radiology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 274 Middle Zhi-Jiang Road, Shanghai, 200071, People's Republic of China
| | - Zehua Li
- Department of Radiology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 274 Middle Zhi-Jiang Road, Shanghai, 200071, People's Republic of China
| | - Qingqing Wen
- GE Healthcare, MR Research, Beijing, PK, People's Republic of China
| | - Guifeng Fu
- GE Healthcare, MR Research, Beijing, PK, People's Republic of China
| | - Shuohui Yang
- Department of Radiology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 274 Middle Zhi-Jiang Road, Shanghai, 200071, People's Republic of China.
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Choi WJ, Ivanics T, Rajendran L, Li Z, Gavira F, Jones O, Gravely A, Claasen M, Yoon PD, Ladak F, Rana M, Gotlieb N, Dini Y, Naccarato K, McCluskey S, Ferreira R, Msallak H, Chow J, Abreu P, Rabindranath M, Selvanathan C, Muaddi H, Magyar CTJ, Englesakis M, Beecroft R, Vogel A, O'Kane G, Hansen B, Sapisochin G. Comparative analysis of treatment modalities for solitary, small (≤3 cm) hepatocellular carcinoma: A systematic review and network meta-analysis of oncologic outcomes. Surgery 2025; 180:108917. [PMID: 39609218 DOI: 10.1016/j.surg.2024.10.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 10/15/2024] [Accepted: 10/17/2024] [Indexed: 11/30/2024]
Abstract
BACKGROUND Solitary hepatocellular carcinoma measuring ≤3 cm represents approximately 30% of hepatocellular carcinoma cases, yet treatment guidelines lack robust evidence. This study compares oncologic outcomes after ablation, liver resection, and liver transplantation for solitary, small hepatocellular carcinoma. METHODS We systematically searched databases up to 7 February 2022, for studies including adults with solitary hepatocellular carcinoma ≤3 cm treated by any ablation, liver resection, or liver transplantation. We excluded non-hepatocellular carcinoma cancers, recurrent/metastatic diseases, and alternative therapies. A frequentist network meta-analysis assessed 5-year overall survival and recurrence-free survival using only adjusted effect estimates while accounting for bias risk. RESULTS We identified 80 studies (4 randomized controlled trials, 72 retrospectives, and 4 prospective cohorts) with 28,211 patients. In the network meta-analysis for 5-year overall survival (26 studies), liver transplantation was associated with the lowest mortality hazard (hazard ratio, 0.47; 95% confidence interval, 0.31-0.73, referenced to liver resection), followed by liver resection (reference), whereas ablation had the greatest mortality hazard (hazard ratio, 1.32; 95% confidence interval, 1.16-1.49, referenced to liver resection). For 5-year recurrence-free survival (19 studies), liver transplantation had the best outcome (hazard ratio, 0.36; 95% confidence interval, 0.20-0.63, referenced to liver transplantation), followed by liver resection (reference), with ablation showing the least favorable outcome (hazard ratio, 1.67; 95% confidence interval, 1.45-1.93, referenced to liver resection). CONCLUSIONS This network meta-analysis provides the evidence for comparing treatment modality outcomes for solitary, small (≤3 cm) hepatocellular carcinoma. LT emerges as the superior choice for achieving a better 5-year OS, followed by liver resection, then ablation. When feasible to preserve liver function, liver resection can be prioritized. Ablation with close surveillance should be reserved for individuals unfit for surgery.
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Affiliation(s)
- Woo Jin Choi
- Department of Surgery, University of Toronto, Toronto, ON, Canada; Institute of Health Policy, Management and Evaluation, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada; University Health Network, HPB Oncology Research, Toronto, ON, Canada. https://twitter.com/WJChoiMD
| | - Tommy Ivanics
- University Health Network, HPB Oncology Research, Toronto, ON, Canada; Department of Surgery, Henry Ford Hospital, Detroit, MI; Department of Surgical Sciences, Akademiska Sjukhuset, Uppsala University, Uppsala, Sweden. https://twitter.com/invanics_t
| | - Luckshi Rajendran
- Department of Surgery, University of Toronto, Toronto, ON, Canada; University Health Network, HPB Oncology Research, Toronto, ON, Canada
| | - Zhihao Li
- University Health Network, HPB Oncology Research, Toronto, ON, Canada
| | - Felipe Gavira
- University Health Network, HPB Oncology Research, Toronto, ON, Canada
| | - Owen Jones
- University Health Network, HPB Oncology Research, Toronto, ON, Canada
| | - Annabel Gravely
- University Health Network, HPB Oncology Research, Toronto, ON, Canada
| | - Marco Claasen
- University Health Network, HPB Oncology Research, Toronto, ON, Canada; Department of Surgery, Division of HPB & Transplant Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | | | - Farah Ladak
- University Health Network, HPB Oncology Research, Toronto, ON, Canada
| | - Mehwish Rana
- University Health Network, HPB Oncology Research, Toronto, ON, Canada
| | - Neta Gotlieb
- Department of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Yasmin Dini
- University Health Network, HPB Oncology Research, Toronto, ON, Canada
| | - Katia Naccarato
- University Health Network, HPB Oncology Research, Toronto, ON, Canada
| | - Sydney McCluskey
- University Health Network, HPB Oncology Research, Toronto, ON, Canada
| | | | - Haythem Msallak
- Department of Surgery, University of Toronto, Toronto, ON, Canada; University Health Network, HPB Oncology Research, Toronto, ON, Canada
| | - James Chow
- University Health Network, HPB Oncology Research, Toronto, ON, Canada
| | - Phillipe Abreu
- University Health Network, HPB Oncology Research, Toronto, ON, Canada
| | | | | | - Hala Muaddi
- Department of Surgery, University of Toronto, Toronto, ON, Canada; University Health Network, HPB Oncology Research, Toronto, ON, Canada; Department of Surgery, Mayo Clinic Rochester, Rochester, MN
| | - Christian T J Magyar
- University Health Network, HPB Oncology Research, Toronto, ON, Canada; Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Marina Englesakis
- Library and Information Services, University Health Network, Toronto, ON, Canada
| | - Rob Beecroft
- Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada
| | - Arndt Vogel
- Division of Gastroenterology and Hepatology, Toronto General Hospital, Toronto, ON, Canada
| | - Grainne O'Kane
- Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada; Department of Medical Oncology, Trinity St. James's Cancer Institute, Trinity College Dublin, Dublin, Ireland
| | - Bettina Hansen
- Department of Epidemiology & Biostatistics, Erasmus MC, Rotterdam, the Netherlands
| | - Gonzalo Sapisochin
- Department of Surgery, University of Toronto, Toronto, ON, Canada; University Health Network, HPB Oncology Research, Toronto, ON, Canada.
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9
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Lu J, Wang F, Zhang W, Ren Y, Yang T, Ratti F, Marques HP, Silva S, Soubrane O, Lam V, Poultsides GA, Popescu I, Grigorie R, Alexandrescu S, Martel G, Workneh A, Guglielmi A, Hugh T, Aldrighetti L, Endo I, Lyu Y, Zhang XF, Pawlik TM. Perioperative Changes in Serum Transaminases Levels Predicts Long-Term Survival Following Liver Resection of Hepatocellular Carcinoma. Ann Surg Oncol 2025; 32:2446-2455. [PMID: 39730966 DOI: 10.1245/s10434-024-16705-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Accepted: 12/03/2024] [Indexed: 12/29/2024]
Abstract
BACKGROUND We sought to define whether and how hepatic ischemia/reperfusion (I/R) as manifested by perioperative aspartate aminotransferase (AST) and alanine aminotransaminase (ALT) levels impact long-term outcomes after curative-intent resection of hepatocellular carcinoma (HCC). PATIENTS AND METHODS Intrasplenic injection of HCC cells was used to establish a murine model of HCC recurrence with versus without I/R injury. Patients who underwent curative resection for HCC were identified from a multi-institutional derivative cohort (DC) and separate external validation (VC) cohort. Perioperative changes of transaminase levels were examined relative to the recurrence-free (RFS) and overall survival (OS) among patients following HCC resection. RESULTS Mice exposed to hepatic I/R injury were more likely to experience tumor recurrence, as well as higher luminescence signal intensity (all p < 0.05) versus mice with no I/R injury. Relative changes between AST and ALT (sum of AST/ALT ratios, SAAR) on postoperative day (POD) 1 and POD 3AST 1 ALT 1 and AST 3 ALT 3 were calculated using the formula: SAAR = 1 2 AST 1 ALT 1 + AST 3 ALT 3 via Fourier transform theory. Among 734 patients in DC, the median SAAR was 2.1. After adjusting for other competing risk factors, SAAR ≥ 2.0 remained strongly associated with risk of postoperative recurrence (ref. SAAR < 2.0, HR 1.32, p = 0.03), whereas SAAR ≥ 3.5 was associated with risk of postoperative mortality (ref. SAAR < 3.5, HR 1.86, p < 0.01). SAAR demonstrated good accuracy to predict postoperative recurrence (c-index 0.724, 0.731) and mortality (c-index 0.655, 0.765) in DC and VC, respectively. CONCLUSIONS Use of routine labs such as AST and ALT can help identify patients at high risk of recurrence and mortality following HCC resection.
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Affiliation(s)
- Jingming Lu
- Department of Hepatobiliary Surgery and Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
- School of Future Technology, Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Fumin Wang
- Department of Hepatobiliary Surgery and Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
- School of Future Technology, Xi'an Jiaotong University, Xi'an, People's Republic of China
| | | | - Yaoxing Ren
- Department of Hepatobiliary Surgery and Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
- School of Future Technology, Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Tian Yang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Navy Medical University, Shanghai, People's Republic of China
| | | | - Hugo P Marques
- Department of Surgery, Curry Cabral Hospital, Lisbon, Portugal
| | - Silvia Silva
- Department of Surgery, Curry Cabral Hospital, Lisbon, Portugal
| | - Olivier Soubrane
- Department of Hepatobiliopancreatic Surgery, APHP, Beaujon Hospital, Clichy, France
| | - Vincent Lam
- Department of Surgery, Westmead Hospital, Sydney, Australia
| | | | - Irinel Popescu
- Department of Surgery, Fundeni Clinical Institute, Bucharest, Romania
| | - Razvan Grigorie
- Department of Surgery, Fundeni Clinical Institute, Bucharest, Romania
| | | | | | - Aklile Workneh
- Department of Surgery, University of Ottawa, Ottawa, Canada
| | | | - Tom Hugh
- Department of Surgery, School of Medicine, The University of Sydney, Sydney, Australia
| | | | - Itaru Endo
- Yokohama City University School of Medicine, Yokohama, Japan
| | - Yi Lyu
- Department of Hepatobiliary Surgery and Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
- School of Future Technology, Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Xu-Feng Zhang
- Department of Hepatobiliary Surgery and Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China.
- School of Future Technology, Xi'an Jiaotong University, Xi'an, People's Republic of China.
| | - Timothy M Pawlik
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA.
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10
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Le Floc'h B, Livin M, Tzedakis S, Robin F, Jeddou H, Boudjema K. Posterior Hepatectomy and Inferior Vena Cava Graft Reconstruction for En Bloc Resection of a Hepatocellular Carcinoma: A Tribute to Couinaud's Liver Anatomy Description. Ann Surg Oncol 2025; 32:2472-2473. [PMID: 39863802 DOI: 10.1245/s10434-024-16855-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 12/28/2024] [Indexed: 01/27/2025]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) associated with major vasculature tumor extension is considered an advanced stage of disease to which palliative radiotherapy or chemotherapy is proposed.1,2 Surgical resection associated with chemotherapy or chemoembolization could be an opportunity to improve overall survival and recurrence-free survival in selected cases in a high-volume hepatobiliary center.3,4 Moreover, it has been 25 years since Couinaud described the entity of a posterior liver located behind an axial plane crossing the portal bifurcation.5 The aim of this video was to show how to reproduce such a resection technique. METHODS We report the case of a 72-year-old male presenting with a 6 cm HCC developed in a well-compensated Child-Pugh A alcohol-related cirrhosis and localized in the dorsal liver sector. The tumor invaded the retrohepatic inferior vena cava (IVC) as well as segment 2 and the right posterior section glissonean pedicles. The initial management of the patient was performed outside of a reference center for hepatobiliary surgery and the tumor was initially considered unresectable. Transarterial chemoembolization was judged ineffective due to the size and location of the tumor. Initial treatment included 6 months of atezolizumab-bevacizumab, permitting tumor volume stability and enabling surgical resection. RESULTS The procedure included an en bloc posterior hepatectomy (H1267)6 with IVC resection and polytetrafluoroethylene (PTFE) graft replacement. A well-tolerated intermittent pedicle and IVC clamping of 30 min in total was used. The duration of surgery was 240 min, with 30 min of total vascular liver exclusion, and total blood loss was 650 mL. The patient was discharged on postoperative day 8. R0 resection was achieved and the patient was free of disease at 1 year post-surgery. CONCLUSION To our knowledge, this video reports the first posterior hepatectomy performed in clinical practice and demonstrates liver anatomy as described by Couinaud in 1999.5 Moreover, complex vascular resections for HCC should be considered a valid therapeutic option in selected cases and high-volume hepatobiliary centers.
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Affiliation(s)
- Bastien Le Floc'h
- Department of Hepatobiliary and Digestive Surgery, Pontchaillou University Hospital, Rennes, France
| | - Marie Livin
- Department of Hepatobiliary and Digestive Surgery, Pontchaillou University Hospital, Rennes, France
| | - Stylianos Tzedakis
- Department of Hepatobiliary and Digestive Surgery, Pontchaillou University Hospital, Rennes, France
- Department of Digestive, Hepatobiliary and Endocrine Surgery, Cochin University Hospital, AP-HP, University of Paris, Paris, France
| | - Fabien Robin
- Department of Hepatobiliary and Digestive Surgery, Pontchaillou University Hospital, Rennes, France
| | - Heithem Jeddou
- Department of Hepatobiliary and Digestive Surgery, Pontchaillou University Hospital, Rennes, France
| | - Karim Boudjema
- Department of Hepatobiliary and Digestive Surgery, Pontchaillou University Hospital, Rennes, France.
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11
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Firat YY, Cicek B, Kara A, Ozturk NK, Ilgun S. Effects of Thyme, Cumin, and Sumac Extracts on Apoptosis and Paraptosis in Hepatocellular Carcinoma: Synergistic, Antagonistic, or Additive Properties. Food Sci Nutr 2025; 13:e70106. [PMID: 40129995 PMCID: PMC11931446 DOI: 10.1002/fsn3.70106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 02/05/2025] [Accepted: 03/06/2025] [Indexed: 03/26/2025] Open
Abstract
This study evaluated the effect of single, double, and triple combined doses of sumac, thyme, and cumin extracts on apoptosis and paraptosis in the HepG2 cell line. The effect of thyme and cumin extracts was higher in proteins (mTOR, caspase-8, caspase-9, Bax and bcl-2) other than caspase-3 protein. The expression of caspase-3 protein was higher in the sumac extract-treated groups. The expression levels of GRP78/Bip and DDIT3/Chop proteins, which are indicators of paraptosis, did not exert a significant difference between the extracts. Even though their protein expression is different, according to MTT results, sumac and thyme extracts showed an additive effect, thyme and cumin extracts showed an antagonistic effect, sumac and cumin extracts showed a synergistic effect, and sumac, thyme, and cumin extracts showed a synergistic effect. Sumac, thyme, and cumin extracts induced cell death by causing apoptosis in HepG2 cells, and they may have a supportive impact on the treatment of hepatocellular carcinoma.
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Affiliation(s)
- Yagmur Yasar Firat
- Department of Nutrition Dietetic, Faculty of Health SciencesErciyes UniversityKayseriTürkiye
| | - Betul Cicek
- Department of Nutrition Dietetic, Faculty of Health SciencesErciyes UniversityKayseriTürkiye
| | - Ayca Kara
- Betül Ziya Eren Genom and Stem Cell CenterErciyes UniversityKayseriTürkiye
| | - Nurefsan Konyaligil Ozturk
- Department of Nutrition Dietetic, Faculty of Health SciencesBolu Abant İzzet Baysal UniversityBoluTürkiye
| | - Selen Ilgun
- Department of Nutrition Dietetic, Faculty of Health SciencesBolu Abant İzzet Baysal UniversityBoluTürkiye
- Department of Pharmacognosy, Faculty of PharmacyErciyes UniversityKayseriTürkiye
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12
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Mourad MAE, Mourad AAE, Elmaaty AA, Hofni A, Khodir AE, Aboubakr EM, Eldehna WM, Al-Karmalawy AA. Novel inhibitors of oncogenic Wnt/TCF-4/β-catenin signaling pathway: Design, synthesis, molecular docking studies and apoptosis inducing activity of pyrimidothiazino-, dihydropyrimidotriazepino- and 1,3,4-thiadiazolopyrimido-indole hybrids. Bioorg Chem 2025; 157:108285. [PMID: 40043386 DOI: 10.1016/j.bioorg.2025.108285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2024] [Revised: 02/14/2025] [Accepted: 02/15/2025] [Indexed: 03/18/2025]
Abstract
Wnt pathway is vital for survival of cancer-initiating cells. β-catenin plays a crucial role in Wnt pathway through interaction with TCF-4 to transcribe oncogenes. β-catenin activation suppresses immune cell infiltration into cancer cells and promotes resistance to chemotherapeutic drugs. In order to target Wnt/TCF-4/β-catenin pathway, a novel series of pyrimidothiazino-, dihydropyrimidotriazepino- and 1,3,4 thiadiazolopyrimido-indole hybrids were designed, synthesized and evaluated for their β-catenin/TCF-4 inhibitory and apoptotic inducing activities. Cytotoxicity of the synthesized hybrids was evaluated against HCT-116, A549 and HepG2 cell lines. Of the synthesized hybrids, 6a, 8b and 12b hybrids elicited superior cytotoxic activity compared to quercetin against the tested cell lines. These hybrids were able to significantly suppress β-catenin and its down-stream signaling target TCF-4 in a dose-dependent manner in HCT-116 cell line. They up-regulated p53, caspase-3, caspase-8, caspase-9 levels and Bax protein expression as well as down-regulated Bcl-2 protein expression. They successfully arrested cell cycle in pre-G1 phase and G0/G1 phase. The synthesized hybrids achieved efficient binding pattern in molecular docking study and have acceptable drug likeness characters.
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Affiliation(s)
- Mai A E Mourad
- Medicinal Chemistry Department, Faculty of Pharmacy, Port-Said University, Port-Said 42511, Egypt; Medicinal Chemistry Department, Pharmacology and Toxicology Department, Faculty of Pharmacy, East Port-Said National University, Port-Said, Egypt.
| | - Ahmed A E Mourad
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Port-Said University, Port-Said 42511, Egypt; Medicinal Chemistry Department, Pharmacology and Toxicology Department, Faculty of Pharmacy, East Port-Said National University, Port-Said, Egypt.
| | - Ayman Abo Elmaaty
- Medicinal Chemistry Department, Faculty of Pharmacy, Port-Said University, Port-Said 42511, Egypt.
| | - Amal Hofni
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, South Valley University, Qena 83523, Egypt.
| | - Ahmed E Khodir
- Department of Pharmacology, Faculty of Pharmacy, Horus University, New Damietta 34518, Egypt.
| | - Esam M Aboubakr
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, South Valley University, Qena 83523, Egypt.
| | - Wagdy M Eldehna
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Pharos University in Alexandria; Canal El Mahmoudia St., Alexandria 21648, Egypt
| | - Ahmed A Al-Karmalawy
- Department of Pharmaceutical Chemistry, College of Pharmacy, The University of Mashreq, Baghdad 10023, Iraq; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt.
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13
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Wu D, Liu Z, Sun Y, Gou C, Shang R, Lu M, Zhang R, Wei H, Li C, Shi Y, Zhang C, Wang Y, Wei D, Chen Z, Bian H. Integrated Analysis of the Anoikis-Related Signature Identifies Rac Family Small GTPase 3 as a Novel Tumor-Promoter Gene in Hepatocellular Carcinoma. MedComm (Beijing) 2025; 6:e70125. [PMID: 40123831 PMCID: PMC11928873 DOI: 10.1002/mco2.70125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 12/30/2024] [Accepted: 12/31/2024] [Indexed: 03/25/2025] Open
Abstract
Anoikis resistance in hepatocellular carcinoma (HCC) cells boosts survival and metastasis. This study aimed to establish an anoikis-related genes (ARGs)-based model for predicting HCC patients' outcomes and investigate the clinicopathological significance and function of crucial ARGs. The transcriptional expression patterns for HCC cohorts were compiled from TCGA, GEO and ICGC. Univariate and LASSO multivariate analyses were performed to screen for prognostic ARGs. Gain- and loss-of-function studies, RNA sequencing, and mass spectrometry were employed to elucidate the underlying mechanisms of ARGs in HCC. We established a five-gene ARGs risk model for HCC prognosis, with an AUC value of 0.812 for 1-year survival. Among the five genes, Rac family small GTPase 3 (RAC3) was upregulated in HCC relative to adjacent normal tissues and negatively correlated to overall survival and disease-free survival of patients with HCC. Silence of RAC3 in HCC cells resulted in an increased cell apoptosis and diminished cell proliferation and invasion. Mechanistically, we uncovered that RAC3 binding with SOX6 propelled the advancement of HCC cells through NNMT-mediated stimulation of the cAMP/MAPK/Rap1 signaling. In particular, EHop-016, a small molecule inhibitor targeting RAC3, significantly suppressed HCC progression.
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Affiliation(s)
- Dong Wu
- Department of Cell BiologyNational Translational Science Center for Molecular MedicineFourth Military Medical UniversityXi'anChina
- State Key Laboratory of New Targets Discovery and Drug Development for Major DiseasesFourth Military Medical UniversityXi'anChina
| | - Ze‐Kun Liu
- Department of Cell BiologyNational Translational Science Center for Molecular MedicineFourth Military Medical UniversityXi'anChina
- State Key Laboratory of New Targets Discovery and Drug Development for Major DiseasesFourth Military Medical UniversityXi'anChina
| | - Ying Sun
- Department of Cell BiologyNational Translational Science Center for Molecular MedicineFourth Military Medical UniversityXi'anChina
- State Key Laboratory of New Targets Discovery and Drug Development for Major DiseasesFourth Military Medical UniversityXi'anChina
| | - Chu‐Heng Gou
- Department of Cell BiologyNational Translational Science Center for Molecular MedicineFourth Military Medical UniversityXi'anChina
- State Key Laboratory of New Targets Discovery and Drug Development for Major DiseasesFourth Military Medical UniversityXi'anChina
- Department of Hepatobiliary SurgeryXijing HospitalFourth Military Medical UniversityXi'anChina
| | - Run‐Ze Shang
- Department of Cell BiologyNational Translational Science Center for Molecular MedicineFourth Military Medical UniversityXi'anChina
- State Key Laboratory of New Targets Discovery and Drug Development for Major DiseasesFourth Military Medical UniversityXi'anChina
| | - Meng Lu
- Department of Cell BiologyNational Translational Science Center for Molecular MedicineFourth Military Medical UniversityXi'anChina
- State Key Laboratory of New Targets Discovery and Drug Development for Major DiseasesFourth Military Medical UniversityXi'anChina
| | - Ren‐Yu Zhang
- Department of Cell BiologyNational Translational Science Center for Molecular MedicineFourth Military Medical UniversityXi'anChina
- State Key Laboratory of New Targets Discovery and Drug Development for Major DiseasesFourth Military Medical UniversityXi'anChina
| | - Hao‐Lin Wei
- Department of Cell BiologyNational Translational Science Center for Molecular MedicineFourth Military Medical UniversityXi'anChina
- State Key Laboratory of New Targets Discovery and Drug Development for Major DiseasesFourth Military Medical UniversityXi'anChina
| | - Can Li
- Department of Cell BiologyNational Translational Science Center for Molecular MedicineFourth Military Medical UniversityXi'anChina
- State Key Laboratory of New Targets Discovery and Drug Development for Major DiseasesFourth Military Medical UniversityXi'anChina
| | - Ying Shi
- Department of Cell BiologyNational Translational Science Center for Molecular MedicineFourth Military Medical UniversityXi'anChina
- State Key Laboratory of New Targets Discovery and Drug Development for Major DiseasesFourth Military Medical UniversityXi'anChina
| | - Cong Zhang
- Department of Cell BiologyNational Translational Science Center for Molecular MedicineFourth Military Medical UniversityXi'anChina
- State Key Laboratory of New Targets Discovery and Drug Development for Major DiseasesFourth Military Medical UniversityXi'anChina
| | - Yu‐Tong Wang
- Department of Cell BiologyNational Translational Science Center for Molecular MedicineFourth Military Medical UniversityXi'anChina
- State Key Laboratory of New Targets Discovery and Drug Development for Major DiseasesFourth Military Medical UniversityXi'anChina
| | - Ding Wei
- Department of Cell BiologyNational Translational Science Center for Molecular MedicineFourth Military Medical UniversityXi'anChina
- State Key Laboratory of New Targets Discovery and Drug Development for Major DiseasesFourth Military Medical UniversityXi'anChina
| | - Zhi‐Nan Chen
- Department of Cell BiologyNational Translational Science Center for Molecular MedicineFourth Military Medical UniversityXi'anChina
- State Key Laboratory of New Targets Discovery and Drug Development for Major DiseasesFourth Military Medical UniversityXi'anChina
| | - Huijie Bian
- Department of Cell BiologyNational Translational Science Center for Molecular MedicineFourth Military Medical UniversityXi'anChina
- State Key Laboratory of New Targets Discovery and Drug Development for Major DiseasesFourth Military Medical UniversityXi'anChina
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14
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Wang F, Lu J, Yang T, Ren Y, Ratti F, Marques HP, Silva S, Soubrane O, Lam V, Poultsides GA, Popescu I, Grigorie R, Alexandrescu S, Martel G, Workneh A, Guglielmi A, Hugh T, Aldrighetti L, Endo I, Lv Y, Zhang XF, Pawlik TM. Perioperative Changes in Serum Transaminase Levels: Impact on Postoperative Morbidity After Liver Resection of Hepatocellular Carcinoma. Ann Surg 2025; 281:624-631. [PMID: 38348655 DOI: 10.1097/sla.0000000000006235] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/14/2025]
Abstract
OBJECTIVES To define how dynamic changes in pre versus postoperative serum aspartate aminotransferase (AST) and alanine transaminase (ALT) levels may impact postoperative morbidity after curative-intent resection of hepatocellular carcinoma (HCC). BACKGROUND Hepatic ischemia/reperfusion can occur at the time of liver resection and may be associated with adverse outcomes after liver resection. METHODS Patients who underwent curative resection for HCC between 2010 and 2020 were identified from an international multi-institutional database. Changes in AST and ALT (CAA) on postoperative day 3 versus preoperative values ( ) were calculated using the formula: based on a fusion index through the Euclidean norm, which was examined relative to the Comprehensive Complication Index (CCI). The impact of CAA on CCI was assessed by the restricted cubic spline regression and Random Forest analyses. RESULTS A total of 759 patients were included in the analytic cohort. Median CAA was 1.7 (range: 0.9-3.25); 431 (56.8%) patients had a CAA <2 215 (28.3%) patients with CAA 2 to 5, and 113 (14.9%) patients had CAA ≥5. The incidence of postoperative complications was 65.0% (n = 493) with a median CCI of 20.9 (interquartile range: 20.9-33.5). Spline regression analysis demonstrated a nonlinear incremental association between CAA and CCI. The optimal cutoff value of CAA was 5, identified by the recursive partitioning technique. After adjusting for other competing risk factors, CAA ≥5 remained strongly associated with the risk of postoperative complications (reference CAA <5, odds ratio: 1.63, 95% CI: 1.05-2.55, P = 0.03). In fact, the use of CAA to predict postoperative complications was very good in both the derivative (area under the curve: 0.88) and external (area under curve: 0.86) cohorts (n = 1137). CONCLUSIONS CAA was an independent predictor of CCI after liver resection for HCC. The use of routine laboratories, such as AST and ALT, can help identify patients at the highest risk of postoperative complications after HCC resection.
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Affiliation(s)
- Fumin Wang
- Department of Hepatobiliary Surgery and Institute of Advanced Surgical Technology and Engineering, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- School of Future Technology, Xi'an Jiaotong University, Xi'an, PR China
| | - Jingming Lu
- Department of Hepatobiliary Surgery and Institute of Advanced Surgical Technology and Engineering, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- School of Future Technology, Xi'an Jiaotong University, Xi'an, PR China
| | - Tian Yang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Navy Medical University, Shanghai, China
| | - Yaoxing Ren
- Department of Hepatobiliary Surgery and Institute of Advanced Surgical Technology and Engineering, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- School of Future Technology, Xi'an Jiaotong University, Xi'an, PR China
| | | | - Hugo P Marques
- Department of Surgery, Curry Cabral Hospital, Lisbon, Portugal
| | - Silvia Silva
- Department of Surgery, Curry Cabral Hospital, Lisbon, Portugal
| | - Olivier Soubrane
- Department of Hepatobiliopancreatic Surgery, APHP, Beaujon Hospital, Clichy
| | - Vincent Lam
- Department of Surgery, Westmead Hospital, Sydney, Australia
| | | | - Irinel Popescu
- Department of Surgery, Fundeni Clinical Institute, Bucharest, Romania
| | - Razvan Grigorie
- Department of Surgery, Fundeni Clinical Institute, Bucharest, Romania
| | | | | | - Aklile Workneh
- Department of Surgery, University of Ottawa, Ottawa, Canada
| | | | - Tom Hugh
- Department of Surgery, The University of Sydney, School of Medicine, Sydney, Australia
| | | | - Itaru Endo
- Yokohama City University School of Medicine, Yokohama, Japan
| | - Yi Lv
- Department of Hepatobiliary Surgery and Institute of Advanced Surgical Technology and Engineering, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- School of Future Technology, Xi'an Jiaotong University, Xi'an, PR China
| | - Xu-Feng Zhang
- Department of Hepatobiliary Surgery and Institute of Advanced Surgical Technology and Engineering, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- School of Future Technology, Xi'an Jiaotong University, Xi'an, PR China
| | - Timothy M Pawlik
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH
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15
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Xiao T, Chen D, Peng L, Li Z, Pan W, Dong Y, Zhang J, Li M. Fluorescence-guided Surgery for Hepatocellular Carcinoma: From Clinical Practice to Laboratories. J Clin Transl Hepatol 2025; 13:216-232. [PMID: 40078203 PMCID: PMC11894393 DOI: 10.14218/jcth.2024.00375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2024] [Revised: 12/06/2024] [Accepted: 12/12/2024] [Indexed: 03/14/2025] Open
Abstract
Fluorescence navigation is a novel technique for accurately identifying hepatocellular carcinoma (HCC) lesions during hepatectomy, enabling real-time visualization. Indocyanine green-based fluorescence guidance has been commonly used to demarcate HCC lesion boundaries, but it cannot distinguish between benign and malignant liver tumors. This review focused on the clinical applications and limitations of indocyanine green, as well as recent advances in novel fluorescent probes for fluorescence-guided surgery of HCC. It covers traditional fluorescent imaging probes such as enzymes, reactive oxygen species, reactive sulfur species, and pH-sensitive probes, followed by an introduction to aggregation-induced emission probes. Aggregation-induced emission probes exhibit strong fluorescence, low background signals, excellent biocompatibility, and high photostability in the aggregate state, but show no fluorescence in dilute solutions. Design strategies for these probes may offer insights for developing novel fluorescent probes for the real-time identification and navigation of HCC during surgery.
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Affiliation(s)
- Tian Xiao
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Didi Chen
- Hubei Key Laboratory of Purification and Application of Plant Anti-Cancer Active Ingredients, Hubei University of Education, Wuhan, Hubei, China
| | - Li Peng
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zhuoxia Li
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Wenming Pan
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yuping Dong
- Beijing Key Laboratory of Construction Tailorable Advanced Functional Materials and Green Applications, School of Materials Science and Engineering, Beijing Institute of Technology, Beijing, China
| | - Jinxiang Zhang
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Min Li
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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16
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Li H, Su B, Jiang Y, Zhang B, Du R, Song C, Hou B, Xu K, Wu L, Gu Y. Circular RNA circDCUN1D4 suppresses hepatocellular carcinoma development via targeting the miR-590-5p/ TIMP3 axis. Mol Cancer 2025; 24:95. [PMID: 40128740 PMCID: PMC11934760 DOI: 10.1186/s12943-025-02300-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Accepted: 03/12/2025] [Indexed: 03/26/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is a major global health concern, necessitating innovative therapeutic strategies. In this study, we investigated the functional role of circular RNA circDCUN1D4 in HCC progression and its potential therapeutic implications. It was found that HCC patients exhibiting higher levels of circDCUN1D4 demonstrated a more favorable survival rate. Furthermore, we revealed that circDCUN1D4 suppressed HCC cell proliferation, migration, and invasion. Mechanistically, circDCUN1D4 was identified as a sponge for miR-590-5p, leading to the downregulation of its downstream target, Tissue Inhibitor of Metalloproteinase 3 (TIMP3). Importantly, circDCUN1D4 administration through In vivo jet-PEI exhibited a robust inhibitory effect on tumor progression without causing notable toxicity in mice. Overall, our findings highlight circDCUN1D4 as a promising therapeutic candidate for HCC, unraveling its intricate regulatory role through the miR-590-5p/TIMP3 axis. This study contributes valuable insights into the potential clinical applications of circRNA-based therapies for HCC.
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Affiliation(s)
- Hongyu Li
- College of Chemistry and Lie Science, Beijing University of Technology, Beijing, 100124, China.
- Allife Medical Science and Technology Co., Ltd. Economic and Technological Development Zone, Beijing, 100176, China.
| | - Bing Su
- College of Chemistry and Lie Science, Beijing University of Technology, Beijing, 100124, China
| | - Yan Jiang
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Boyang Zhang
- Allife Medical Science and Technology Co., Ltd. Economic and Technological Development Zone, Beijing, 100176, China
| | - Rulong Du
- Allife Medical Science and Technology Co., Ltd. Economic and Technological Development Zone, Beijing, 100176, China
| | - Can Song
- Allife Medical Science and Technology Co., Ltd. Economic and Technological Development Zone, Beijing, 100176, China
| | - Bin Hou
- Allife Medical Science and Technology Co., Ltd. Economic and Technological Development Zone, Beijing, 100176, China
| | - Kun Xu
- College of Chemistry and Lie Science, Beijing University of Technology, Beijing, 100124, China.
| | - Lida Wu
- Allife Medical Science and Technology Co., Ltd. Economic and Technological Development Zone, Beijing, 100176, China.
| | - Yuchun Gu
- Allife Medical Science and Technology Co., Ltd. Economic and Technological Development Zone, Beijing, 100176, China.
- Molecular Pharmacology Laboratory, Institute of Molecular Medicine, Peking University, Beijing, 100871, China.
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17
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Wei S, Xu G, Zhao S, Zhang C, Feng Y, Yang W, Lu R, Zhou J, Ma Y. EGR2 promotes liver cancer metastasis by enhancing IL-8 expression through transcription regulation of PDK4 in M2 macrophages. Int Immunopharmacol 2025; 153:114484. [PMID: 40139095 DOI: 10.1016/j.intimp.2025.114484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 03/04/2025] [Accepted: 03/10/2025] [Indexed: 03/29/2025]
Abstract
Liver tumor is a common digestive system tumor, and its development is closely related to complex cytokines, tumor microenvironment and immunoregulatory mechanisms. Tumor-associated macrophages play a great role in a series of liver cancer development by secreting various cytokines and transmitting multiple signals, but how macrophages regulate the various biological behaviors of liver cancer cells at the microscopic level is a challenge we still need to overcome. In this research, we first identified the Early Growth Response 2 (EGR2) gene, which exhibited significant expression in M2 macrophages in comparison to M0 and M1 cell types, utilizing RNA sequencing. Subsequently, we validated this finding through a battery of methodologies, including WB, qRT-PCR, and immunofluorescence assays. We further employed a co-culture model involving MHCC97L and macrophages to investigate the impact of EGR2 downregulation within M2 cells on the in vivo and in vitro metastatic and invasive capabilities of MHCC97L cells. Subsequently, we directed our attention to investigating the impact of EGR2 on the levels of interleukin-8 (IL-8). Through comprehensive analyses including RNA sequencing, CUT-and-Tag, and ChIP techniques, we demonstrated that EGR2 can bind to the promoter region of the Pyruvate Dehydrogenase Kinase 4 (PDK4) gene. Finally, we introduced a virus overexpressing PDK4 and demonstrated that EGR2 could regulate the transcriptional level of PDK4 to affect the expression of IL-8, and ultimately alter the metastatic ability of hepatocellular carcinoma cells. Our study demonstrates that EGR2 may be a valuable target for future intervention in the disease process of hepatocellular carcinoma and refines the mechanism at the microscopic level of Tumor-associated macrophages.
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Affiliation(s)
- Song Wei
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Gaoxin Xu
- Department of General Surgery, Affiliated Kunshan Hospital of Jiangsu University,Kunshan,Suzhou,China
| | - Siqi Zhao
- Department of Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, , Zhejiang, China
| | - Chenwei Zhang
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Yongheng Feng
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Weijun Yang
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Renhe Lu
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Jin Zhou
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
| | - Yong Ma
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
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Wang D, Tan M, Touch S, Kouy S, Sou S, Liu K, Zhu Y, Zhu H, Nov P. Burden of disease and risk factors for primary liver cancer by etiology in the United States, 1990-2021: results from the Global Burden of Disease Study, 2021. Ann Hepatol 2025:101906. [PMID: 40122522 DOI: 10.1016/j.aohep.2025.101906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2024] [Revised: 02/11/2025] [Accepted: 02/12/2025] [Indexed: 03/25/2025]
Abstract
INTRODUCTION AND OBJECTIVES The distribution of major causes of liver cancer (LC) in the United States (US) has changed significantly over time. This study analyzes recent temporal trends in the causes of LC in the US from 1990 to 2021 and predicts future trends. MATERIALS AND METHODS We obtained detailed data on LC in the US from the Global Burden of Disease (GBD) 2021 study. Estimated annual percentage change (EAPC) values for LC in the US were then calculated using linear regression models. An exponential smoothing (ES) projection model and Bayesian Age-Period-Cohort (BAPC) projection model were then used to predict the future disease burden of LC. Risk factors for LC were also assessed. RESULTS In 2021, the disease burden of LC in the US was significantly higher than in 1990. Hepatitis C virus (HCV)-associated LC resulted in the greatest burden of disease. The fastest growing burden of disease was attributed to metabolic dysfunction-associated steatotic liver disease (MASLD)-associated LC. Higher burdens of disease were seen in older and male populations. CONCLUSIONS In the US, the disease burden of LC from different etiologies continues to rise. As such, targeted prevention and control strategies should be developed to address these unique disease characteristics.
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Affiliation(s)
- Duanyu Wang
- Department of Oncology, Xiangya Hospital of Central South University, Changsha, Hunan Province, 410119, China
| | - Minghao Tan
- Department of Gastrointestinal Surgery, Liuzhou Workers Hospital, Liuzhou, Guangxi Province, 545005, China
| | - Socheat Touch
- Department of Radiation Oncology and Oncology, LuangMe Hospital of University of Health Sciences, Phnom Penh 120110, Cambodia
| | - Samnang Kouy
- Department of Radiation Oncology and Oncology, LuangMe Hospital of University of Health Sciences, Phnom Penh 120110, Cambodia
| | - Syphanna Sou
- Department of Radiation Oncology and Oncology, LuangMe Hospital of University of Health Sciences, Phnom Penh 120110, Cambodia
| | - Kun Liu
- Department of Oncology, Xiangya Hospital of Central South University, Changsha, Hunan Province, 410119, China
| | - Youwen Zhu
- Department of Oncology, Xiangya Hospital of Central South University, Changsha, Hunan Province, 410119, China
| | - Hong Zhu
- Department of Oncology, Xiangya Hospital of Central South University, Changsha, Hunan Province, 410119, China.
| | - Pengkhun Nov
- Oncology Center, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong Province, 510282, China.
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19
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Yan X, Fan J, Qin W, Liao M, Li S, Suo L, Xie Y, Jiang X, Zou D, Liao W. Hypericin Nanoparticles-Associated Photodynamic Therapy Modulates the Biological Behavior of Hepatocellular Carcinoma by SERPINE1. Int J Nanomedicine 2025; 20:3713-3730. [PMID: 40130195 PMCID: PMC11932138 DOI: 10.2147/ijn.s507037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Accepted: 03/12/2025] [Indexed: 03/26/2025] Open
Abstract
Background In recent years, photodynamic therapy (PDT) has gradually attracted the attention of researchers due to its therapeutic potential for treating malignant tumors. Hypericin (HC) is anticipated to enhance the therapeutic effect on tumors as an efficient photosensitizer (PS) for PDT. However, the role and mechanism of PDT in hepatocellular carcinoma (HCC) remain unclear. Methods In this study, we investigated the efficacy of hypericin nanoparticles (HC-NPs)-associated PDT (HC-NPs-PDT) on HCC to explore its anti-HCC mechanism both in vitro and in vivo. Cellular molecular experiments, as well as HCC mouse tumor models, were utilized to validate the impact of HC-NPs-PDT on HCC. Additionally, molecular docking and related experiments were employed to investigate its potential mechanism. Results Our findings demonstrated that HC-NPs-PDT effectively inhibits the viability, migration, and invasion abilities of HCC cells, as well as suppresses the growth of subcutaneous HCC tumors in BALB/C-nu nude mice. SERPINE1 (also known as PAI, PAI-1, PAI1, PLANH1) may be a key target of HC, as its mRNA and protein levels were significantly up-regulated following HC-NPs-PDT. This upregulation led to a decrease in mitochondrial membrane potential and promoted apoptosis of HCC cells. Additionally, inhibition of SERPINE1 partially restored changes in mitochondrial membrane potential. Conclusion These results suggest that HC-NPs-PDT may regulate the biological behavior of HCC by upregulating SERPINE1 expression, offering a new perspective for treating HCC.
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Affiliation(s)
- Xuanzhi Yan
- Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, 541001, People’s Republic of China
| | - Jiaxing Fan
- Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, 541001, People’s Republic of China
| | - Wanying Qin
- Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, 541001, People’s Republic of China
| | - Minjun Liao
- Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, 541001, People’s Republic of China
- Peking University People’s Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Disease, Beijing, 100044, People’s Republic of China
| | - Siming Li
- Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, 541001, People’s Republic of China
| | - Liya Suo
- Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, 541001, People’s Republic of China
| | - Yujin Xie
- Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, 541001, People’s Republic of China
| | - Xin Jiang
- Guangxi Key Laboratory of Drug Discovery and Optimization, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, 541001, People’s Republic of China
| | - Dengfeng Zou
- Guangxi Key Laboratory of Drug Discovery and Optimization, School of Pharmacy, Guilin Medical University, Guilin, Guangxi, 541199, People’s Republic of China
| | - Weijia Liao
- Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, 541001, People’s Republic of China
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20
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Ye Y, Zeng Y, Huang S, Zhu C, Wang Q. A Chemotherapy Response-Related Gene Signature and DNAJC8 as Key Mediators of Hepatocellular Carcinoma Progression and Drug Resistance. J Hepatocell Carcinoma 2025; 12:579-595. [PMID: 40130083 PMCID: PMC11932135 DOI: 10.2147/jhc.s506706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 02/21/2025] [Indexed: 03/26/2025] Open
Abstract
Background Chemotherapy resistance in hepatocellular carcinoma presents a significant challenge to improved patient outcomes. Identifying genes associated with chemotherapy response can enhance treatment strategies and prognostic models. Methods We analyzed the expression of chemotherapy response-related gene in hepatocellular carcinoma using TCGA and GSE109211 cohorts. We constructed a prognostic model using Least Absolute Shrinkage and Selection Operator (LASSO) analysis and assessed its efficacy using Kaplan-Meier survival analysis. Additionally, we evaluated the immune landscape and gene mutation profiles between different chemotherapy response-related gene (CRRG) subtypes. DNAJC8's role in hepatocellular carcinoma cell functions and chemotherapy resistance was further explored through gene knockdown experiments in vitro and in vivo. Results Differential expression analysis identified 220 common genes associated with chemotherapy response. The prognostic model incorporating seven key genes efficiently distinguished responders from non-responders and indicated poorer overall survival for the CRRG-high subtype. The CRRG value correlated with tumor stage and grade, and mutation profiles showed distinct patterns between CRRG subtypes. The CRRG-high subtype exhibited an immune-suppressive phenotype with higher expression of PD-L1 and CTLA-4. High DNAJC8 expression was linked to poor prognosis in multiple cohorts. Knocking down DNAJC8 significantly inhibited hepatocellular carcinoma cell proliferation, migration, invasion, and reduced sorafenib IC50. Conclusion The seven-gene CRRG model, particularly DNAJC8, holds potential for predicting chemotherapy response and serves as a therapeutic target in hepatocellular carcinoma.
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Affiliation(s)
- Yan Ye
- Ganzhou Key Laboratory of Molecular Medicine, The Affiliated Ganzhou Hospital of Nanchang University, Ganzhou, People’s Republic of China
| | - Yanmei Zeng
- Ganzhou Key Laboratory of Molecular Medicine, The Affiliated Ganzhou Hospital of Nanchang University, Ganzhou, People’s Republic of China
| | - Shenggang Huang
- Ganzhou Key Laboratory of Molecular Medicine, The Affiliated Ganzhou Hospital of Nanchang University, Ganzhou, People’s Republic of China
- Department of Gastroenterology, The Affiliated Ganzhou Hospital of Nanchang University, Ganzhou, People’s Republic of China
| | - Chunping Zhu
- Ganzhou Key Laboratory of Molecular Medicine, The Affiliated Ganzhou Hospital of Nanchang University, Ganzhou, People’s Republic of China
- Department of Gastroenterology, The Affiliated Ganzhou Hospital of Nanchang University, Ganzhou, People’s Republic of China
| | - Qingshui Wang
- College of Integrative Medicine, Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, People’s Republic of China
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21
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Zhang J, Tian T, Tian S, Yao J, Zhang Y, Xie R, Yang T, Han B. Study on the Mechanism of QRICH1 Mediating PRMT1 to Regulate the Arginine Methylation Modification of cGAS to Promote Arsenics-Induced Pyroptosis in Hepatocellular Carcinoma Cells. J Hepatocell Carcinoma 2025; 12:597-614. [PMID: 40124968 PMCID: PMC11930257 DOI: 10.2147/jhc.s505266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Accepted: 03/04/2025] [Indexed: 03/25/2025] Open
Abstract
Purpose This study aims to investigate the mechanism of action of arsenic-based agents against hepatocellular carcinoma (HCC) and to identify effective drug targets for HCC treatment. Methods Huh7 and HepG2 cells treated with NaAsO2 were assessed for cell viability, pyroptosis, migration, and invasion after undergoing lentiviral transfection. An orthotopic liver tumor model was established and divided into a model group and a treatment group. Proteins associated with QRICH1, PRMT1, cGAS-STING, and the classical pyroptosis pathway were quantified using Western blotting. The intracellular expression and localization of PRMT1 and NLRP3 in HCC were analyzed through cellular immunofluorescence. Co-immunoprecipitation (Co-IP) was performed to examine the protein interactions between PRMT1 and cGAS, as well as between STING and NLRP3. Chromatin immunoprecipitation (ChIP) was used to confirm QRICH1 enrichment in the PRMT1 promoter region. Results NaAsO2 treatment significantly inhibited the proliferation of Huh7 and HepG2 cells and effectively blocked their migration and invasion capabilities, while promoting cellular pyroptosis. Quantitative polymerase chain reaction(QRCR) and ChIP assays confirmed that NaAsO2 regulates PRMT1 expression by down-regulate QRICH1 binding in the PRMT1 promoter region. Additionally, NaAsO2 decreased the expression of the QRICH1-PRMT1 complex and upregulated the cGAS-STING signaling pathway, activating the downstream NLRP3-dependent classical pyroptosis pathway. Overexpression of QRICH1 reversed these effects. Conclusion NaAsO2 inhibits the expression of the QRICH1-PRMT1 axis, activates cGAS-STING signaling pathway transduction, and induces pyroptosis in HCC cells, thereby increasing the infiltration of immune cells in liver cancer tissues.
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Affiliation(s)
- Jiayuan Zhang
- Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China
| | - Tian Tian
- Department of Eugenic Genetics, Guiyang Maternal and Child Health Care Hospital, Guiyang, Guizhou, 550003, People’s Republic of China
| | - Shanshan Tian
- Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China
| | - Jinhai Yao
- Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China
| | - Yingwan Zhang
- Qianxinan People’s Hospital, Qianxinan Affiliated Hospital of Zunyi Medical University, Xingyi, Guizhou, 562400, People’s Republic of China
| | - Rujia Xie
- Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China
| | - Ting Yang
- Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China
| | - Bing Han
- Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China
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22
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Chen J, Liu Y, Wang Z, Zhang B, Feng Y. Nanocarriers for the delivery of plant-extracted camptothecin derivatives and hepatocellular carcinoma treatment. Nat Prod Res 2025:1-12. [PMID: 40102036 DOI: 10.1080/14786419.2025.2479249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Revised: 02/21/2025] [Accepted: 03/09/2025] [Indexed: 03/20/2025]
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide and a major cause of death in cirrhosis. The prognosis of HCC is poor, with a mortality rate close to the morbidity rate. Once HCC develops distant metastasis, the area affected by the cancer cells is significantly enlarged, and there is still no effective treatment for HCC. Therefore, the development of effective drugs is essential to improve the survival rate of HCC patients. We designed and optimised a delivery system for compound 1, derived from camptothecin extract, by developing a multifunctional fluorescent drug delivery platform composed of polylactic acid (PLA), chitosan (CS), and fluorescein isothiocyanate (FITC) (PLA-CS-FITC). This system successfully encapsulated CP1 and compound 1, forming a PLA-CS-FITC@CP1@1 composite nanocarrier with dual functions for drug delivery and real-time fluorescence monitoring. The effects of the system on HCC proliferation and its regulation were evaluated by treating HCC cells in vitro, which provided an experimental basis for the development of drugs for HCC.
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Affiliation(s)
- Jie Chen
- Hepatobiliary Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yanfeng Liu
- Hepatobiliary Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Zelin Wang
- Hepatobiliary Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Bingyuan Zhang
- Hepatobiliary Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yujie Feng
- Hepatobiliary Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
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Yasukawa K, Shimada S, Akiyama Y, Taniai T, Igarashi Y, Tsukihara S, Tanji Y, Umemura K, Kamachi A, Nara A, Yamane M, Akahoshi K, Shimizu A, Soejima Y, Tanabe M, Tanaka S. ACVR2A attenuation impacts lactate production and hyperglycolytic conditions attracting regulatory T cells in hepatocellular carcinoma. Cell Rep Med 2025:102038. [PMID: 40139191 DOI: 10.1016/j.xcrm.2025.102038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 10/01/2024] [Accepted: 03/03/2025] [Indexed: 03/29/2025]
Abstract
Although ACVR2A mutations are prevalent in non-viral hepatocellular carcinomas (HCCs), the underlying mechanism remains unelucidated. Our molecular investigation reveals that ACVR2A impairment induces hyperglycolysis through the inactivation of the SMAD signaling pathway. Using syngeneic transplantation models and human clinical samples, we clarify that ACVR2A-deficient HCC cells produce and secrete lactate via the upregulation of lactate dehydrogenase A (LDHA) and monocarboxylate transporter 4 (MCT4) expression levels, which promotes regulatory T (Treg) cell accumulation and then acquires resistance to immune checkpoint inhibitors. Remarkably, genetic knockdown and pharmacological inhibition of MCT4 ameliorate the high-lactate milieu in ACVR2A-deficient HCC, resulting in the suppression of intratumoral Treg cell recruitment and the restoration of the sensitivity to PD-1 blockade. These findings furnish compelling evidence that lactate attenuates anti-tumor immunity and that therapeutics targeting this pathway present a promising strategy for mitigating immunotherapy resistance in ACVR2A-deficient HCC.
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Affiliation(s)
- Koya Yasukawa
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Shu Shimada
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
| | - Yoshimitsu Akiyama
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan
| | - Tomohiko Taniai
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, The Jikei University School of Medicine, Tokyo 105-8471, Japan
| | - Yosuke Igarashi
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, The Jikei University School of Medicine, Tokyo 105-8471, Japan
| | - Shu Tsukihara
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Department of Surgery, The Jikei University School of Medicine, Tokyo 105-8471, Japan
| | - Yoshiaki Tanji
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, The Jikei University School of Medicine, Tokyo 105-8471, Japan
| | - Kentaro Umemura
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Atsushi Kamachi
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Atsushi Nara
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Department of Hepato-Biliary-Pancreatic Surgery, Tokyo Medical and Dental University, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan
| | - Masahiro Yamane
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Department of Hepato-Biliary-Pancreatic Surgery, Tokyo Medical and Dental University, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan
| | - Keiichi Akahoshi
- Department of Hepato-Biliary-Pancreatic Surgery, Tokyo Medical and Dental University, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan
| | - Akira Shimizu
- Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Yuji Soejima
- Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Minoru Tanabe
- Department of Hepato-Biliary-Pancreatic Surgery, Tokyo Medical and Dental University, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan
| | - Shinji Tanaka
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Department of Hepato-Biliary-Pancreatic Surgery, Tokyo Medical and Dental University, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
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24
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Hu J, Tang H, Jia CC, Zhang XY, Xu Y, Tan JP, Fan J, Jia S, Zhou J. Personalized MRD Assessment in Perisurgical ctDNA for Prognostic Prediction in Hepatocellular Carcinoma. Clin Cancer Res 2025; 31:1047-1056. [PMID: 39526910 DOI: 10.1158/1078-0432.ccr-24-1897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 09/19/2024] [Accepted: 11/06/2024] [Indexed: 11/16/2024]
Abstract
PURPOSE Detecting residual disease is a critical clinical requirement in the perisurgical management of patients with resectable hepatocellular carcinoma (HCC). Previous studies focused on specific genomic regions exhibiting limited sensitivity and failed to meet the minimal residual disease (MRD) testing threshold. We introduce a next-generation sequencing-based assay, informed by baseline samples, facilitating MRD detection in hepatectomized patients with HCC and offering prognostic predictions. EXPERIMENTAL DESIGN This study involved 88 patients with HCC who underwent surgical resections from January 2016 to May 2016 in Zhongshan Hospital, Fudan University. Tumor and normal tissue samples were collected during surgery, whereas plasma samples were obtained both before surgery and up to 7 days after surgery. Using a next-generation sequencing-based personalized ctDNA assay, we analyzed the MRD in both presurgical and postsurgical blood samples and its correlation with prognosis. RESULTS With a median follow-up period of 80.7 months, our findings demonstrated significant correlations between presurgical ctDNA tumor fractions, postsurgical plasma MRD status, and both recurrence-free survival and overall survival. Postsurgical MRD status emerged as the most significant risk factor for cancer recurrence (HR = 2.162; 95% confidence interval, 1.09-4.30; P = 0.027) compared with other clinical characteristics in multivariate Cox regression analysis. Notably, MRD status showed potential as a prognostic indicator among clinically low-recurrent-risk patients, such as those with Barcelona Clinic Liver Cancer stages 0 to A or China Liver Cancer Staging stages I to II. CONCLUSIONS Evaluating personalized MRD provided crucial prognostic insights into recurrence-free survival and overall survival. It efficiently identified patients at high risk of recurrence, even among those initially perceived as low-risk cases. See related commentary by Pinato et al., p. 955.
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MESH Headings
- Humans
- Carcinoma, Hepatocellular/surgery
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/blood
- Carcinoma, Hepatocellular/mortality
- Liver Neoplasms/surgery
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- Liver Neoplasms/blood
- Liver Neoplasms/mortality
- Neoplasm, Residual/pathology
- Male
- Female
- Circulating Tumor DNA/genetics
- Circulating Tumor DNA/blood
- Prognosis
- Middle Aged
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/blood
- High-Throughput Nucleotide Sequencing
- Aged
- Neoplasm Recurrence, Local/genetics
- Neoplasm Recurrence, Local/pathology
- Neoplasm Recurrence, Local/blood
- Neoplasm Recurrence, Local/surgery
- Adult
- Hepatectomy
- Follow-Up Studies
- Precision Medicine/methods
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Affiliation(s)
- Jie Hu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Haoran Tang
- Huidu (Shanghai) Medical Sciences, Ltd., Shanghai, China
| | - Can-Can Jia
- Huidu (Shanghai) Medical Sciences, Ltd., Shanghai, China
| | - Xiang-Yu Zhang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Ying Xu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Jin-Peng Tan
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Jia Fan
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Shidong Jia
- Huidu (Shanghai) Medical Sciences, Ltd., Shanghai, China
| | - Jian Zhou
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
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25
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Mui S, Shi J, Wen K, Yan Y, Li H, Wang W, Zhou Z, Xiao Z. Multi-omics analysis identifies OSGEPL1 as an oncogene in hepatocellular carcinoma. Discov Oncol 2025; 16:328. [PMID: 40090949 PMCID: PMC11911280 DOI: 10.1007/s12672-025-02066-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Accepted: 03/05/2025] [Indexed: 03/19/2025] Open
Abstract
PURPOSE N6-Threonylcarbamoyladenosine (t6A) modification irregularities and their associated enzymes genes (OSGEP, OSGEPL1, TPRKB, GON7, TP53RK, YRDC, and LAGE3) are linked to various malignancies development, including Hepatocellular Carcinoma (HCC), yet the specific mechanisms remain obscure. This gap in knowledge is significant, as understanding the mechanisms of t6A modification could reveal new insights into HCC pathogenesis and potentially identify novel therapeutic targets. METHODS We leveraged data from The Cancer Genome Atlas (TCGA) to analyze the expression of t6A-associated genes, with a focus on OSGEPL1 in HCC. Our analyses included survival outcome, gene expression, functional enrichment, immune cell infiltration, and somatic mutation data. RESULTS We discovered that OSGEPL1 is upregulated in HCC and is correlated with tumor grade, pathological T stage, and overall stage. It inversely impacts overall survival and immune cell infiltration. In vitro experiments confirmed the role of OSGEPL1 in promoting HCC cell proliferation. CONCLUSIONS This study implicates t6A modification pathway dysregulation in HCC prognosis, identifying OSGEPL1 as a potential therapeutic target. These findings provide novel insights into HCC pathogenesis and may guide future treatment strategies.
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Affiliation(s)
- Sintim Mui
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
| | - Juanyi Shi
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
- Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
| | - Kai Wen
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
| | - Yongcong Yan
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
| | - Huoming Li
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
| | - Weidong Wang
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
| | - Zhenyu Zhou
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China.
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China.
| | - Zhiyu Xiao
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China.
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China.
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26
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Tang Y, Hu H, Chen S, Hao B, Xu X, Zhu H, Zhan W, Zhang T, Hu H, Chen G. Multi-omics analysis revealed the novel role of NQO1 in microenvironment, prognosis and immunotherapy of hepatocellular carcinoma. Sci Rep 2025; 15:8591. [PMID: 40074806 PMCID: PMC11903666 DOI: 10.1038/s41598-025-92700-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Accepted: 03/03/2025] [Indexed: 03/14/2025] Open
Abstract
NAD(P)H dehydrogenase quinone 1 (NQO1) is overexpressed in various cancers and is strongly associated with an immunosuppressive microenvironment and poor prognosis. In this study, we explored the role of NQO1 in the microenvironment, prognosis and immunotherapy of Hepatocellular carcinoma (HCC) using multi-omics analysis and machine learning. The results revealed that NQO1 was significantly overexpressed in HCC cells. NQO1+HCC cells were correlated with poor prognosis and facilitated tumor-associated macrophages (TAMs) polarization to M2 macrophages. We identified core NQO1-related genes (NRGs) and developed the NRGs-related risk-scores in hepatocellular carcinoma (NRSHC). The comprehensive nomogram integrating NRSHC, age, and pathological tumor-node-metastasis (pTNM) Stage achieved an area under the curve (AUC) above 0.7, demonstrating its accuracy in predicting survival outcomes and immunotherapy responses of HCC patients. High-risk patients exhibited worse prognoses but greater sensitivity to immunotherapy. Additionally, a web-based prediction tool was designed to enhance clinical utility. In conclusion, NQO1 may play a critical role in M2 polarization and accelerates HCC progression. The NRSHC model and accompanying tools offer valuable insights for personalized HCC treatment.
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Affiliation(s)
- Ya Tang
- School of Public Health, Hengyang Medical College, University of South China, 28 Western Changsheng Road, Hengyang, 421001, Hunan, China
- Department of Hepatobiliary Pancreatic Surgery, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Haihong Hu
- Department of Pharmacy, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Siyuan Chen
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Bo Hao
- Department of Pharmacy, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Xuefeng Xu
- Department of Function, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Hongxia Zhu
- Department of Pharmacy, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
- School of Pharmacy, Hengyang Medical College, University of South China, 28 Western Changsheng Road, Hengyang, 421001, Hunan, China
| | - Wendi Zhan
- Department of Pharmacy, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
- School of Pharmacy, Hengyang Medical College, University of South China, 28 Western Changsheng Road, Hengyang, 421001, Hunan, China
| | - Taolan Zhang
- Department of Pharmacy, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
- School of Pharmacy, Hengyang Medical College, University of South China, 28 Western Changsheng Road, Hengyang, 421001, Hunan, China.
- Research Center for Clinical Trial, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
| | - Hongjuan Hu
- Department of Public Health Service, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421000, Hunan, China.
| | - Guodong Chen
- Department of Hepatobiliary Pancreatic Surgery, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
- Department of General Surgery, Turpan City People's Hospital, Turpan, 838000, China.
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27
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Molina-Pelayo FA, Zarate-Lopez D, García-Carrillo R, Rodríguez-Beas C, Íñiguez-Palomares R, Rodríguez-Mejía JL, Soto-Guzmán A, Velasco-Loyden G, Sierra-Martínez M, Virgen-Ortiz A, Sánchez-Pastor E, Magaña-Vergara NE, Baltiérrez-Hoyos R, Alamilla J, Chagoya de Sánchez V, Dagnino-Acosta A, Chávez E, Castro-Sánchez L. miRNAs-Set of Plasmatic Extracellular Vesicles as Novel Biomarkers for Hepatocellular Carcinoma Diagnosis Across Tumor Stage and Etiologies. Int J Mol Sci 2025; 26:2563. [PMID: 40141205 PMCID: PMC11942138 DOI: 10.3390/ijms26062563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2025] [Revised: 03/05/2025] [Accepted: 03/07/2025] [Indexed: 03/28/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer, often diagnosed at advanced stages due to insufficient early screening and monitoring. MicroRNAs (miRNAs) are key regulators of gene expression and potential biomarkers for cancer diagnosis. This study investigated the diagnostic potential of miRNAs in Extracellular Vesicles (EVs) from HCC. miRNA expression in EVs was analyzed using HCC cell lines, circulating EVs from a Diethylnitrosamine (DEN)-induced liver tumor rat model, and plasma samples from HCC patients. Receiver Operating Characteristics (ROCs) were applied to evaluate the diagnostic accuracy of circulating EV miRNAs in patients. Five miRNAs (miR-183-5p, miR-19a-3p, miR-148b-3p, miR-34a-5p, and miR-215-5p) were consistently up-regulated in EVs across in vitro and in vivo HCC models. These miRNAs showed statistically significant differences in HCC patients stratified by TNM staging and Edmondson-Steiner grading compared to healthy controls. They also differentiated HCC patients with various etiologies from the control group and distinguished HCC patients, with or without liver cirrhosis, from cirrhotic and healthy individuals. Individually and as a panel, they demonstrated high sensitivity, specificity, and accuracy in identifying HCC patients. Their consistent upregulation across models and clinical samples highlights their robustness as biomarkers for HCC diagnosis, offering the potential for early disease management and prognosis.
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Affiliation(s)
- Francisco A. Molina-Pelayo
- Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima 28045, Colima, Mexico; (F.A.M.-P.); (D.Z.-L.); (R.G.-C.); (J.L.R.-M.); (A.V.-O.); (E.S.-P.); (J.A.); (A.D.-A.)
| | - David Zarate-Lopez
- Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima 28045, Colima, Mexico; (F.A.M.-P.); (D.Z.-L.); (R.G.-C.); (J.L.R.-M.); (A.V.-O.); (E.S.-P.); (J.A.); (A.D.-A.)
| | - Rosendo García-Carrillo
- Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima 28045, Colima, Mexico; (F.A.M.-P.); (D.Z.-L.); (R.G.-C.); (J.L.R.-M.); (A.V.-O.); (E.S.-P.); (J.A.); (A.D.-A.)
| | - César Rodríguez-Beas
- Departamento de Física, Universidad de Sonora, Hermosillo 83000, Sonora, Mexico; (C.R.-B.); (R.Í.-P.)
| | - Ramón Íñiguez-Palomares
- Departamento de Física, Universidad de Sonora, Hermosillo 83000, Sonora, Mexico; (C.R.-B.); (R.Í.-P.)
| | - José L. Rodríguez-Mejía
- Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima 28045, Colima, Mexico; (F.A.M.-P.); (D.Z.-L.); (R.G.-C.); (J.L.R.-M.); (A.V.-O.); (E.S.-P.); (J.A.); (A.D.-A.)
| | - Adriana Soto-Guzmán
- Departamento de Medicina y Ciencias de la Salud, Universidad de Sonora, Hermosillo 83000, Sonora, Mexico;
| | - Gabriela Velasco-Loyden
- Departamento de Biología Celular y Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico; (G.V.-L.); (V.C.d.S.)
| | - Mónica Sierra-Martínez
- Unidad de investigación en Salud, Hospital Regional de Alta Especialidad de Ixtapaluca, Servicios de Salud del Instituto Mexicano del Seguro Social para el Bienestar (IMSS-BIENESTAR), Ciudad de México 01020, Mexico;
| | - Adolfo Virgen-Ortiz
- Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima 28045, Colima, Mexico; (F.A.M.-P.); (D.Z.-L.); (R.G.-C.); (J.L.R.-M.); (A.V.-O.); (E.S.-P.); (J.A.); (A.D.-A.)
| | - Enrique Sánchez-Pastor
- Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima 28045, Colima, Mexico; (F.A.M.-P.); (D.Z.-L.); (R.G.-C.); (J.L.R.-M.); (A.V.-O.); (E.S.-P.); (J.A.); (A.D.-A.)
| | - Nancy E. Magaña-Vergara
- Facultad de Ciencias Químicas, Universidad de Colima, Coquimatlán 28400, Colima, Mexico;
- SECIHTI—Universidad de Colima, Colima 28045, Colima, Mexico
| | | | - Javier Alamilla
- Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima 28045, Colima, Mexico; (F.A.M.-P.); (D.Z.-L.); (R.G.-C.); (J.L.R.-M.); (A.V.-O.); (E.S.-P.); (J.A.); (A.D.-A.)
- SECIHTI—Universidad de Colima, Colima 28045, Colima, Mexico
| | - Victoria Chagoya de Sánchez
- Departamento de Biología Celular y Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico; (G.V.-L.); (V.C.d.S.)
| | - Adán Dagnino-Acosta
- Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima 28045, Colima, Mexico; (F.A.M.-P.); (D.Z.-L.); (R.G.-C.); (J.L.R.-M.); (A.V.-O.); (E.S.-P.); (J.A.); (A.D.-A.)
- SECIHTI—Universidad de Colima, Colima 28045, Colima, Mexico
| | - Enrique Chávez
- Departamento de Biología Celular y Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico; (G.V.-L.); (V.C.d.S.)
| | - Luis Castro-Sánchez
- Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima 28045, Colima, Mexico; (F.A.M.-P.); (D.Z.-L.); (R.G.-C.); (J.L.R.-M.); (A.V.-O.); (E.S.-P.); (J.A.); (A.D.-A.)
- SECIHTI—Universidad de Colima, Colima 28045, Colima, Mexico
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28
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Naghdi S, Mishra P, Roy SS, Weaver D, Walter L, Davies E, Antony AN, Lin X, Moehren G, Feitelson MA, Reed CA, Lindsten T, Thompson CB, Dang HT, Hoek JB, Knudsen ES, Hajnóczky G. VDAC2 and Bak scarcity in liver mitochondria enables targeting hepatocarcinoma while sparing hepatocytes. Nat Commun 2025; 16:2416. [PMID: 40069152 PMCID: PMC11897174 DOI: 10.1038/s41467-025-56898-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Accepted: 02/05/2025] [Indexed: 03/15/2025] Open
Abstract
Differences between normal tissues and invading tumors that allow tumor targeting while saving normal tissue are much sought after. Here we show that scarcity of VDAC2, and the consequent lack of Bak recruitment to mitochondria, renders hepatocyte mitochondria resistant to permeabilization by truncated Bid (tBid), a Bcl-2 Homology 3 (BH3)-only, Bcl-2 family protein. Increased VDAC2 and Bak is found in most human liver cancers and mitochondria from tumors and hepatic cancer cell lines exhibit VDAC2- and Bak-dependent tBid sensitivity. Exploring potential therapeutic targeting, we find that combinations of activators of the tBid pathway with inhibitors of the Bcl-2 family proteins that suppress Bak activation enhance VDAC2-dependent death of hepatocarcinoma cells with little effect on normal hepatocytes. Furthermore, in vivo, combination of S63845, a selective Mcl-1 inhibitor, with tumor-nectrosis factor-related, apoptosis-induncing ligand (TRAIL) peptide reduces tumor growth, but only in tumors expressing VDAC2. Thus, we describe mitochondrial molecular fingerprint that discriminates liver from hepatocarcinoma and allows sparing normal tissue while targeting tumors.
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Affiliation(s)
- Shamim Naghdi
- MitoCare Center, Department of Pathology and Genomic Medicine and Thomas Jefferson University, Philadelphia, PA, USA
| | - Piyush Mishra
- MitoCare Center, Department of Pathology and Genomic Medicine and Thomas Jefferson University, Philadelphia, PA, USA
| | - Soumya Sinha Roy
- MitoCare Center, Department of Pathology and Genomic Medicine and Thomas Jefferson University, Philadelphia, PA, USA
| | - David Weaver
- MitoCare Center, Department of Pathology and Genomic Medicine and Thomas Jefferson University, Philadelphia, PA, USA
| | - Ludivine Walter
- MitoCare Center, Department of Pathology and Genomic Medicine and Thomas Jefferson University, Philadelphia, PA, USA
| | - Erika Davies
- MitoCare Center, Department of Pathology and Genomic Medicine and Thomas Jefferson University, Philadelphia, PA, USA
| | - Anil Noronha Antony
- MitoCare Center, Department of Pathology and Genomic Medicine and Thomas Jefferson University, Philadelphia, PA, USA
| | - Xuena Lin
- MitoCare Center, Department of Pathology and Genomic Medicine and Thomas Jefferson University, Philadelphia, PA, USA
| | - Gisela Moehren
- MitoCare Center, Department of Pathology and Genomic Medicine and Thomas Jefferson University, Philadelphia, PA, USA
| | - Mark A Feitelson
- MitoCare Center, Department of Pathology and Genomic Medicine and Thomas Jefferson University, Philadelphia, PA, USA
| | - Christopher A Reed
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Tullia Lindsten
- Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA
- Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
| | - Craig B Thompson
- Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA
- Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
| | - Hien T Dang
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA, USA
| | - Jan B Hoek
- MitoCare Center, Department of Pathology and Genomic Medicine and Thomas Jefferson University, Philadelphia, PA, USA
| | - Erik S Knudsen
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - György Hajnóczky
- MitoCare Center, Department of Pathology and Genomic Medicine and Thomas Jefferson University, Philadelphia, PA, USA.
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29
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Gao D, Zhou Z, Chen L, Zheng J, Yang J. CGREF1 facilitates the cell proliferation, migration and invasion of hepatocellular carcinoma cells via regulation of EIF3H/ Wnt/β-Catenin signaling axis. BMC Cancer 2025; 25:435. [PMID: 40069645 PMCID: PMC11895259 DOI: 10.1186/s12885-025-13808-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Accepted: 02/25/2025] [Indexed: 03/15/2025] Open
Abstract
BACKGROUND Although Cell growth regulator with EF-hand domain 1 (CGREF1) has been predicted to be upregulated in multiple cancer types, its definitive function role in carcinogenesis, particularly in hepatocellular carcinoma (HCC), remains poorly characterized. METHODS Comprehensive bioinformatics analysis was initially conducted using the University of ALabama at Birmingham CANcer data analysis Portal (UALCAN) and Gene Expression Profiling Interactive Analysis (GEPIA) databases to investigate CGREF1 mRNA expression patterns in HCC tissues and their clinical correlation with patient survival outcomes. Experimental validation was subsequently performed through real-time quantitative polymerase chain reaction (RT-qPCR), immunohistochemistry (IHC), and Western blot techniques. Functional characterization studies employing genetic knockdown and overexpression models in HCC cell lines demonstrated CGREF1's regulatory effects on malignant phenotypes, as evidenced by 3-(4,5-dimethylthiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assay, colony formation assay and Transwell migration and invasion assays. were adopted to investigate the role of CGREF1 in the proliferation, invasion, and migration of HCC cells. Mechanistic investigations integrating bioinformatics predictions with Western blot analysis revealed CGREF1 mediated-modulation of the Wnt/β-Catenin signaling axis, elucidating its molecular underpinnings in HCC progression. RESULTS The results demonstrated that CGREF1 is highly expressed in HCC tissues, and HCC patients with elevated CGREF1 expression exhibited significantly shorter survival times. Upregulation of CGREF1 promoted the proliferation, migration, and invasion of HCC cells, whereas inhibition of CGREF1 expression suppressed these phenotypes. Mechanistically, CGREF1 activates the Wnt/β-Catenin signaling pathway through the upregulation of eukaryotic translation initiation factor 3 H subunit (EIF3H). Furthermore, partial inhibition of EIF3H attenuated the effects of CGREF1 overexpression on the proliferation, migration, and invasion of HCC cells. CONCLUSION CGREF1 is upregulated in HCC and acted as an oncogene through the CGREF1/EIF3H/Wnt/β-Catenin signaling axis. These findings suggest that CGREF1 may emerge as a potential therapeutic target for HCC.
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Affiliation(s)
- Dongkai Gao
- Department of Infectious Diseases, Zhuji People's Hospital of Zhejiang Province, No. 9 Jianmin Road, Taozhu Street, Zhuji City, Shaoxing City, Zhejiang Province, 311800, China.
| | - Zumo Zhou
- Department of Infectious Diseases, Zhuji People's Hospital of Zhejiang Province, No. 9 Jianmin Road, Taozhu Street, Zhuji City, Shaoxing City, Zhejiang Province, 311800, China
| | - Lin Chen
- Department of Infectious Diseases, Zhuji People's Hospital of Zhejiang Province, No. 9 Jianmin Road, Taozhu Street, Zhuji City, Shaoxing City, Zhejiang Province, 311800, China
| | - Jun Zheng
- Hepatobiliary Surgery, Zhuji People's Hospital of Zhejiang Province, Zhuji City, Shaoxing City, Zhejiang Province, China
| | - Jinna Yang
- Department of Infectious Diseases, Zhuji People's Hospital of Zhejiang Province, No. 9 Jianmin Road, Taozhu Street, Zhuji City, Shaoxing City, Zhejiang Province, 311800, China
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Kong Q, Li K. Predicting early recurrence of hepatocellular carcinoma after thermal ablation based on longitudinal MRI with a deep learning approach. Oncologist 2025; 30:oyaf013. [PMID: 40110765 PMCID: PMC11923588 DOI: 10.1093/oncolo/oyaf013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 01/13/2025] [Indexed: 03/22/2025] Open
Abstract
BACKGROUND Accurate prediction of early recurrence (ER) is essential to improve the prognosis of patients with hepatocellular carcinoma (HCC) underwent thermal ablation (TA). Therefore, a deep learning model system using longitudinal magnetic resonance imaging (MRI) was developed to predict ER of patients with HCC. METHODS From 2014, April to 2017, May, a total of 289 eligible patients with HCC underwent TA were retrospectively enrolled from 3 hospitals and assigned into one training cohort (n = 254) and one external testing cohort (n = 35). Two deep learning models (Pre and PrePost) were developed using the pre-operative MRI and longitudinal MRI (pre- and post-operative) to predict ER for the patients with HCC after TA, respectively. Then, an integrated model (DL_Clinical) incorporating PrePost model signature and clinical variables was built for post-ablation ER risk stratification for the patients with HCC. RESULTS In the external testing cohort, the area under the receiver operating characteristic curve (AUC) of the DL_Clinical model was better than that of the Clinical (0.740 vs 0.571), Pre (0.740 vs 0.648), and PrePost model (0.740 vs 0.689). Additionally, there was a significant difference in RFS between the high- and low-risk groups which were divided by the DL_Clinical model (P = .04). CONCLUSIONS The PrePost model developed using longitudinal MRI showed outstanding performance for predicting post-ablation ER of HCC. The DL_Clinical model could stratify the patients into high- and low-risk groups, which may help physicians in treatment and surveillance strategy selection in clinical practice.
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Affiliation(s)
- Qingyang Kong
- Department of Ultrasound, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Kai Li
- Department of Ultrasound, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China
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Pan H, Ruan M, Jin R, Zhang J, Li Y, Wu D, Zhang L, Sun W, Wang R. Immune checkpoint inhibitor plus tyrosine kinase inhibitor with or without transarterial chemoembolization for unresectable hepatocellular carcinoma. Front Oncol 2025; 15:1385304. [PMID: 40129919 PMCID: PMC11930818 DOI: 10.3389/fonc.2025.1385304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 02/11/2025] [Indexed: 03/26/2025] Open
Abstract
Background and aims Transcatheter arterial chemoembolization (TACE) has been combined with immune checkpoint inhibitor (ICI)-based systemic therapies for unresectable hepatocellular carcinoma (uHCC) with promising efficacy. However, whether the addition of TACE to the combination of ICI and tyrosine kinase inhibitor (TKI) (ICI+TKI+TACE) is superior to ICI+TKI combination therapy is still not clear. Thus, this study compares the efficacy of ICI+TKI+TACE triple therapy and ICI+TKI doublet therapy in patients with uHCC. Methods uHCC patients treated with either ICI+TKI+TACE triple therapy or ICI+TKI doublet therapy were retrospectively recruited between January 2016 and December 2021 at Eastern Hepatobiliary Surgery Hospital. The patients from ICI+TKI+TACE group and ICI+TKI group were further subjected to propensity score matching (PSM). The primary outcome was progression-free survival (PFS). The secondary outcomes were overall survival (OS) and objective response rate (ORR). Post-progression survival (PPS) as well as treatment-related adverse events (TRAEs) were also assessed. Results A total of 120 patients were matched. The median PFS was 8.4 months in ICI+TKI+TACE triple therapy group versus 6.6 months in ICI+TKI doublet therapy group (HR 0.72, 95%CI 0.48-1.08; p=0.115). Similar results were obtained in term of OS (26.9 versus 24.2 months, HR 0.88, 95% CI 0.51-1.52; p=0.670). The ORR in the triple therapy group was comparable with that in the doublet therapy group (16.6% versus 21.6%, p=0.487). Further subgroup analysis for PFS illustrated that patients without previous locoregional treatment (preLRT) (10.5 versus 3.7 months, HR 0.35 [0.16-0.76]; p=0.009), without previous treatment (10.5 versus 3.5 months, HR 0.34 [0.14-0.81]; p=0.015) or treated with lenvatinib (14.8 versus 6.9 months, HR 0.52 [0.31-0.87]; p=0.013) can significantly benefit from triple therapy compared with doublet therapy. A remarkable interaction between treatment and preLRT (p=0.049) or TKIs-combined (p=0.005) was also detected in term of PFS. Post progression treatment significantly improved PPS in both groups. The incidence of TRAEs was comparable between two groups. Conclusions The addition of TACE to ICI+TKI combination therapy did not result in a substantial improvement in efficacy and prognosis of patients. However, in selected uHCC patients (without preLRT or treated with lenvatinib as combination), ICI+TKI+TACE triple therapy may remarkably improve PFS.
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Affiliation(s)
- Hongyu Pan
- The First Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Naval Medical University, Shanghai, China
| | - Minghao Ruan
- The First Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Naval Medical University, Shanghai, China
| | - Riming Jin
- The First Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Naval Medical University, Shanghai, China
| | - Jin Zhang
- The First Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Naval Medical University, Shanghai, China
| | - Yao Li
- The First Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Naval Medical University, Shanghai, China
| | - Dong Wu
- The First Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Naval Medical University, Shanghai, China
| | - Lijie Zhang
- The Department of Information, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Wen Sun
- National Center for Liver Cancer, The Naval Medical University, Shanghai, China
| | - Ruoyu Wang
- The First Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Naval Medical University, Shanghai, China
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Liu F, Xiao L, Zhao L, Tao Y, Huang D, Chen Z, He C, Wu C. Prostate-specific membrane antigen-targeting radiopharmaceuticals: a new frontier in hepatic malignancies. Front Oncol 2025; 15:1547459. [PMID: 40123907 PMCID: PMC11926431 DOI: 10.3389/fonc.2025.1547459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Accepted: 02/18/2025] [Indexed: 03/25/2025] Open
Abstract
Background/Objectives Prostate-specific membrane antigen (PSMA) is overexpressed in prostate hypercellularity, making it an effective target for molecular imaging and therapy of prostate cancer. PSMA is expressed in the neovasculature of hepatic malignancies and regulates tumor cell invasion and angiogenesis. The diagnosis and treatment of hepatic malignancies remain challenging. Thus, radiopharmaceuticals targeting PSMA are gaining prominence in the treatment of hepatic malignancies. Therefore, this review aims to discuss the applications of PSMA-targeting radiopharmaceuticals in hepatic malignant tumors, focusing on hepatocellular carcinoma (HCC), to assess their value as a diagnostic and therapeutic agent for hepatic malignancies. Methods The potentials of PSMA-targeting radiopharmaceuticals for diagnostic and therapeutic use in hepatic malignancies were investigated. Moreover, their characteristics, diagnostic and therapeutic efficacies, and potential synergies when used in conjunction with other therapeutic modalities were elucidated. Results Computed tomography (CT) and magnetic resonance imaging (MRI) are the most common imaging modalities in clinical practice; however, their sensitivity is not optimal. PSMA positron emission tomography/CT can be used as a complementary modality to conventional imaging for characterizing lesions, staging and/or re-staging HCC, and assessing treatment response when conventional imaging results are unclear. Moreover, most patients with HCC are diagnosed at an advanced stage in which treatment options are limited. Hence, PSMA-based radioligand therapy serves as a promising alternative treatment when multiple treatments fail. Conclusions Further research and clinical transformation are required to effectively diagnose and treat HCC via PSMA targeting. This will have significant clinical application prospects in primary and secondary hepatic malignancies.
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Affiliation(s)
- Fucen Liu
- National Health Commission (NHC) Key Laboratory of Nuclear Technology Medical Transformation (MIANYANG CENTRAL HOSPITAL), Mianyang, China
- Department of Nuclear Medicine, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Liming Xiao
- National Health Commission (NHC) Key Laboratory of Nuclear Technology Medical Transformation (MIANYANG CENTRAL HOSPITAL), Mianyang, China
- Department of Nuclear Medicine, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Ling Zhao
- National Health Commission (NHC) Key Laboratory of Nuclear Technology Medical Transformation (MIANYANG CENTRAL HOSPITAL), Mianyang, China
- Department of Nuclear Medicine, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
- Institute of Basic Medicine, North Sichuan Medical College, Nanchong, China
| | - Yi Tao
- National Health Commission (NHC) Key Laboratory of Nuclear Technology Medical Transformation (MIANYANG CENTRAL HOSPITAL), Mianyang, China
- Department of Nuclear Medicine, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Dan Huang
- National Health Commission (NHC) Key Laboratory of Nuclear Technology Medical Transformation (MIANYANG CENTRAL HOSPITAL), Mianyang, China
- Department of Nuclear Medicine, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Zhengguo Chen
- National Health Commission (NHC) Key Laboratory of Nuclear Technology Medical Transformation (MIANYANG CENTRAL HOSPITAL), Mianyang, China
- Department of Nuclear Medicine, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Chuandong He
- National Health Commission (NHC) Key Laboratory of Nuclear Technology Medical Transformation (MIANYANG CENTRAL HOSPITAL), Mianyang, China
- Department of Nuclear Medicine, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Chunyan Wu
- National Health Commission (NHC) Key Laboratory of Nuclear Technology Medical Transformation (MIANYANG CENTRAL HOSPITAL), Mianyang, China
- Department of Nuclear Medicine, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
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Zhang J, Zhang Z, Yang C, Liu Q, Song T. Development of a MVI associated HCC prognostic model through single cell transcriptomic analysis and 101 machine learning algorithms. Sci Rep 2025; 15:7977. [PMID: 40055377 PMCID: PMC11889200 DOI: 10.1038/s41598-025-91475-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 02/20/2025] [Indexed: 03/12/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is an exceedingly aggressive form of cancer that often carries a poor prognosis, especially when it is complicated by the presence of microvascular invasion (MVI). Identifying patients at high risk of MVI is crucial for personalized treatment strategies. Utilizing the single-cell RNA-sequencing dataset (GSE242889) of HCC, we identified malignant cell subtypes associated with microvascular invasion (MVI), in conjunction with the TCGA dataset, selected a set of MVI-related genes (MRGs). We developed an optimal prognostic model comprising 11 genes (NOP16, YIPF1, HMMR, NDC80, DYNLL1, CDC34, NLN, KHDRBS3, MED8, SLC35G2, RAB3B) based on MVI-related signature genes by integrating single-cell transcriptomic analysis with 101 machine learning algorithms. This model is meticulously crafted to forecast the prognosis of individuals afflicted with hepatocellular carcinoma (HCC). Additionally, we affirmed the predictive precision and superiority of our model through a meta-analysis against existing HCC models. Furthermore, we explored the differences between high- and low-risk groups through mutation and immune infiltration analyses. Lastly, we investigated immunotherapy responses and drug sensitivities between risk groups, providing novel therapeutic insights for liver cancer.
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Affiliation(s)
- Jiayi Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China
| | - Zheng Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China
| | - Chenqing Yang
- Department of Gynaecology and Obstetrics Department, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China
| | - Qingguang Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China.
| | - Tao Song
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China.
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Guo E, Li L, Yang J, Zhou Y, Bai L, Zhu W, Hu Q, Wang H, Liu H. HOXB4/METTL7B cascade mediates malignant phenotypes of hepatocellular carcinoma through TKT m6A modification. Biol Direct 2025; 20:26. [PMID: 40045399 PMCID: PMC11884015 DOI: 10.1186/s13062-025-00620-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 02/17/2025] [Indexed: 03/09/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma is a fatal malignancy that lacking specific therapies. Homeobox B4 (HOXB4) was negatively correlated with poor prognosis in cancers, but its role in hepatocellular carcinoma has not been elucidated. RESULTS We confirmed that HOXB4 was downregulated in hepatocellular carcinoma tissues and lower HOXB4 expression associated with poor prognosis. Gain- and loss-of function experiments were performed to understand the functional consequences. We revealed that HOXB4 overexpression inhibited proliferation and metastasis of hepatocellular carcinoma cells, accompanied with the decrease in epithelial-mesenchymal transition and increase in cell apoptosis. Database analysis showed that HOXB4 was positively correlated with the immune infiltration. PD-L1 expression was decreased in HOXB4 overexpressed hepatocellular carcinoma cells. HOXB4 overexpression was confirmed to inhibit the progression of hepatocellular carcinoma and promote T cell infiltration in vivo. N6-methyladenosine (m6A) modification was implicated in the tumorigenesis. RNA-seq analysis showed that HOXB4 overexpression modulated METTL7B expression. With the performance of dual-luciferase reporter, ChIP, and DNA pulldown assays, we revealed that HOXB4 binding to METTL7B promoter and inhibited its mRNA expression. The increased aggressiveness of hepatocellular carcinoma cells and the enhanced immune escape, triggered by HOXB4 knockdown, were inhibited via METTL7B downregulation. Methylated RNA immunoprecipitation assay displayed that METTL7B controlled the mRNA decay of TKT in m6A methylation. METTL7B overexpression increase the expression of TKT, ultimately promoting hepatocellular carcinoma progression and immune evasion. CONCLUSIONS HOXB4 mediated the malignant phenotypes and modulated the immune evasion via METTL7B/TKT axis. The HOXB4/METTL7B cascade and its downstream changes might be novel targets for blocking hepatocellular carcinoma progression.
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Affiliation(s)
- Enshuang Guo
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
- Precision Medicine Center, Gene Hospital of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
| | - Lei Li
- Department of Osteology, Yellow River Central Hospital of the Yellow River Conservancy Commission, Zhengzhou, 450003, China
| | - Jiankun Yang
- Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yongjian Zhou
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Precision Medicine Center, Gene Hospital of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Lu Bai
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Precision Medicine Center, Gene Hospital of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Weiwei Zhu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Precision Medicine Center, Gene Hospital of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Qiuyue Hu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Precision Medicine Center, Gene Hospital of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Huifen Wang
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Precision Medicine Center, Gene Hospital of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Hongqiang Liu
- Department of Emergency, Henan Province Hospital of Traditional Chinese Medicine, Zhengzhou, 450002, China
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Cao S, Yu S, Huang L, Seery S, Xia Y, Zhao Y, Si Z, Zhang X, Zhu J, Lang R, Kou J, Zhang H, Wei L, Zhou G, Sun L, Wang L, Li T, He Q, Zhu Z. Deep learning for hepatocellular carcinoma recurrence before and after liver transplantation: a multicenter cohort study. Sci Rep 2025; 15:7730. [PMID: 40044774 PMCID: PMC11882823 DOI: 10.1038/s41598-025-91728-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Accepted: 02/24/2025] [Indexed: 03/09/2025] Open
Abstract
Hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) is a major contributor to mortality. We developed a recurrence prediction system for HCC patients before and after LT. Data from patients with HCC who underwent LT were retrospectively collected from three specialist centres in China. Pre- and post-operative variables were selected using support vector machine, random forest, and logistic regression (LR). Then, pre- and post-operative models were developed using three machine learning methods: LR, stacking, and two survival-based approaches. Models were evaluated using seven assessment indices, and patients were classified as either high- or low-risk based on recurrence risk. 466 patients were included and followed for a median of 51.0 months (95% CI 47.8-54.2). The pre-DeepSurv model (pre-DSM) had a C-index of 0.790 ± 0.003 during training, 0.775 ± 0.037 during testing, and 0.765 ± 0.001 and 0.819 ± 0.002 during external validation. After incorporating clinicopathologic variables, the post-DeepSurv model (post-DSM) had a 0.835 ± 0.008 C-index during training, 0.812 ± 0.082 during testing, and 0.839 ± 0.001 and 0.831 ± 0.002 during external validation. The post-DSM outperformed the Milan criteria by more accurately identifying patients at high risk of recurrence. Tumour recurrence predictions also improved significantly with DeepSurv. Both pre- and post-DSMs have the potential to guide personalised surveillance strategies for LT patients with HCC.
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Affiliation(s)
- Shuang Cao
- Liver Transplantation Center, Clinical Research Center for Pediatric Liver Transplantation, State Key Lab of Digestive Health, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, 95 Yong'an Road, Xicheng District, Beijing, 100050, China
| | - Sihan Yu
- Cardiology Department, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Liangbin Huang
- Department of Breast and Thyroid Surgery, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, 410028, Hunan, China
| | - Samuel Seery
- Department of Humanities and Social Sciences, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
- School of Pharmacy, Newcastle University, Newcastle, NE1 4LP, UK
| | - Yu Xia
- Graduate School, Tsinghua University, Beijing, 100084, China
| | - Yongwei Zhao
- State Key Laboratory of Processors, Institute of Computing Technology, Chinese Academy of Sciences, Beijing, 100190, China
| | - Zhongzhou Si
- Department of Liver Transplantation, The Second Xiang-ya Hospital, Central South University, Changsha, 410011, China
| | - Xinxue Zhang
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China
| | - Jiqiao Zhu
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China
| | - Ren Lang
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China
| | - Jiantao Kou
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China
| | - Haiming Zhang
- Liver Transplantation Center, Clinical Research Center for Pediatric Liver Transplantation, State Key Lab of Digestive Health, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, 95 Yong'an Road, Xicheng District, Beijing, 100050, China
| | - Lin Wei
- Liver Transplantation Center, Clinical Research Center for Pediatric Liver Transplantation, State Key Lab of Digestive Health, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, 95 Yong'an Road, Xicheng District, Beijing, 100050, China
| | - Guangpeng Zhou
- Liver Transplantation Center, Clinical Research Center for Pediatric Liver Transplantation, State Key Lab of Digestive Health, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, 95 Yong'an Road, Xicheng District, Beijing, 100050, China
| | - Liying Sun
- Liver Transplantation Center, Clinical Research Center for Pediatric Liver Transplantation, State Key Lab of Digestive Health, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, 95 Yong'an Road, Xicheng District, Beijing, 100050, China
| | - Lei Wang
- Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, 100026, China.
| | - Ting Li
- Department of Liver Transplantation, The Second Xiang-ya Hospital, Central South University, Changsha, 410011, China.
| | - Qiang He
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China.
| | - Zhijun Zhu
- Liver Transplantation Center, Clinical Research Center for Pediatric Liver Transplantation, State Key Lab of Digestive Health, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, 95 Yong'an Road, Xicheng District, Beijing, 100050, China.
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Catalano G, Alaimo L, Chatzipanagiotou OP, Ruzzenente A, Aucejo F, Marques HP, Lam V, Hugh T, Bhimani N, Kitago M, Endo I, Martel G, Popescu I, Cauchy F, Poultsides GA, Gleisner A, Pawlik TM. Analysis of a modified surgical desirability of outcome ranking (mDOOR) among patients undergoing surgery for Hepatocellular carcinoma. HPB (Oxford) 2025:S1365-182X(25)00072-3. [PMID: 40090779 DOI: 10.1016/j.hpb.2025.02.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 02/17/2025] [Accepted: 02/28/2025] [Indexed: 03/18/2025]
Abstract
BACKGROUND Composite measures represent a validated method for evaluating surgical care quality. We defined a modified Desirability Of Outcome Ranking (mDOOR) and compared it with textbook outcome (TO). METHODS In this cohort study, patients undergoing curative-intent surgery for HCC were identified from an international cohort. The performance and agreement of mDOOR, TO, and other measures of postoperative course with respect to overall survival (OS) were compared using Harrell's Concordance-index (C-index) and Cohen's kappa. RESULTS Among 2181 patients, 77.6 % (n = 1692) achieved the most desirable outcome (i.e., DOOR1), whereas roughly one-half of patients achieved TO (n = 1,171, 53.7 %). Patients with lower mDOOR had a better 5-year OS compared with patients with higher mDOOR (64.7 % vs. 51.9 %; p < 0.001). On multivariable analysis, higher mDOOR was associated with worse OS (HR 1.35, 95%CI 1.28-1.44; p < 0.001). The mDOOR demonstrated improved performance compared with the comprehensive complication index (C-index: 0.696 vs. 0.649; p < 0.001) and the Accordion score (C-index: 0.696 vs. 0.653; p = 0.002). CONCLUSION Roughly 4 out of 5 patients achieved the most desirable outcome. Higher mDOOR was associated with worse long-term outcomes. A composite outcome ranking may provide more insight on surgical outcomes, complementing traditional metrics.
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Affiliation(s)
- Giovanni Catalano
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA; Department of Surgery, University of Verona, Verona, Italy
| | - Laura Alaimo
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA; Department of Surgery, University of Verona, Verona, Italy
| | | | | | - Federico Aucejo
- Cleveland Clinic Foundation, Digestive Diseases and Surgery Institute, Department of Hepato-pancreato-biliary & Liver Transplant Surgery, Cleveland, OH, USA
| | - Hugo P Marques
- Department of Surgery, Curry Cabral Hospital, Lisbon, Portugal
| | - Vincent Lam
- Department of Surgery, Westmead Hospital, Sydney, Australia
| | - Tom Hugh
- Department of Surgery, The University of Sydney, School of Medicine, Sydney, Australia
| | - Nazim Bhimani
- Department of Surgery, The University of Sydney, School of Medicine, Sydney, Australia
| | - Minoru Kitago
- Department of Surgery, Keio University, Tokyo, Japan
| | - Itaru Endo
- Yokohama City University School of Medicine, Yokohama, Japan
| | | | - Irinel Popescu
- Department of Surgery, Fundeni Clinical Institute, Bucharest, Romania
| | - François Cauchy
- Department of Hepatobiliopancreatic Surgery and Liver Transplantation, AP-HP, Beaujon Hospital, Clichy, France
| | | | - Ana Gleisner
- Department of Surgery, UC Denver, Denver, CO, USA
| | - Timothy M Pawlik
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
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Catalano G, Alaimo L, Chatzipanagiotou OP, Ruzzenente A, Ratti F, Aldrighetti L, Marques HP, Cauchy F, Lam V, Poultsides GA, Hugh T, Popescu I, Alexandrescu S, Martel G, Kitago M, Endo I, Gleisner A, Shen F, Pawlik TM. Predicting the complexity of minimally invasive liver resection for hepatocellular carcinoma using machine learning. HPB (Oxford) 2025:S1365-182X(25)00073-5. [PMID: 40090780 DOI: 10.1016/j.hpb.2025.02.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Revised: 12/19/2024] [Accepted: 02/28/2025] [Indexed: 03/18/2025]
Abstract
BACKGROUND Despite technical advancements, minimally invasive liver surgery (MILS) for hepatocellular carcinoma (HCC) remains challenging. Nonetheless, effective tools to assess MILS complexity are still lacking. Machine learning (ML) models could improve the accuracy of such tools. METHODS Patients who underwent curative-intent MILS for HCC were identified using an international database. An XGBoost ML model was developed to predict surgical complexity using clinical and radiological characteristics. RESULTS Among 845 patients, 186 (22.0 %) were classified as high-risk patients. In this subgroup, median Charlson Comorbidity Index (CCI) (5.0, IQR 3.0-7.0 vs. 2.0, IQR 2.0-5.0, p < 0.001) and tumor burden score (TBS) (median 4.12, IQR 3.0-5.1 vs. 4.22, IQR 3.2-7.1, p < 0.001) were higher. The model was able to effectively predict complexity of surgery in both the training and testing cohorts with high discriminating power (ROC-AUC: 0.86, 95%CI 0.82-0.89 vs. 0.73, 95%CI 0.65-0.81). The most influential variables were CCI, TBS, BMI, extent of resection, and sex. Patients predicted to have a complex surgery were more likely to develop severe complications (OR 4.77, 95%CI 1.82-13.9, p = 0.002). An easy-to-use calculator was developed. CONCLUSION Preoperative ML-prediction of complex MILS for HCC may improve preoperative planning, resource allocation, and patient outcomes.
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Affiliation(s)
- Giovanni Catalano
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA; Department of Surgery, University of Verona, Verona, Italy
| | - Laura Alaimo
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA; Department of Surgery, University of Verona, Verona, Italy
| | - Odysseas P Chatzipanagiotou
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | | | | | | | - Hugo P Marques
- Department of Surgery, Curry Cabral Hospital, Lisbon, Portugal
| | - François Cauchy
- Department of Hepatobiliopancreatic Surgery and Liver Transplantation, AP-HP, Beaujon Hospital, Clichy, France
| | - Vincent Lam
- Department of Surgery, Westmead Hospital, Sydney, Australia
| | | | - Tom Hugh
- Department of Surgery, The University of Sydney, School of Medicine, Sydney, Australia
| | - Irinel Popescu
- Department of Surgery, Fundeni Clinical Institute, Bucharest, Romania
| | | | | | - Minoru Kitago
- Department of Surgery, Keio University, Tokyo, Japan
| | - Itaru Endo
- Yokohama City University School of Medicine, Yokohama, Japan
| | - Ana Gleisner
- Department of Surgery, University of Colorado, Denver, CO, USA
| | - Feng Shen
- Department of Hepatic Surgery IV, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Timothy M Pawlik
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA.
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Ning L, Gao Z, Chen D, Han J, Xie G, Sun J. Causality of blood metabolites on hepatocellular carcinoma and cholangiocarcinoma: a metabolome-wide mendelian randomization study. BMC Cancer 2025; 25:389. [PMID: 40038628 DOI: 10.1186/s12885-025-13690-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 02/07/2025] [Indexed: 03/06/2025] Open
Abstract
BACKGROUND Reportedly, there is an association between body metabolites and the risk of Hepatocellular Carcinoma (HCC) & Cholangiocarcinoma (CCA), possibly due to disrupted metabolic pathways leading to oxidative stress and an imbalance in cell proliferation and apoptosis, thereby increasing the risk of cancer. However, whether metabolites play a role in the onset of HCC or CCA remains inconclusive. OBJECTIVE The aim of our study is to explore the potential causal relationship between metabolites and the risk of HCC&CCA. METHODS Our study investigated the causal relationship between 1400 metabolites and HCC&CCA using publicly available genome-wide association study data. Single nucleotide polymorphisms (SNPs) associated with both metabolites and HCC&CCA were chosen as instrumental variables (IVs). The main approaches employed include inverse variance weighted (IVW), MR-Egger regression, and weighted median estimator (WME), with odds ratios (OR) used as the assessment criterion. Heterogeneity testing and sensitivity analyses were conducted to validate the results. We also conducted a reverse MR analysis to further validate the relationship between exposure and disease outcomes. RESULTS This Mendelian Randomization (MR) study indicates a significant causal relationship between 19 metabolites and the risk of HCC&CCA. Among them, the risk factors include "Bilirubin (E, Z or Z, E) levels," "Bilirubin (Z, Z) to taurocholate ratio," "Dimethylarginine (sdma + adma) levels," "N-methyltaurine levels," "4-vinylguaiacol sulfate levels," "Cholate to adenosine 3',5'-cyclic monophosphate (cAMP) ratio," "Glycohyocholate levels," "Cholesterol levels," and "4-methylguaiacol sulfate levels." The incidence risk of HCC and CCA increases with the elevation of these metabolites. Protective factors include "Ursodeoxycholate levels," "3-hydroxybutyroylglycine levels," "Linoleoylcholine levels," "Nonanoylcarnitine (C9) levels," "Pristanate levels," "Heptenedioate (C7:1-DC) levels," "Mannonate levels," "N-acetyl-L-glutamine levels," "Sphinganine levels," and "N-lactoyl isoleucine levels." The incidence risk of HCC and CCA potentially decreases as the levels of these metabolites increase. Heterogeneity tests show that most instrumental variables do not exhibit inter-gene heterogeneity, and the possibility of pleiotropy in the analysis is very low according to the sensitivity analysis. The reverse MR analysis did not yield positive results. CONCLUSION Our study has unveiled the intricate causal relationships between metabolites and the risk of HCC&CCA. Through our analysis, we identified nine metabolites, including "Bilirubin (E, Z or Z, E) levels," "Dimethylarginine (sdma + adma) levels," "Cholesterol levels,"ect, as risk factors for HCC&CCA. The incidence risk of HCC and CCA increases with their elevation. On the other hand, ten metabolites, such as "Ursodeoxycholate levels," "Linoleoylcholine levels," "Pristanate levels," ect, were identified as protective factors for HCC&CCA. The risk of developing HCC and CCA decreases with an increase in these metabolites. In conclusion, these findings further explore the physiological metabolic pathways underlying the pathogenesis of HCC and CCA, emphasizing future research directions. They pave the way for researchers to delve into the biological mechanisms of these diseases, facilitating early intervention and treatment strategies for these conditions.
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Affiliation(s)
- Lin Ning
- Department of Traditional Chinese medicine, The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Zhanhua Gao
- Department of Hepatobiliary Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Di Chen
- Department of Hepatobiliary Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Jie Han
- Department of Hepatobiliary Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Guanyue Xie
- Department of Hepatobiliary Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Jianguang Sun
- Department of Traditional Chinese medicine, The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China.
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Tatour M, Baker FA, Saadi T, Yahia A, Hazzan R. Advancements in autoimmune hepatitis epidemiology, treatment and complication - a 15-year retrospective study. Clin Res Hepatol Gastroenterol 2025; 49:102570. [PMID: 40049285 DOI: 10.1016/j.clinre.2025.102570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 03/02/2025] [Accepted: 03/03/2025] [Indexed: 03/24/2025]
Abstract
INTRODUCTION AND OBJECTIVES Autoimmune hepatitis (AIH) is a rare, heterogeneous liver disease marked by autoantibodies, hypergammaglobulinemia, and distinct histological features. Predominantly affecting women, its incidence and prevalence show significant regional variability globally. Therefore, our aim is to examine the trends of AIH and to assess its demographics, management, and disease progression using an extensive population-based database. MATERIALS AND METHODS This retrospective, population-based study analyzed data from 2.7 million adults in Clalit Health Services, focusing on autoimmune hepatitis (AIH) diagnoses between 2009 and 2023. Data reordered included demographics, clinical details, and treatment regimens. Key outcomes tracked were the development of cirrhosis and its complications. RESULTS This study included 992 AIH patients with a median age of 51.5 years, 80.4 % female, and a median follow-up of 6.1 years. Obesity was present in 23.2 %, and 10.9 % had thyroid disease. At diagnosis, 22.9 % had cirrhosis, and an additional 137 patients developed cirrhosis during follow-up, leading to a total prevalence of 36.5 %. Among cirrhotic patients, 29.9 % experienced decompensation, 25.3 % developed ascites, 9.3 % had variceal bleeding, and 10.4 % developed hepatic encephalopathy. Hepatocellular carcinoma (HCC) occurred in 5.24 % of cirrhotic patients, with an incidence rate of 6.32 cases per 1000 patient-years. Overall, 11.2 % of cirrhotic patients underwent liver transplantation. The proportion of AIH patients diagnosed with cirrhosis at the time of diagnosis significantly decreased over the study period (p = 0.0028). CONCLUSIONS This study demonstrates a decreasing trend in AIH patients diagnosed with cirrhosis, suggesting earlier detection and improved management, alongside a lower documented incidence of HCC.
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Affiliation(s)
- Mifleh Tatour
- Clalit Health Services, Nof Hagalil, Israel; Department of Family Medicine, Clalit Health Services, Afula, Israel.
| | - Fadi Abu Baker
- Department of Gastroenterology and Hepatology, Hillel Yaffe Medical Center, Hadera 38100, Israel; Rappaport Faculty of Medicine, Technion - Institute of Technology, Haifa, Israel
| | - Tarek Saadi
- Rappaport Faculty of Medicine, Technion - Institute of Technology, Haifa, Israel; Liver Unit, Rambam Health Care Campus, Haifa, Israel
| | - Ahmad Yahia
- Department of Gastroenterology and Hepatology, Emek Medical Center, Afula, Israel
| | - Rawi Hazzan
- Clalit Health Services, Nof Hagalil, Israel; Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel.
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Geng J, Xie M, Yan M, Xie X, Wang F, Zhu R, Han M. Invariant NK T cells counteract HCC metastasis by mediating the migration of splenic CD4 + T cells into the white pulp and infiltration of B cells. Commun Biol 2025; 8:351. [PMID: 40033139 DOI: 10.1038/s42003-025-07798-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 02/21/2025] [Indexed: 03/05/2025] Open
Abstract
Despite significant advances in the diagnosis and treatment of hepatocellular carcinoma (HCC), metastasis and recurrence remain two major obstacles to improving the clinical outcomes for HCC patients. Here, we demonstrate that splenic invariant natural killer T (iNKT) cells can significantly inhibit Hepa1-6-mediated intrahepatic HCC metastasis. Interestingly, in the HCC metastasis model, iNKT deficiency can result in a significant decrease in percentage and absolute number of CD4+ T cell and interleukin-4 level, thus suggesting the involvement of the cross-talk between iNKTs and CD4+ T cells in limiting HCC metastasis to the spleen. Transcriptional signatures of CD4+ T cells following iNKT deficiency displaying impairment of their cell migration function. During HCC metastasis, splenic iNKT rapidly secrete interferon-γ to promote the migration of CD4+ T cells from the marginal zone into the white pulp, thereby triggering subsequent migration of splenic B cells to the liver and exerting anti-tumor immune effects on Hepa1-6 cells. In conclusion, interactions between interferon-γ and its receptor on iNKT and CD4+ T cells can effectively coordinate immune activity between the marginal zone and the white pulp, thereby ultimately inhibiting intrahepatic HCC metastasis. These findings reveal the mechanism underlying the resistance of splenic iNKT to tumor metastasis.
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Affiliation(s)
- Jinke Geng
- Center for Medical Laboratory Science, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu, China
| | - Mengxiao Xie
- Department of Laboratory Medicine, Jiangsu Province Hospital, Nanjing, Jiangsu, China
| | - Meina Yan
- Center for Medical Laboratory Science, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu, China
| | - Xiaoyan Xie
- Center for Medical Laboratory Science, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu, China
| | - Fuxin Wang
- Center for Human Reproduction and Genetics, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu, China
| | - Rui Zhu
- Center for Human Reproduction and Genetics, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu, China.
| | - Mutian Han
- Center for Medical Laboratory Science, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu, China.
- Center for Research and Experimental, Suzhou Vocational Health College, Suzhou, Jiangsu, China.
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Zeng Y, Wu H, Zhu Y, Li C, Du D, Song Y, Su S, Qin J, Jiang G. MRI-based intra-tumoral ecological diversity features and temporal characteristics for predicting microvascular invasion in hepatocellular carcinoma. Front Oncol 2025; 15:1510071. [PMID: 40098699 PMCID: PMC11911209 DOI: 10.3389/fonc.2025.1510071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Accepted: 02/10/2025] [Indexed: 03/19/2025] Open
Abstract
Objective To investigate the predictive value of radiomics models based on intra-tumoral ecological diversity (iTED) and temporal characteristics for assessing microvascular invasion (MVI) in patients with hepatocellular carcinoma (HCC). Material and Methods We retrospectively analyzed the data of 398 HCC patients who underwent dynamic contrast-enhanced MRI with Gd-EOB-DTPA (training set: 318; testing set: 80). The tumors were segmented into five distinct habitats using case-level clustering and a Gaussian mixture model was used to determine the optimal clusters based on the Bayesian information criterion to produce an iTED feature vector for each patient, which was used to assess intra-tumoral heterogeneity. Radiomics models were developed using iTED features from the arterial phase (AP), portal venous phase (PVP), and hepatobiliary phase (HBP), referred to as MiTED-AP, MiTED-PVP, and MiTED-HBP, respectively. Additionally, temporal features were derived by subtracting the PVP features from the AP features, creating a delta-radiomics model (MDelta). Conventional radiomics features were also extracted from the AP, PVP, and HBP images, resulting in three models: MCVT-AP, MCVT-PVP, and MCVT-HBP. A clinical-radiological model (CR model) was constructed, and two fusion models were generated by combining the radiomics or/and CR models using a stacking algorithm (fusion_R and fusion_CR). Model performance was evaluated using AUC, accuracy, sensitivity, and specificity. Results The MDelta model demonstrated higher sensitivity compared to the MCVT-AP and MCVT-PVP models. No significant differences in performance were observed across different imaging phases for either conventional radiomics (p = 0.096-0.420) or iTED features (p = 0.106-0.744). Similarly, for images from the same phase, we found no significant differences between the performance of conventional radiomics and iTED features (AP: p = 0.158; PVP: p = 0.844; HBP: p = 0.157). The fusion_R and fusion_CR models enhanced MVI discrimination, achieving AUCs of 0.823 (95% CI: 0.816-0.831) and 0.830 (95% CI: 0.824-0.835), respectively. Conclusion Delta radiomics features are temporal and predictive of MVI, providing additional predictive information for MVI beyond conventional AP and PVP features. The iTED features provide an alternative perspective in interpreting tumor characteristics and hold the potential to replace conventional radiomics features to some extent for MVI prediction.
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Affiliation(s)
- Yuli Zeng
- Department of Medical Imaging, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, Guangdong, China
| | - Huiqin Wu
- Department of Medical Imaging, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, Guangdong, China
| | - Yanqiu Zhu
- Department of Radiology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Chao Li
- Department of Radiology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Dongyang Du
- School of Computer Science, Inner Mongolia University, Inner Mongolia, China
| | - Yang Song
- Magnetic Resonance (MR) Scientific Marketing, Siemens Healthineers Ltd., Shanghai, China
| | - Sulian Su
- Department of Radiology, Xiamen Humanity Hospital of Fujian Medical University, Xiamen, Fujian, China
| | - Jie Qin
- Department of Radiology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Guihua Jiang
- Department of Medical Imaging, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, Guangdong, China
- Department of Radiology, Xiamen Humanity Hospital of Fujian Medical University, Xiamen, Fujian, China
- Guangzhou Key Laboratory of Molecular Functional Imaging and Artificial Intelligence for Major Brain Diseases, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong, China
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Sueshige Y, Shiraiwa K, Tanaka R, Abe H, Tatsuta R, Saito T, Iwao M, Endo M, Arakawa M, Murakami K, Itoh H. Sensitive quantification of free lenvatinib using ultra-high performance liquid chromatography coupled to tandem mass spectrometry and the clinical significance of measuring free lenvatinib concentration. Clin Chim Acta 2025; 569:120188. [PMID: 39938627 DOI: 10.1016/j.cca.2025.120188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2024] [Revised: 01/20/2025] [Accepted: 02/09/2025] [Indexed: 02/14/2025]
Abstract
BACKGROUND AND AIMS Lenvatinib, an oral molecular target drug used for the treatment of hepatocellular carcinoma (HCC), has a high protein binding rate, resulting in high variability of free drug concentration in blood depending on patient conditions and drug interactions. In this study, an ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) assay was established to measure free lenvatinib concentrations. The novel assay was used to measure free lenvatinib concentrations in plasma of HCC patients, and the effect of hepatic dysfunction on free lenvatinib concentrations was evaluated. MATERIALS AND METHODS We studied 31 HCC patients treated orally with lenvatinib at Oita University Hospital. Blood samples were collected at seven time points on the first day of lenvatinib administration to measure total and free lenvatinib concentrations using UHPLC-MS/MS. RESULTS Pharmacokinetic (PK) parameters were calculated, and hepatic function was assessed using Child-Pugh (CP) classification and CP score. Patients were divided into CP class A (n = 22) and class B (n = 9), and PK parameters were compared between the two groups. The CP class B group had significantly higher trough concentrations (Ctrough) of total and free lenvatinib as well as Ctrough normalized to dose (Ctrough/Dose) compared to the class A group. A significant positive correlation was found between CP score and both Ctrough and Ctrough/Dose of total and free lenvatinib. However, free lenvatinib concentration tended to reflect the effects of hepatic function decline more sensitively than total concentration. In addition, plasma albumin concentration correlated significantly with protein binding rate. CONCLUSIONS The results of this study indicate that free lenvatinib concentration may reflect the effects of declining hepatic function more sensitively than total lenvatinib concentration. Therefore, measurement of free lenvatinib concentration may be clinically useful in patients with impaired hepatic function.
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Affiliation(s)
- Yoshio Sueshige
- Department of Clinical Pharmacy, Oita University Hospital, Yufu-shi, Oita, Japan
| | - Ken Shiraiwa
- Department of Clinical Pharmacy, Oita University Hospital, Yufu-shi, Oita, Japan.
| | - Ryota Tanaka
- Department of Clinical Pharmacy, Oita University Hospital, Yufu-shi, Oita, Japan
| | - Hironori Abe
- Department of Clinical Pharmacy, Oita University Hospital, Yufu-shi, Oita, Japan
| | - Ryosuke Tatsuta
- Department of Clinical Pharmacy, Oita University Hospital, Yufu-shi, Oita, Japan
| | - Tomoko Saito
- Department of Gastroenterology, Oita University Faculty of Medicine, Yufu-shi, Oita, Japan
| | - Masao Iwao
- Department of Gastroenterology, Oita University Faculty of Medicine, Yufu-shi, Oita, Japan
| | - Mizuki Endo
- Department of Gastroenterology, Oita University Faculty of Medicine, Yufu-shi, Oita, Japan
| | - Mie Arakawa
- Department of Gastroenterology, Oita University Faculty of Medicine, Yufu-shi, Oita, Japan
| | - Kazunari Murakami
- Department of Gastroenterology, Oita University Faculty of Medicine, Yufu-shi, Oita, Japan
| | - Hiroki Itoh
- Department of Clinical Pharmacy, Oita University Hospital, Yufu-shi, Oita, Japan
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Chen Z, Ou L, Ma L. SOX11 exacerbates ferroptosis to reduce lenvatinib resistance in liver cancer cells by promoting ubiquitination degradation of SREBF1 through upregulating UBE3A. Mol Cell Biochem 2025:10.1007/s11010-025-05218-x. [PMID: 40025300 DOI: 10.1007/s11010-025-05218-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Accepted: 01/26/2025] [Indexed: 03/04/2025]
Abstract
Lenvatinib is one of the most commonly used first-line drugs for liver cancer. However, lenvatinib resistance occurs in a large proportion of patients, posing a significant challenge. Ferroptosis, an iron-dependent form of cell death, plays a pivotal role in overcoming drug resistance. This study investigates the role of SRY-related HMG-box transcription factor 11 (SOX11) in regulating lenvatinib resistance in liver cancer through its impact on ferroptosis. qRT-PCR, western blot, and immunohistochemistry were performed to examine the expression of key molecules in patient samples and cell lines. Functional studies, including cell viability and proliferation assays, colony formation assays, flow cytometry, and measurements of iron metabolism markers, were conducted to explore the biological effects of these molecules. Additionally, Co-IP, ChIP, dual-luciferase reporter assays, and in vivo tumorigenesis experiments were performed to uncover the underlying regulatory mechanisms. Our results showed that UBE3A was markedly downregulated in lenvatinib-resistant liver cancer tissues and cells, and its overexpression markedly reduced lenvatinib resistance in liver cancer cells by promoting ferroptosis. Mechanically, UBE3A reduced lenvatinib resistance in lenvatinib-resistant liver cancer cells by mediating ubiquitination-independent degradation of SREBF1. In addition, SOX11 upregulation reduced lenvatinib resistance in liver cancer cells by promoting ferroptosis through transcriptionally activated UBE3A expression. In summary, SOX11 upregulation promoted ferroptosis in liver cancer cells by promoting SREBF1 ubiquitination degradation through transcriptionally elevating UBE3A expression, thereby sensitizing lenvatinib-resistant liver cancer cells to lenvatinib.
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Affiliation(s)
- Zushun Chen
- Department of Hepatobiliary, Pancreas and Spleen Surgery, Guangxi Medical University Cancer Center, 71 Hedi Road, Qingxiu District, Nanning, 530021, Guangxi, People's Republic of China
| | - Lisong Ou
- Department of Hepatobiliary, Pancreas and Spleen Surgery, Guangxi Medical University Cancer Center, 71 Hedi Road, Qingxiu District, Nanning, 530021, Guangxi, People's Republic of China
| | - Liang Ma
- Department of Hepatobiliary, Pancreas and Spleen Surgery, Guangxi Medical University Cancer Center, 71 Hedi Road, Qingxiu District, Nanning, 530021, Guangxi, People's Republic of China.
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Chen S, Liu J, Zhang S, Zhao L, Zhang J, Han P, Zhang Q, Liu Y, Wang F, Li J. Deciphering m6A signatures in hepatocellular carcinoma: Single-cell insights, immune landscape, and the protective role of IGFBP3. ENVIRONMENTAL TOXICOLOGY 2025; 40:367-383. [PMID: 38366283 DOI: 10.1002/tox.24177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 01/23/2024] [Accepted: 01/26/2024] [Indexed: 02/18/2024]
Abstract
RNA m6 methyladenosine (m6A) modifications impact tumor biology and immune processes, particularly in hepatocellular malignant tumors. Using a consensus clustering algorithm on 371 hepatocellular carcinoma (HCC) samples, we identified three m6A-modified subtypes and correlated them with positive tumor microenvironment (TME) markers for distinct immune phenotypes. Stratifying patients based on m6A scores revealed a low presentation group with better immune penetration, lower tumor mutation load, and increased expression of immune checkpoint markers like CTLA-4 and PD-1, suggesting enhanced responsiveness to immunization therapy. A machine-learning model of 23 m6A genes was constructed. Single-cell analysis revealed a surprising enrichment of IGFBP3 in astrocytes, prompting the exploration of associated signaling pathways. Experimental verification shows that IGFBP3 is significantly enhanced in normal tissues, while immunohistochemical analysis shows that its expression is lower in tumor tissues, indicating its protective effect in HCC and a good prognosis. Importantly, high IGFBP3 expression is associated with better outcomes in patients receiving immunotherapy. Moreover, cytotoxic T lymphocyte (CTL) experiments have confirmed that high expression of IGFBP3 is associated with stronger T cell-killing ability. In summary, the comprehensive evaluation of m6A modification, immune characteristics, and single-cell analysis in this study not only revealed the TME of HCC but also made significant contributions to the progress of personalized HCC immunotherapy targeting IGFBP3. This study provides a solid theoretical foundation for clinical translation and emphasizes its potential impact on developing effective treatment strategies.
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Affiliation(s)
- Shujia Chen
- Clinical School of the Second People's Hospital, Tianjin Medical University, Tianjin, China
| | - Jie Liu
- Clinical School of the Second People's Hospital, Tianjin Medical University, Tianjin, China
- Department of Hepatology, Tianjin Second People's Hospital, Tianjin, China
| | - Shuting Zhang
- Clinical School of the Second People's Hospital, Tianjin Medical University, Tianjin, China
| | - Lili Zhao
- Department of Hepatology, Tianjin Second People's Hospital, Tianjin, China
| | - Jindong Zhang
- Department of Gastroenterology, Peking University Third Hospital, Beijing, China
| | - Ping Han
- Clinical School of the Second People's Hospital, Tianjin Medical University, Tianjin, China
| | - Qian Zhang
- Clinical School of the Second People's Hospital, Tianjin Medical University, Tianjin, China
| | - Yao Liu
- Clinical School of the Second People's Hospital, Tianjin Medical University, Tianjin, China
| | - Fengmei Wang
- Department of Hepatology and Gastroenterology, Tianjin First Center Hospital, Tianjin, China
| | - Jia Li
- Department of Hepatology, Tianjin Second People's Hospital, Tianjin, China
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Toshida K, Itoh S, Iseda N, Tanaka S, Nakazono K, Tomiyama T, Yoshiya S, Toshima T, Harada N, Kohashi K, Taniguchi K, Oda Y, Yoshizumi T. The Impact of TP53-Induced Glycolysis and Apoptosis Regulator on Prognosis in Hepatocellular Carcinoma: Association with Tumor Microenvironment and Ferroptosis. Liver Cancer 2025; 14:36-57. [PMID: 40144470 PMCID: PMC11936447 DOI: 10.1159/000540180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Accepted: 06/28/2024] [Indexed: 03/28/2025] Open
Abstract
Introduction TP53-induced glycolysis and apoptosis regulator (TIGAR) is a p53 target protein that has critical roles in glycolysis and redox balance. The reports about the effect of TIGAR on prognosis and its biological role in hepatocellular carcinoma (HCC) are limited. Methods A total of 386 patients with HCC who had undergone hepatic resection were enrolled. Immunohistochemical staining for TIGAR was performed. Additionally, the regulation of malignant activity and ferroptosis by TIGAR was investigated in vitro. Results Patients were divided into TIGAR-positive (n = 80, 20.7%) and -negative (n = 306, 79.3%) groups. TIGAR positivity was significantly correlated with lower albumin, higher α-fetoprotein/ des-gamma-carboxyprothrombin, larger tumor size/number of tumors, and greater proportions of BCLC staging C/single nodular type/poor differentiation/microscopic vascular invasion/microscopic intrahepatic metastasis. In multivariate analysis, TIGAR positivity was an independent prognostic factor (p < 0.0001). In addition, TIGAR positivity was significantly associated with a smaller number of cluster of differentiation (CD) 8-positive T cells (p = 0.0450), larger number of CD68-positive macrophages (p = 0.0058), larger number of programmed death-ligand 1-positive cases (p = 0.0002), and larger number of vessels that encapsulate tumor cluster-positive cases (p = 0.0004). In vitro, TIGAR knockdown decreased cell motility and induced ferroptosis. TIGAR knockdown inhibited the phosphorylation of adenosine monophosphate-activated protein kinase and acetyl-CoA carboxylase. Ferroptosis induced by TIGAR knockdown was inhibited by liproxstatin and baicalein treatment. The combination of TIGAR knockdown and lenvatinib further induced ferroptosis. Conclusion High expression of TIGAR impacted the clinical outcome of HCC patients and TIGAR was associated not only with tumor microenvironment but also with resistance to ferroptosis.
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Affiliation(s)
- Katsuya Toshida
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shinji Itoh
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Norifumi Iseda
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shugo Tanaka
- Department of Integrative Pathology, Faculty of Medicine, Hokkaido University, Sapporo, Japan
| | - Kensuke Nakazono
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Department of Integrative Pathology, Faculty of Medicine, Hokkaido University, Sapporo, Japan
| | - Takahiro Tomiyama
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shohei Yoshiya
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takeo Toshima
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Noboru Harada
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kenichi Kohashi
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Koji Taniguchi
- Department of Integrative Pathology, Faculty of Medicine, Hokkaido University, Sapporo, Japan
| | - Yoshinao Oda
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tomoharu Yoshizumi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Bai S, Dai Y, Yang P, Lei Z, Liu F, Yang Z, Li F, Xia Y, Shen F, Wang K. Development models to predict complication and prognosis following liver resection for hepatocellular carcinoma in patients with clinically significant portal hypertension. Am J Surg 2025; 241:116172. [PMID: 39765145 DOI: 10.1016/j.amjsurg.2024.116172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2024] [Revised: 12/07/2024] [Accepted: 12/28/2024] [Indexed: 02/14/2025]
Abstract
BACKGROUND Postoperative complications are potential factors influencing the prognosis of patients with HCC combined with CSPH. This study aims to explore the risk factors affecting the occurrence of postoperative complications, investigate potential factors influencing long-term prognosis in these patients, and establish predictive models. METHODS From April 2018 to December 2021, a total of 190 patients with HCC combined with CSPH who underwent curative liver resection in our hospital were included, comprising 69 cases in the complication group and 121 cases in the non-complication group. LASSO-Logistic regression was employed to identify risk factors influencing postoperative complications and establish a predictive model. LASSO-Cox regression was used to determine prognostic factors for long-term outcomes in patients with HCC combined with CSPH and establish a predictive model. RESULTS LASSO regression selected variables including ALBI grade, preoperative ascites, major hepatectomy, and portal vein occlusion time >15 min. These variables were incorporated into logistic regression (P < 0.05) to establish a nomogram for predicting postoperative complications, with a C-index of 0.723. Results from the multivariable Cox regression analysis showed that postoperative complications, maximum tumor diameter, and microvascular invasion were risk factors for recurrence, while postoperative complications, maximum tumor diameter, microvascular invasion, and prealbumin were risk factors for overall survival. The C-index values for the respective nomograms were 0.635 and 0.734. The calibration curves and ROC curves demonstrated good performance for all three nomograms. CONCLUSIONS The three nomograms achieved optimal predictive performance for postoperative complications, recurrence, and overall survival in patients with HCC combined with CSPH undergoing curative resection.
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Affiliation(s)
- Shilei Bai
- Department of Hepatic Surgery II, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, PR China.
| | - Yizhe Dai
- Department of Hepatic Surgery IV, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, PR China.
| | - Pinghua Yang
- Department of Biliary Surgery IV, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, PR China.
| | - Zhengqing Lei
- Department of Hepatobiliary Surgery, Zhongda Hospital, Southeast University, School of Medicine, Nanjing, Jiangsu, PR China.
| | - Fuchen Liu
- Department of Hepatic Surgery III, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, PR China.
| | - Zhao Yang
- Department of Hepatic Surgery II, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, PR China.
| | - Fengwei Li
- Department of Hepatic Surgery II, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, PR China.
| | - Yong Xia
- Department of Hepatic Surgery IV, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, PR China.
| | - Feng Shen
- Department of Hepatic Surgery IV, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, PR China.
| | - Kui Wang
- Department of Hepatic Surgery II, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, PR China.
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Desterke C, Francés R, Monge C, Fu Y, Marchio A, Pineau P, Mata-Garrido J. Single-cell RNAseq reveals adverse metabolic transcriptional program in intrahepatic cholangiocarcinoma malignant cells. Biochem Biophys Rep 2025; 41:101949. [PMID: 40034261 PMCID: PMC11872667 DOI: 10.1016/j.bbrep.2025.101949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 01/21/2025] [Accepted: 02/06/2025] [Indexed: 03/05/2025] Open
Abstract
Intrahepatic cholangiocarcinoma (ICA) is a highly aggressive primary liver cancer, which originates from the epithelial cells of the bile ducts. The transcriptional profile of metabolic enzymes was investigated at both bulk and single-cell levels in tumor samples from distinct ICA cohorts. In a training cohort (TCGA consortium), 16 genes encoding for metabolic enzymes were found overexpressed in cases with poor survival. A computed metabolic gene expression score was significantly associated with worse ICA prognosis at the univariate level (overall survival [OS] log-rank p = 8.2e-4). After adjusting for Ishak fibrosis score and tumor staging, the metabolic expression remained an independent predictor of poor prognosis (multivariate OS log-rank p = 0.01). Seven genes encoding key enzymes (FH, MAT2B, PLOD2, PLOD1, PDE6D, ALDOC, and NT5DC3) were validated as markers of the proliferative subclass of ICA in the GSE32225 dataset, related to poor prognosis. The metabolic score was significantly different between the inflammatory and proliferative subclasses in the validation cohort (p < 2.2e-16). At the single-cell level, in the tumor microenvironment of 10 ICA patients, these seven enzymes were predominantly expressed by malignant cells. The single-cell metabolic score was thus higher in malignant cells. This study identifies a metabolic transcriptional program linked to poor prognosis in ICA, independent of fibrosis and tumor staging.
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Affiliation(s)
- Christophe Desterke
- Faculté de Médecine du Kremlin Bicêtre, Université Paris-Saclay, INSERM UMRS-1310, Le Kremlin-Bicêtre, France
| | - Raquel Francés
- Energy & Memory, Brain Plasticity Unit, CNRS, ESPCI Paris, PSL Research University, Paris, France
| | - Claudia Monge
- Institut Pasteur, Université Paris Cité, Unité Organisation Nucléaire et Oncogenèse, INSERM U993, Paris, France
| | - Yuanji Fu
- Université Paris Cité, INSERM, CNRS, Institut Necker Enfants Malades, F-75015, Paris, France
| | - Agnès Marchio
- Institut Pasteur, Université Paris Cité, Unité Organisation Nucléaire et Oncogenèse, INSERM U993, Paris, France
| | - Pascal Pineau
- Institut Pasteur, Université Paris Cité, Unité Organisation Nucléaire et Oncogenèse, INSERM U993, Paris, France
| | - Jorge Mata-Garrido
- Institut Pasteur, Université Paris Cité, Unité Organisation Nucléaire et Oncogenèse, INSERM U993, Paris, France
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Chen P, Li K, Chen J, Hei H, Geng J, Huang N, Lei M, Jia H, Ren J, Jin C. Enhanced effect of radiofrequency ablation on HCC by siRNA-PD-L1-endostatin Co-expression plasmid delivered. Transl Oncol 2025; 53:102319. [PMID: 39938403 PMCID: PMC11869540 DOI: 10.1016/j.tranon.2025.102319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 01/07/2025] [Accepted: 02/02/2025] [Indexed: 02/14/2025] Open
Abstract
Hepatocellular carcinoma (HCC) poses a significant clinical challenge due to high mortality and limited treatment options. Radiofrequency ablation (RFA) is commonly used but can be limited by tumor recurrence. This study explores the potential of combining RFA with an attenuated Salmonella strain carrying siRNA-PD-L1 and endostatin to enhance HCC treatment. In this study, an H22 subcutaneous tumor mouse model was used, with animals divided into five groups for treatment with a blank control, a blank Salmonella plasmid, RFA alone, siRNA-PD-L1-endostatin, or a combination of RFA and siRNA-PD-L1-endostatin. The combination therapy significantly reduced tumor growth, angiogenesis, and PD-L1/VEGF expression in tumor tissues post-RFA. Additionally, it induced tumor cell apoptosis, inhibited proliferation and migration, and increased the infiltration of T lymphocytes, granzyme B+T cells, and CD86+macrophages within tumors. There was also a notable rise in T and NK cell populations in the spleen. In conclusion, combining RFA with siRNA-PD-L1-endostatin delivered by attenuated Salmonella synergistically enhances anti-tumor effects, boosts the anti-tumor immune response, and improves RFA efficacy for HCC.
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Affiliation(s)
- Pengfei Chen
- Department of Radiology, the First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi 710061, PR China; Department of Interventional Radiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, PR China
| | - Kun Li
- Department of Interventional Radiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, PR China
| | - Jinwei Chen
- Department of Interventional Radiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, PR China
| | - He Hei
- Department of Radiology, the First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi 710061, PR China
| | - Jiaxin Geng
- Xinxiang Engineering Technology Research Center of immune checkpoint drug for Liver-Intestinal Tumors, Xinxiang Medical University, Xinxiang, Henan, PR China
| | - Nannan Huang
- Department of Orthopedics, Zhengyang county traditional Chinese medicine hospital, Zhumadian, Henan, PR China
| | - Mengyu Lei
- Xinxiang Engineering Technology Research Center of immune checkpoint drug for Liver-Intestinal Tumors, Xinxiang Medical University, Xinxiang, Henan, PR China
| | - Huijie Jia
- Xinxiang Engineering Technology Research Center of immune checkpoint drug for Liver-Intestinal Tumors, Xinxiang Medical University, Xinxiang, Henan, PR China
| | - Jianzhuang Ren
- Department of Interventional Radiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, PR China
| | - Chenwang Jin
- Department of Radiology, the First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi 710061, PR China; Shaanxi Engineering Research Center of Computational Imaging and Medical Intelligence, 277 West Yanta Road, Xi'an, Shaanxi 710061, PR China.
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Wu S, Weng J, Pan Y, Wen Z, Zeng J, Lou Y, Tong S, Liao P, Li N, Yu Z, Xia J. Disulfiram/Cu targeting FOXO6 modulates sensitivity of hepatocellular carcinoma to lenvatinib via disrupt choline metabolic. Cell Signal 2025; 127:111563. [PMID: 39694126 DOI: 10.1016/j.cellsig.2024.111563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Revised: 11/22/2024] [Accepted: 12/09/2024] [Indexed: 12/20/2024]
Abstract
Disulfiram/Cu(DSF/Cu) has a known pharmacokinetic and safety profile, exerting a strong antitumor effect. Oral tyrosine kinase inhibitors including lenvatinib are approved as first-line therapy for treating advanced unresectable hepatocellular carcinoma (HCC). These patients still have limited survival due to drug resistance. Disulfiram/Cu and lenvatinib are the promising antitumor treatments. In this study, we studied whether Disulfiram/Cu increased lenvatinib sensitivity in HCC cells. Moreover, the potential drug targets of Disulfiram/Cu and associated mechanisms were explored. We mainly investigated Autophagic flux was determined via immunofluorescence analysis and confocal microscopy. p-PI3K, p-AKT, p62, LC3B, FOXO6, and CHKA proteins associated with autophagy were detected by immunoblotting. In addition, antitumour activity of Disulfiram/Cu in combination with lenvatinib was examined in vivo through construction of the nude mouse transplant tumor model. Furthermore, our results show disulfiram/Cu combined with lenvatinib exerted the synergistic impact on treating HCC in vitro. Mechanistically, transcriptome combined with metabolome reveals Disulfiram/Cu targeting FOXO6 induction of autophagy mediated inhibits cell growth in hepatocellular carcinoma by downregulating CHKα for inhibiting AKT pathway activation while blocking choline metabolic reprogramming in HCC. These effects mostly explain the tumor-promoting effect of FOXO6 on HCC. In general, the results illustrate the mechanistic associations between metabolites and tumor cell malignant phenotype, contributing to developing new anti-HCC pharmacological treatments by Inhibiting FOXO6 for disrupting choline metabolic pathway.
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Affiliation(s)
- Shiyi Wu
- Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325035, China
| | - Jialu Weng
- Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325035, China
| | - Yating Pan
- Department of Respiratory Medicine, Yongkang First People's Hospital, Yongkang 321300, China
| | - Zhikai Wen
- Department of Liver and Gall Surgery, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou 325200, China
| | - Jing Zeng
- Department of Otorhinolaryngology, Hanshou County Hospital of Traditional Chinese Medicine, Changdei 415900, China
| | - Yunwei Lou
- Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325035, China
| | - Songjian Tong
- Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325035, China
| | - Pan Liao
- The School of Medicine, Nankai University 94 Weijin Road, Tianjin 300071, China
| | - Na Li
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang, 325001, China
| | - Zhijie Yu
- Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325035, China.
| | - Jinglin Xia
- Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325035, China; Liver Cancer Institute, Zhongshan Hospital of Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China.
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Yang L, Yi Y, Mei Z, Huang D, Tang S, Hu L, Liu L. Circular RNAs in cancer stem cells: Insights into their roles and mechanisms (Review). Int J Mol Med 2025; 55:50. [PMID: 39930823 PMCID: PMC11781527 DOI: 10.3892/ijmm.2025.5491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Accepted: 01/03/2025] [Indexed: 02/14/2025] Open
Abstract
Cancer stem cells (CSCs) represent a small, yet pivotal subpopulation of tumor cells that play significant roles in tumor initiation, progression and therapeutic resistance. Circular RNAs (circRNAs) are a distinct class of RNAs characterized by their closed‑loop structures, lacking 5' to 3'ends. There is growing evidence that circRNAs are integral to the development and regulation of CSCs. Aberrant expression of circRNAs in CSCs can contribute to oncogenic properties and drug resistance. Specifically, oncogenic circRNAs modulate CSC behavior via key signaling pathways, thereby promoting CSC self‑renewal and maintenance, as well as tumor progression. This review summarizes the latest research on the functional roles and regulatory mechanisms of circRNAs in CSC behavior and discusses potential applications and challenges of targeting circRNAs in CSCs. Understanding the intricate interactions between circRNAs and CSCs may lead to novel therapeutic strategies that effectively combat treatment resistance and improve patient outcomes.
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Affiliation(s)
- Lunyu Yang
- Department of Medical Laboratory, Chongqing Liangjiang New Area People's Hospital, Chongqing 401121, P.R. China
| | - Yuling Yi
- Department of Medical Laboratory, Chongqing Liangjiang New Area People's Hospital, Chongqing 401121, P.R. China
| | - Zhu Mei
- Department of Medical Laboratory, Chongqing Liangjiang New Area People's Hospital, Chongqing 401121, P.R. China
| | - Dongmei Huang
- Department of Medical Laboratory, Chongqing Liangjiang New Area People's Hospital, Chongqing 401121, P.R. China
| | - Sitian Tang
- Department of Medical Laboratory, Chongqing Liangjiang New Area People's Hospital, Chongqing 401121, P.R. China
| | - Liyi Hu
- Department of Medical Laboratory, Chongqing Liangjiang New Area People's Hospital, Chongqing 401121, P.R. China
| | - Ling Liu
- Department of Medical Laboratory, Chongqing Liangjiang New Area People's Hospital, Chongqing 401121, P.R. China
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