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Zhang X, Zhang X, Luo QK, Fu Q, Liu P, Pan CJ, Liu CJ, Zhang HW, Qin T. Pretreatment radiomic imaging features combined with immunological indicators to predict targeted combination immunotherapy response in advanced hepatocellular carcinoma. World J Clin Oncol 2025; 16:102735. [DOI: 10.5306/wjco.v16.i4.102735] [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: 10/27/2024] [Revised: 12/16/2024] [Accepted: 01/23/2025] [Indexed: 03/26/2025] Open
Abstract
BACKGROUND Early symptoms of hepatocellular carcinoma (HCC) are not obvious, and more than 70% of which does not receive radical hepatectomy, when first diagnosed. In recent years, molecular-targeted drugs combined with immunotherapy and other therapeutic methods have provided new treatment options for middle and advanced HCC (aHCC). Predicting the effect of targeted combined immunotherapy has become a hot topic in current research.
AIM To explore the relationship between nodule enhancement in hepatobiliary phase and the efficacy of combined targeted immunotherapy for aHCC.
METHODS Data from 56 patients with aHCC for magnetic resonance imaging with gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid were retrospectively collected. Signal intensity of intrahepatic nodules was measured, and the hepatobiliary relative enhancement ratio (RER) was calculated. Progression-free survival (PFS) of patients with high and low reinforcement of HCC nodules was compared. The model was validated using receiver operating characteristic curves. Univariate and multivariate logistic regression and Kaplan-Meier analysis were performed to explore factors influencing the efficacy of targeted immunization and PFS.
RESULTS Univariate and multivariate analyses revealed that the RER, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and prognostic nutritional index were significantly associated with the efficacy of tyrosine kinase inhibitors combined with immunotherapy (P < 0.05). The area under the curve of the RER for predicting the efficacy of tyrosine kinase inhibitors combined with anti-programmed death 1 antibody in patients with aHCC was 0.876 (95% confidence interval: 0.781-0.971, P < 0.05), the optimal cutoff value was 0.904, diagnostic sensitivity was 87.5%, and specificity was 79.2%. Kaplan-Meier analysis showed that neutrophil-to-lymphocyte ratio < 5, platelet-to-lymphocyte ratio < 300, prognostic nutritional index < 45, and RER < 0.9 significantly improved PFS.
CONCLUSION AHCC nodules enhancement in the hepatobiliary stage was significantly correlated with PFS. Imaging information and immunological indicators had high predictive efficacy for targeted combined immunotherapy and were associated with PFS.
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Affiliation(s)
- Xu Zhang
- Department of Hepato-Biliary-Pancreatic Surgery, Zhengzhou University People’s Hospital & Henan Provincial People’s Hospital, Zhengzhou 450003, Henan Province, China
| | - Xu Zhang
- Department of Hepato-Biliary-Pancreatic Surgery, Zhengzhou University People’s Hospital & Henan Provincial People’s Hospital, Zhengzhou 450003, Henan Province, China
| | - Qian-Kun Luo
- Department of Hepato-Biliary-Pancreatic Surgery, Zhengzhou University People’s Hospital & Henan Provincial People’s Hospital, Zhengzhou 450003, Henan Province, China
| | - Qiang Fu
- Department of Hepato-Biliary-Pancreatic Surgery, Zhengzhou University People’s Hospital & Henan Provincial People’s Hospital, Zhengzhou 450003, Henan Province, China
| | - Pan Liu
- Department of Hepato-Biliary-Pancreatic Surgery, Zhengzhou University People’s Hospital & Henan Provincial People’s Hospital, Zhengzhou 450003, Henan Province, China
| | - Chang-Jie Pan
- Department of Hepato-Biliary-Pancreatic Surgery, Zhengzhou University People’s Hospital & Henan Provincial People’s Hospital, Zhengzhou 450003, Henan Province, China
| | - Chuan-Jiang Liu
- Department of Hepato-Biliary-Pancreatic Surgery, Zhengzhou University People’s Hospital & Henan Provincial People’s Hospital, Zhengzhou 450003, Henan Province, China
| | - Hong-Wei Zhang
- Department of Hepato-Biliary-Pancreatic Surgery, Zhengzhou University People’s Hospital & Henan Provincial People’s Hospital, Zhengzhou 450003, Henan Province, China
| | - Tao Qin
- Department of Hepato-Biliary-Pancreatic Surgery, Zhengzhou University People’s Hospital & Henan Provincial People’s Hospital, Zhengzhou 450003, Henan Province, China
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Wei H, Peng J. Integrated Analysis of Bulk and Single-Cell RNA Sequencing Data Reveal a Novel Prognostic Signature of Combining Cuproptosis- and Ferroptosis-Related Genes in Hepatocellular Carcinoma. Int J Mol Sci 2025; 26:2779. [PMID: 40141422 PMCID: PMC11943219 DOI: 10.3390/ijms26062779] [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: 01/13/2025] [Revised: 03/04/2025] [Accepted: 03/07/2025] [Indexed: 03/28/2025] Open
Abstract
As a common malignancy, hepatocellular carcinoma (HCC) proliferation and metastasis could be promoted by ferroptosis and cuproptosis. In this study, we screened out the differentially expressed cuproptosis- and ferroptosis-related genes (CFRGs) and identified the 17 informative prognosis-associated genes. A CFRG scoring model was constructed based on the subtypes identified by consensus clustering analysis and principal component analysis (PCA). Furthermore, the immune profile, expression of immune checkpoint genes (ICGs) and drug susceptibility were also compared between the two CFRG score groups. The results showed that patients with a high CFRG score had higher survival probabilities. The correlation analysis suggested that CFRG scores were negatively correlated with activated CD4.T.cell. The expression patterns of thirty ICGs and the half-maximal inhibitory concentration (IC50) values of 128 drugs displayed significant differences between the two CFRG score groups. A statistically significant difference in the efficacy of sorafenib was found between the two CFRG score groups. Moreover, based on multivariate COX regression analysis and weighted gene co-expression network analysis (WGCNA), we screened DLAT and SLC2A1 as signature genes. Molecular docking analysis revealed that DLAT and SLC2A1 had a strong binding affinity toward camptothecin, rapamycin, dactolisib, and luminespib. The correlation between the CFRG score and single-cell characteristics was further explored. The study depended on our understanding of the biological function of CFRGs in HCC and provided new insights for developing treatment strategies.
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Affiliation(s)
- Hua Wei
- School of Resources and Environmental Science and Engineering, Hubei University of Science and Technology, Xianning 437100, China
- Research Center of Beidou, Industrial Development of Key Research Institute of Humanities and Social Sciences of Hubei Province, Hubei University of Science and Technology, Xianning 437100, China
| | - Jiaxin Peng
- School of Computer Science, National Unversity of Defense Technology, Changsha 410073, China;
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Fu YC, Liang SB, Luo M, Wang XP. Intratumoral heterogeneity and drug resistance in cancer. Cancer Cell Int 2025; 25:103. [PMID: 40102941 PMCID: PMC11917089 DOI: 10.1186/s12935-025-03734-w] [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: 05/22/2024] [Accepted: 03/06/2025] [Indexed: 03/20/2025] Open
Abstract
Intratumoral heterogeneity is the main cause of tumor treatment failure, varying across disease sites (spatial heterogeneity) and polyclonal properties of tumors that evolve over time (temporal heterogeneity). As our understanding of intratumoral heterogeneity, the formation of which is mainly related to the genomic instability, epigenetic modifications, plastic gene expression, and different microenvironments, plays a substantial role in drug-resistant as far as tumor metastasis and recurrence. Understanding the role of intratumoral heterogeneity, it becomes clear that a single therapeutic agent or regimen may only be effective for subsets of cells with certain features, but not for others. This necessitates a shift from our current, unchanging treatment approach to one that is tailored against the killing patterns of cancer cells in different clones. In this review, we discuss recent evidence concerning global perturbations of intratumoral heterogeneity, associations of specific intratumoral heterogeneity in lung cancer, the underlying mechanisms of intratumoral heterogeneity potentially leading to formation, and how it drives drug resistance. Our findings highlight the most up-to-date progress in intratumoral heterogeneity and its role in mediating tumor drug resistance, which could support the development of future treatment strategies.
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Affiliation(s)
- Yue-Chun Fu
- Department of Clinical Laboratory, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Shao-Bo Liang
- Department of Radiation Oncology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Min Luo
- Department of Clinical Laboratory, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, China.
| | - Xue-Ping Wang
- Department of Clinical Laboratory, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, China.
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Liu B, Xie Y, Zhang Y, Tang G, Lin J, Yuan Z, Liu X, Wang X, Huang M, Luo Y, Yu H. Spatial deconvolution from bulk DNA methylation profiles determines intratumoral epigenetic heterogeneity. Cell Biosci 2025; 15:7. [PMID: 39844296 PMCID: PMC11756021 DOI: 10.1186/s13578-024-01337-y] [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: 09/30/2024] [Accepted: 12/09/2024] [Indexed: 01/24/2025] Open
Abstract
BACKGROUND Intratumoral heterogeneity emerges from accumulating genetic and epigenetic changes during tumorigenesis, which may contribute to therapeutic failure and drug resistance. However, the lack of a quick and convenient approach to determine the intratumoral epigenetic heterogeneity (eITH) limit the application of eITH in clinical settings. Here, we aimed to develop a tool that can evaluate the eITH using the DNA methylation profiles from bulk tumors. METHODS Genomic DNA of three laser micro-dissected tumor regions, including digestive tract surface, central bulk, and invasive front, was extracted from formalin-fixed paraffin-embedded sections of colorectal cancer patients. The genome-wide methylation profiles were generated with methylation array. The most variable methylated probes were selected to construct a DNA methylation-based heterogeneity (MeHEG) estimation tool that can deconvolve the proportion of each reference tumor region with the support vector machine model-based method. A PCR-based assay for quantitative analysis of DNA methylation (QASM) was developed to specifically determine the methylation status of each CpG in MeHEG assay at single-base resolution to realize fast evaluation of epigenetic heterogeneity. RESULTS In the discovery set with 79 patients, the differentially methylated CpGs among the three tumor regions were found. The 7 most representative CpGs were identified and subsequently selected to develop the MeHEG algorithm. We validated its performance of deconvolution of tumor regions in an independent cohort. In addition, we showed the significant association of MeHEG-based epigenetic heterogeneity with the genomic heterogeneity in mutation and copy number variation in our in-house and TCGA cohorts. Besides, we found that the patients with higher MeHEG score had worse disease-free and overall survival outcomes. Finally, we found dynamic change of epigenetic heterogeneity based on MeHEG score in cancer cells under the treatment of therapeutic drugs. CONCLUSION By developing a 7-loci panel using a machine learning approach combined with the QASM assay for PCR-based application, we present a valuable method for evaluating intratumoral heterogeneity. The MeHEG algorithm offers novel insights into tumor heterogeneity from an epigenetic perspective, potentially enriching current knowledge of tumor complexity and providing a new tool for clinical and research applications in cancer biology.
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Affiliation(s)
- Binbin Liu
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, Guangdong, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Erheng Road, Guangzhou, 510655, Guangdong, China
- Guangdong Institute of Gastroenterology, Guangzhou, 510655, Guangdong, China
| | - Yumo Xie
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, Guangdong, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Erheng Road, Guangzhou, 510655, Guangdong, China
- Guangdong Institute of Gastroenterology, Guangzhou, 510655, Guangdong, China
| | - Yu Zhang
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Erheng Road, Guangzhou, 510655, Guangdong, China
- Guangdong Institute of Gastroenterology, Guangzhou, 510655, Guangdong, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, Guangdong, China
| | - Guannan Tang
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Erheng Road, Guangzhou, 510655, Guangdong, China
- Guangdong Institute of Gastroenterology, Guangzhou, 510655, Guangdong, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, Guangdong, China
| | - Jinxin Lin
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, Guangdong, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Erheng Road, Guangzhou, 510655, Guangdong, China
- Guangdong Institute of Gastroenterology, Guangzhou, 510655, Guangdong, China
| | - Ze Yuan
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Erheng Road, Guangzhou, 510655, Guangdong, China
- Guangdong Institute of Gastroenterology, Guangzhou, 510655, Guangdong, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, Guangdong, China
| | - Xiaoxia Liu
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Erheng Road, Guangzhou, 510655, Guangdong, China
- Guangdong Institute of Gastroenterology, Guangzhou, 510655, Guangdong, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, Guangdong, China
- Ministry of Education, Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-sen University), Guangzhou, Guangdong, China
- Innovation Center of the Sixth Affiliated Hospital, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xiaolin Wang
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Erheng Road, Guangzhou, 510655, Guangdong, China
- Guangdong Institute of Gastroenterology, Guangzhou, 510655, Guangdong, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, Guangdong, China
- Ministry of Education, Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-sen University), Guangzhou, Guangdong, China
- Innovation Center of the Sixth Affiliated Hospital, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Meijin Huang
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, Guangdong, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Erheng Road, Guangzhou, 510655, Guangdong, China
- Guangdong Institute of Gastroenterology, Guangzhou, 510655, Guangdong, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, Guangdong, China
- Ministry of Education, Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-sen University), Guangzhou, Guangdong, China
- Innovation Center of the Sixth Affiliated Hospital, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yanxin Luo
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, Guangdong, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Erheng Road, Guangzhou, 510655, Guangdong, China
- Guangdong Institute of Gastroenterology, Guangzhou, 510655, Guangdong, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, Guangdong, China
- Ministry of Education, Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-sen University), Guangzhou, Guangdong, China
- Innovation Center of the Sixth Affiliated Hospital, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Huichuan Yu
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Erheng Road, Guangzhou, 510655, Guangdong, China.
- Guangdong Institute of Gastroenterology, Guangzhou, 510655, Guangdong, China.
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, Guangdong, China.
- Ministry of Education, Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-sen University), Guangzhou, Guangdong, China.
- Innovation Center of the Sixth Affiliated Hospital, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China.
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Yin Y, Zhang W, Chen Y, Zhang Y, Shen X. Radiomics predicting immunohistochemical markers in primary hepatic carcinoma: Current status and challenges. Heliyon 2024; 10:e40588. [PMID: 39660185 PMCID: PMC11629216 DOI: 10.1016/j.heliyon.2024.e40588] [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: 02/21/2024] [Revised: 09/28/2024] [Accepted: 11/19/2024] [Indexed: 12/12/2024] Open
Abstract
Primary hepatic carcinoma, comprising hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), and combined hepatocellular cholangiocarcinoma (cHCC-CCA), ranks among the most common malignancies worldwide. The heterogeneity of tumors is a primary factor impeding the efficacy of treatments for primary hepatic carcinoma. Immunohistochemical markers may play a potential role in characterizing this heterogeneity, providing significant guidance for prognostic analysis and the development of personalized treatment plans for the patients with primary hepatic carcinoma. Currently, primary hepatic carcinoma immunohistochemical analysis primarily relies on invasive techniques such as surgical pathology and tissue biopsy. Consequently, the non-invasive preoperative acquisition of primary hepatic carcinoma immunohistochemistry has emerged as a focal point of research. As an emerging non-invasive diagnostic technique, radiomics possesses the potential to extensively characterize tumor heterogeneity. It can predict immunohistochemical markers associated with hepatocellular carcinoma preoperatively, demonstrating significant auxiliary utility in clinical guidance. This article summarizes the progress in using radiomics to predict immunohistochemical markers in primary hepatic carcinoma, addresses the challenges faced in this field of study, and anticipates its future application prospects.
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Affiliation(s)
- Yunqing Yin
- The Second Clinical Medical College, Jinan University, China
| | - Wei Zhang
- Department of Intervention, Shenzhen People's Hospital, Shenzhen, 518020, Guangdong, China
| | - Yanhui Chen
- Department of Intervention, Shenzhen Bao'an People's Hospital, Shenzhen, 518100, Guangdong, China
| | - Yanfang Zhang
- Department of Intervention, Shenzhen People's Hospital, Shenzhen, 518020, Guangdong, China
| | - Xinying Shen
- Department of Intervention, Shenzhen People's Hospital, Shenzhen, 518020, Guangdong, China
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Li J, Fu Y, Zhang H, Ma H. Molecular and pathological landscape of the AT-rich interaction domain 1A (ARID1A) mutation in hepatocellular carcinoma. Pathol Res Pract 2024; 266:155763. [PMID: 39706068 DOI: 10.1016/j.prp.2024.155763] [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: 07/27/2024] [Revised: 11/17/2024] [Accepted: 12/08/2024] [Indexed: 12/23/2024]
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, with complex etiological factors and a diverse genetic landscape. Among the critical genetic mutations in HCC, the AT-rich interaction domain 1 A (ARID1A) gene, a key component of the SWI/SNF chromatin remodeling complex, stands out due to its significant role in both tumor suppression and oncogenesis. This review comprehensively examines the molecular and pathological impacts of ARID1A mutations in HCC. ARID1A mutations, which occur in approximately 7.9 % of HCC cases, predominantly involve truncating mutations leading to loss of function. These mutations are associated with various aggressive cancer features, including larger tumor size, higher rates of metastasis, and poor prognosis. The dual role of ARID1A in HCC is context-dependent, acting as a tumor suppressor by regulating cell cycle control, DNA damage repair, and gene expression, while also displaying oncogenic properties in specific contexts by promoting early tumorigenesis through oxidative stress pathways. Understanding the molecular mechanisms of ARID1A, including its interactions with key cellular pathways such as PI3K/AKT/mTOR, β-catenin, and PD-L1, provides insights into its complex role in HCC pathogenesis. Furthermore, ARID1A's impact on cancer stem cell maintenance, metabolic reprogramming, and immune evasion underscores its potential as a therapeutic target. This review highlights the need for context-specific therapeutic strategies targeting ARID1A, which could lead to more effective treatments for HCC, addressing both its tumor-suppressive and oncogenic activities.
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Affiliation(s)
- Junfeng Li
- Department of Oncology, Dianjiang People's Hospital of Chongqing, Chongqing, China.
| | - Yuxia Fu
- Department of Ultrasound, Dianjiang People's Hospital of Chongqing, Chongqing, China
| | - Hongchuan Zhang
- Department of Oncology, Dianjiang People's Hospital of Chongqing, Chongqing, China
| | - Hong Ma
- Department of Oncology, Dianjiang People's Hospital of Chongqing, Chongqing, China
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Ma S, Pan X, Gan J, Guo X, He J, Hu H, Wang Y, Ning S, Zhi H. DNA methylation heterogeneity attributable to a complex tumor immune microenvironment prompts prognostic risk in glioma. Epigenetics 2024; 19:2318506. [PMID: 38439715 PMCID: PMC10936651 DOI: 10.1080/15592294.2024.2318506] [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: 07/26/2023] [Accepted: 02/07/2024] [Indexed: 03/06/2024] Open
Abstract
Gliomas are malignant tumours of the human nervous system with different World Health Organization (WHO) classifications, glioblastoma (GBM) with higher grade and are more malignant than lower-grade glioma (LGG). To dissect how the DNA methylation heterogeneity in gliomas is influenced by the complex cellular composition of the tumour immune microenvironment, we first compared the DNA methylation profiles of purified human immune cells and bulk glioma tissue, stratifying three tumour immune microenvironmental subtypes for GBM and LGG samples from The Cancer Genome Atlas (TCGA). We found that more intermediate methylation sites were enriched in glioma tumour tissues, and used the Proportion of sites with Intermediate Methylation (PIM) to compare intertumoral DNA methylation heterogeneity. A larger PIM score reflected stronger DNA methylation heterogeneity. Enhanced DNA methylation heterogeneity was associated with stronger immune cell infiltration, better survival rates, and slower tumour progression in glioma patients. We then created a Cell-type-associated DNA Methylation Heterogeneity Contribution (CMHC) score to explore the impact of different immune cell types on heterogeneous CpG site (CpGct) in glioma tissues. We identified eight prognosis-related CpGct to construct a risk score: the Cell-type-associated DNA Methylation Heterogeneity Risk (CMHR) score. CMHR was positively correlated with cytotoxic T-lymphocyte infiltration (CTL), and showed better predictive performance for IDH status (AUC = 0.96) and glioma histological phenotype (AUC = 0.81). Furthermore, DNA methylation alterations of eight CpGct might be related to drug treatments of gliomas. In conclusion, we indicated that DNA methylation heterogeneity is associated with a complex tumour immune microenvironment, glioma phenotype, and patient's prognosis.
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Affiliation(s)
- Shuangyue Ma
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
- Liangzhu Laboratory, Zhejiang University, Hangzhou, China
| | - Xu Pan
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Jing Gan
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Xiaxin Guo
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Jiaheng He
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Haoyu Hu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Yuncong Wang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Shangwei Ning
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Hui Zhi
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
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Chen J, Kaya NA, Zhang Y, Kendarsari RI, Sekar K, Lee Chong S, Seshachalam VP, Ling WH, Jin Phua CZ, Lai H, Yang H, Lu B, Lim JQ, Ma S, Chew SC, Chua KP, Santiago Alvarez JJ, Wu L, Ooi L, Yaw-Fui Chung A, Cheow PC, Kam JH, Wei-Chieh Kow A, Ganpathi IS, Bunchaliew C, Thammasiri J, Koh PS, Bee-Lan Ong D, Lim J, de Villa VH, Dela Cruz RD, Loh TJ, Wan WK, Leow WQ, Yang Y, Liu J, Skanderup AJ, Pang YH, Ting Soon GS, Madhavan K, Kiat-Hon Lim T, Bonney G, Goh BKP, Chew V, Dan YY, Toh HC, Sik-Yin Foo R, Tam WL, Zhai W, Kah-Hoe Chow P. A multimodal atlas of hepatocellular carcinoma reveals convergent evolutionary paths and 'bad apple' effect on clinical trajectory. J Hepatol 2024; 81:667-678. [PMID: 38782118 DOI: 10.1016/j.jhep.2024.05.017] [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: 04/23/2023] [Revised: 05/06/2024] [Accepted: 05/14/2024] [Indexed: 05/25/2024]
Abstract
BACKGROUND & AIMS Hepatocellular carcinoma (HCC) is a highly fatal cancer characterized by high intra-tumor heterogeneity (ITH). A panoramic understanding of its tumor evolution, in relation to its clinical trajectory, may provide novel prognostic and treatment strategies. METHODS Through the Asia-Pacific Hepatocellular Carcinoma trials group (NCT03267641), we recruited one of the largest prospective cohorts of patients with HCC, with over 600 whole genome and transcriptome samples from 123 treatment-naïve patients. RESULTS Using a multi-region sampling approach, we revealed seven convergent genetic evolutionary paths governed by the early driver mutations, late copy number variations and viral integrations, which stratify patient clinical trajectories after surgical resection. Furthermore, such evolutionary paths shaped the molecular profiles, leading to distinct transcriptomic subtypes. Most significantly, although we found the coexistence of multiple transcriptomic subtypes within certain tumors, patient prognosis was best predicted by the most aggressive cell fraction of the tumor, rather than by overall degree of transcriptomic ITH level - a phenomenon we termed the 'bad apple' effect. Finally, we found that characteristics throughout early and late tumor evolution provide significant and complementary prognostic power in predicting patient survival. CONCLUSIONS Taken together, our study generated a comprehensive landscape of evolutionary history for HCC and provides a rich multi-omics resource for understanding tumor heterogeneity and clinical trajectories. IMPACT AND IMPLICATIONS This prospective study, utilizing comprehensive multi-sector, multi-omics sequencing and clinical data from surgically resected hepatocellular carcinoma (HCC), reveals critical insights into the role of tumor evolution and intra-tumor heterogeneity (ITH) in determining the prognosis of HCC. These findings are invaluable for oncology researchers and clinicians, as they underscore the influence of distinct evolutionary paths and the 'bad apple' effect, where the most aggressive tumor fraction dictates disease progression. These insights not only enhance prognostic accuracy post-surgical resection but also pave the way for personalized treatment strategies tailored to specific tumor evolutionary and transcriptomic profiles. The coexistence of multiple subtypes within the same tumor prompts a re-appraisal of the utilities of depending on single samples to represent the entire tumor and suggests the need for clinical molecular imaging. This research thus marks a significant step forward in the clinical understanding and management of HCC, underscoring the importance of integrating tumor evolutionary dynamics and multi-omics biomarkers into therapeutic decision-making. CLINICAL TRIAL NUMBER NCT03267641 (Observational cohort).
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Affiliation(s)
- Jianbin Chen
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Genome, Singapore 138672, Republic of Singapore.
| | - Neslihan Arife Kaya
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Genome, Singapore 138672, Republic of Singapore; School of Biological Sciences, Nanyang Technological University, Singapore 637551, Republic of Singapore
| | - Ying Zhang
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Genome, Singapore 138672, Republic of Singapore
| | - Raden Indah Kendarsari
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Genome, Singapore 138672, Republic of Singapore
| | - Karthik Sekar
- Program in Clinical and Translational Liver Cancer Research, Division of Medical Science, National Cancer Center Singapore, Republic of Singapore
| | - Shay Lee Chong
- Program in Clinical and Translational Liver Cancer Research, Division of Medical Science, National Cancer Center Singapore, Republic of Singapore
| | - Veerabrahma Pratap Seshachalam
- Program in Clinical and Translational Liver Cancer Research, Division of Medical Science, National Cancer Center Singapore, Republic of Singapore
| | - Wen Huan Ling
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Genome, Singapore 138672, Republic of Singapore; Program in Clinical and Translational Liver Cancer Research, Division of Medical Science, National Cancer Center Singapore, Republic of Singapore
| | - Cheryl Zi Jin Phua
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Genome, Singapore 138672, Republic of Singapore
| | - Hannah Lai
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Genome, Singapore 138672, Republic of Singapore
| | - Hechuan Yang
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Genome, Singapore 138672, Republic of Singapore; Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing, P.R. China
| | - Bingxin Lu
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Genome, Singapore 138672, Republic of Singapore; Cell & Developmental Biology, Division of Biosciences, Faculty of Life Sciences, Bloomsbury, London WC1E 6AP, UK
| | - Jia Qi Lim
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Genome, Singapore 138672, Republic of Singapore
| | - Siming Ma
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Genome, Singapore 138672, Republic of Singapore
| | - Sin Chi Chew
- Program in Clinical and Translational Liver Cancer Research, Division of Medical Science, National Cancer Center Singapore, Republic of Singapore
| | - Khi Pin Chua
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Genome, Singapore 138672, Republic of Singapore
| | - Jacob Josiah Santiago Alvarez
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Genome, Singapore 138672, Republic of Singapore
| | - Lingyan Wu
- Program in Clinical and Translational Liver Cancer Research, Division of Medical Science, National Cancer Center Singapore, Republic of Singapore
| | - London Ooi
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital and National Cancer Centre Singapore, Republic of Singapore
| | - Alexander Yaw-Fui Chung
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital and National Cancer Centre Singapore, Republic of Singapore
| | - Peng Chung Cheow
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital and National Cancer Centre Singapore, Republic of Singapore
| | - Juinn Huar Kam
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital and National Cancer Centre Singapore, Republic of Singapore
| | - Alfred Wei-Chieh Kow
- Division of Hepatobiliary & Pancreatic Surgery, Department of Surgery, University Surgical Cluster, National University Health System, Singapore 119228, Republic of Singapore
| | - Iyer Shridhar Ganpathi
- Division of Hepatobiliary & Pancreatic Surgery, Department of Surgery, University Surgical Cluster, National University Health System, Singapore 119228, Republic of Singapore
| | - Chairat Bunchaliew
- Hepato-Pancreato-Biliary Surgery Unit, Department of Surgery, National Cancer Institute, Bangkok, Thailand
| | | | - Peng Soon Koh
- Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Diana Bee-Lan Ong
- Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Jasmine Lim
- Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Vanessa H de Villa
- Department of Surgery and Center for Liver Disease Management and Transplantation, The Medical City, Pasig City, Metro Manila, Philippines
| | | | - Tracy Jiezhen Loh
- Department of Pathology, Singapore General Hospital, Singapore 169608, Republic of Singapore
| | - Wei Keat Wan
- Department of Pathology, Singapore General Hospital, Singapore 169608, Republic of Singapore
| | - Wei Qiang Leow
- Department of Pathology, Singapore General Hospital, Singapore 169608, Republic of Singapore
| | - Yi Yang
- School of Data Science, The Chinese University of Hong Kong-Shenzhen, Shenzhen 518172, China
| | - Jin Liu
- School of Data Science, The Chinese University of Hong Kong-Shenzhen, Shenzhen 518172, China
| | - Anders Jacobsen Skanderup
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Genome, Singapore 138672, Republic of Singapore
| | - Yin Huei Pang
- Department of Pathology, National University Health System, Singapore 119074, Republic of Singapore
| | - Gwyneth Shook Ting Soon
- Department of Pathology, National University Health System, Singapore 119074, Republic of Singapore
| | - Krishnakumar Madhavan
- Division of Hepatobiliary & Pancreatic Surgery, Department of Surgery, University Surgical Cluster, National University Health System, Singapore 119228, Republic of Singapore
| | - Tony Kiat-Hon Lim
- Department of Pathology, Singapore General Hospital, Singapore 169608, Republic of Singapore
| | - Glenn Bonney
- Division of Hepatobiliary & Pancreatic Surgery, Department of Surgery, University Surgical Cluster, National University Health System, Singapore 119228, Republic of Singapore
| | - Brian K P Goh
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital and National Cancer Centre Singapore, Republic of Singapore
| | - Valerie Chew
- Translational Immunology Institute (TII), SingHealth Duke-NUS Academic Medical Centre, Singapore, Republic of Singapore
| | - Yock Young Dan
- Division of Gastroenterology and Hepatology, University Medicine Cluster, National University Hospital, Singapore, Republic of Singapore
| | - Han Chong Toh
- Division of Medical Oncology, National Cancer Center Singapore, 169610 Singapore, Republic of Singapore
| | - Roger Sik-Yin Foo
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Genome, Singapore 138672, Republic of Singapore; Cardiovascular Research Institute, National University of Singapore, National University Healthcare System, Singapore 119228, Republic of Singapore
| | - Wai Leong Tam
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Genome, Singapore 138672, Republic of Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, Singapore 117597, Republic of Singapore; Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore 117599, Republic of Singapore; NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University Singapore, 14 Medical Drive, Singapore 117599, Republic of Singapore.
| | - Weiwei Zhai
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Genome, Singapore 138672, Republic of Singapore; Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing, P.R. China; Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming 650223, P.R. China.
| | - Pierce Kah-Hoe Chow
- Program in Clinical and Translational Liver Cancer Research, Division of Medical Science, National Cancer Center Singapore, Republic of Singapore; Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital and National Cancer Centre Singapore, Republic of Singapore; SingHealth-Duke-NUS Academic Surgery Program, Duke-NUS Graduate Medical School, Singapore 169857, Republic of Singapore.
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9
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Zajanckauskaite A, Lingelbach M, Juozapaitė D, Utkus A, Rukšnaitytė G, Jonuškienė G, Gulla A. Utilization of Microfluidic Droplet-Based Methods in Diagnosis and Treatment Methods of Hepatocellular Carcinoma: A Review. Genes (Basel) 2024; 15:1242. [PMID: 39457366 PMCID: PMC11508129 DOI: 10.3390/genes15101242] [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: 04/16/2024] [Revised: 08/20/2024] [Accepted: 09/13/2024] [Indexed: 10/28/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and is associated with high morbidity and mortality. One of the main challenges in the management of HCC is late clinical presentation and thus diagnosis of the disease, which results in poor survival. The pathogenesis of HCC is complex and involves chronic liver injury and genetic alterations. Diagnosis of HCC can be made either by biopsy or imaging; however, conventional tissue-based biopsy methods and serological biomarkers such as AFP have limited clinical applications. While hepatocellular carcinoma is associated with a range of molecular alterations, including the activation of oncogenic signaling pathways, such as Wnt-TGFβ, PI3K-AKT-mTOR, RAS-MAPK, MET, IGF, and Wnt-β-catenin and TP53 and TERT promoter mutations, microfluidic applications have been limited. Early diagnosis is crucial for advancing treatments that would address the heterogeneity of HCC. In this context, microfluidic droplet-based methods are crucial, as they enable comprehensive analysis of the genome and transcriptome of individual cells. Single-cell RNA sequencing (scRNA-seq) allows the examination of individual cell transcriptomes, identifying their heterogeneity and cellular evolutionary relationships. Other microfluidic methods, such as Drop-seq, InDrop, and ATAC-seq, are also employed for single-cell analysis. Here, we examine and compare these microfluidic droplet-based methods, exploring their advantages and limitations in liver cancer research. These technologies provide new opportunities to understand liver cancer biology, diagnosis, treatment, and prognosis, contributing to scientific efforts in combating this challenging disease.
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Affiliation(s)
- Akvilė Zajanckauskaite
- Department of Human and Medical Genetics, Faculty of Medicine, Vilnius University, 01513 Vilnius, Lithuania
| | - Miah Lingelbach
- School of Osteopathic Medicine, A.T. Still University, Mesa, AZ 85206, USA;
| | - Dovilė Juozapaitė
- Vilnius Santaros Klinikos Biobank, Vilnius University Hospital Santaros Klinikos, 08661 Vilnius, Lithuania
| | - Algirdas Utkus
- Department of Human and Medical Genetics, Faculty of Medicine, Vilnius University, 01513 Vilnius, Lithuania
| | | | - Goda Jonuškienė
- Clinic of Hematology and Oncology, Institute of Clinical Medicine, Faculty of Medicine, 01513 Vilnius, Lithuania
| | - Aistė Gulla
- Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, 01513 Vilnius, Lithuania
- Department of Surgery, George Washington University, Washington, DC 20052, USA
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10
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Lyu X, Sze KMF, Lee JMF, Husain A, Tian L, Imbeaud S, Zucman-Rossi J, Ng IOL, Ho DWH. Disparity landscapes of viral-induced structural variations in HCC: Mechanistic characterization and functional implications. Hepatology 2024:01515467-990000000-01027. [PMID: 39270063 DOI: 10.1097/hep.0000000000001087] [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: 01/31/2024] [Accepted: 08/29/2024] [Indexed: 09/15/2024]
Abstract
BACKGROUND AND AIMS HCC is the most common type of primary liver cancer and is a common malignancy worldwide. About half of all new liver cancers worldwide each year occur in China, including Hong Kong, due to a high prevalence of HBV infection. HBV DNA integrates into the human genome, disrupting the endogenous tumor suppressors/regulatory genes or enhancing the activity of proto-oncogenes. It would be useful to examine the different NGS-based databases to provide a more unbiased and comprehensive survey of HBV integration. APPROACH AND RESULTS We aimed to take advantage of publicly available data sets of different regional cohorts to determine the disparity landscapes of integration events among sample cohorts, tissue types, chromosomal positions, individual host, and viral genes, as well as genic locations. By comparing HCC tumors with non tumorous livers, the landscape of HBV integration was delineated in gene-independent and gene-dependent manners. Moreover, we performed mechanistic investigations on how HBV-TERT integration led to TERT activation and derived a score to predict patients' prognostication according to their clonal disparity landscape of HBV integration. CONCLUSIONS Our study uncovered the different levels of clonal enrichment of HBV integration and identified mechanistic insights and prognostic biomarkers. This strengthens our understanding of HBV-associated hepatocarcinogenesis.
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Affiliation(s)
- Xueying Lyu
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
- Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Hong Kong
| | - Karen Man-Fong Sze
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
- Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Hong Kong
| | - Joyce Man-Fong Lee
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
- Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Hong Kong
| | - Abdullah Husain
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
- Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Hong Kong
| | - Lu Tian
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
- Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Hong Kong
| | - Sandrine Imbeaud
- Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Inserm, Paris, France
- FunGeST lab, Equipe Labellisée Ligue Nationale Contre le Cancer, Labex Onco-Immunology, Institute du Cancer Paris CARPEM, AP-HP, Paris, France
| | - Jessica Zucman-Rossi
- Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Inserm, Paris, France
- FunGeST lab, Equipe Labellisée Ligue Nationale Contre le Cancer, Labex Onco-Immunology, Institute du Cancer Paris CARPEM, AP-HP, Paris, France
| | - Irene Oi-Lin Ng
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
- Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Hong Kong
| | - Daniel Wai-Hung Ho
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
- Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Hong Kong
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11
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Zhang G, Xiao Y, Liu H, Wu Y, Xue M, Li J. Integrated machine learning screened glutamine metabolism-associated biomarker SLC1A5 to predict immunotherapy response in hepatocellular carcinoma. Immunobiology 2024; 229:152841. [PMID: 39096658 DOI: 10.1016/j.imbio.2024.152841] [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: 06/14/2024] [Revised: 07/26/2024] [Accepted: 07/30/2024] [Indexed: 08/05/2024]
Abstract
Hepatocellular carcinoma (HCC) stands as one of the most prevalent malignancies. While PD-1 immune checkpoint inhibitors have demonstrated promising therapeutic efficacy in HCC, not all patients exhibit a favorable response to these treatments. Glutamine is a crucial immune cell regulatory factor, and tumor cells exhibit glutamine dependence. In this study, HCC patients were divided into two subtypes (C1 and C2) based on glutamine metabolism-related genes via consensus clustering. The C1 pattern, in contrast to C2, was associated with a lower survival probability among HCC patients. Additionally, the C1 pattern exhibited higher proportions of patients with advanced tumor stages. The activity of C1 in glutamine metabolism and transport is significantly enhanced, while its oxidative phosphorylation activity is reduced. And, C1 was mainly involved in the progression-related pathway of HCC. Furthermore, C1 exhibited high levels of immunosuppressive cells, cytokine-receptor interactions and immune checkpoint genes, suggesting C1 as an immunosuppressive subtype. After stepwise selection based on integrated four machine learning methods, SLC1A5 was finally identified as the pivotal gene that distinguishes the subtypes. The expression of SLC1A5 was significantly positively correlated with immunosuppressive status. SLC1A5 showed the most significant correlation with macrophage infiltration, and this correlation was confirmed through the RNA-seq data of CLCA project and our cohort. Low-SLC1A5-expression samples had better immunogenicity and responsiveness to immunotherapy. As expected, SubMap and survival analysis indicated that individuals with low SLC1A5 expression were more responsive to anti-PD1 therapy. Collectively, this study categorized HCC patients based on glutamine metabolism-related genes and proposed two subclasses with different clinical traits, biological behavior, and immune status. Machine learning was utilized to identify the hub gene SLC1A5 for HCC classification, which also could predict immunotherapy response.
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Affiliation(s)
- Guixiong Zhang
- Department of Interventional Oncology, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province 510080, PR China
| | - Yitai Xiao
- Department of Endoscopy, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong Province 510060, PR China
| | - Hang Liu
- Department of Interventional Oncology, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province 510080, PR China
| | - Yanqin Wu
- Department of Interventional Oncology, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province 510080, PR China
| | - Miao Xue
- Department of Interventional Oncology, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province 510080, PR China
| | - Jiaping Li
- Department of Interventional Oncology, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province 510080, PR China.
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12
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Chen K, Shuen TWH, Chow PKH. The association between tumour heterogeneity and immune evasion mechanisms in hepatocellular carcinoma and its clinical implications. Br J Cancer 2024; 131:420-429. [PMID: 38760445 PMCID: PMC11300599 DOI: 10.1038/s41416-024-02684-w] [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: 12/15/2023] [Revised: 04/04/2024] [Accepted: 04/05/2024] [Indexed: 05/19/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide. The emergence of combination therapy, atezolizumab (anti-PDL1, immune checkpoint inhibitor) and bevacizumab (anti-VEGF) has revolutionised the management of HCC. Despite this breakthrough, the best overall response rate with first-line systemic therapy is only about 30%, owing to intra-tumoural heterogeneity, complex tumour microenvironment and the lack of predictive biomarkers. Many groups have attempted to classify HCC based on the immune microenvironment and have consistently observed better outcomes in immunologically "hot" HCC. We summarised possible mechanisms of tumour immune evasion based on the latest literature and the rationale for combination/sequential therapy to improve treatment response. Lastly, we proposed future strategies and therapies to overcome HCC immune evasion to further improve treatment outcomes of HCC.
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Affiliation(s)
- Kaina Chen
- Department of Gastroenterology & Hepatology, Singapore General Hospital, Singapore, Singapore
- Duke-NUS Medical School, Singapore, Singapore
| | - Timothy W H Shuen
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Pierce K H Chow
- Duke-NUS Medical School, Singapore, Singapore.
- Department of Hepato-pancreato-biliary and Transplant Surgery, National Cancer Centre Singapore and Singapore General Hospital, Singapore, Singapore.
- Program in Translational and Clinical Liver Cancer Research, National Cancer Centre Singapore, Singapore, Singapore.
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13
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Zheng J, Wang Y, Zhou Y, Li Z, Yang L, Gao J, Zhu J. Augmentation of hepatocellular carcinoma malignancy by annexin A5 through modulation of invasion and angiogenesis. Scand J Gastroenterol 2024; 59:939-953. [PMID: 38742797 DOI: 10.1080/00365521.2024.2353103] [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: 03/15/2024] [Revised: 04/13/2024] [Accepted: 05/05/2024] [Indexed: 05/16/2024]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) continues to play a substantial role in cancer-related morbidity and mortality, largely owing to its pronounced tumor heterogeneity and propensity for recurrence. This underscores the pressing need for in-depth examination of its highly malignant mechanisms. Annexin A5 (ANXA5), recognized as a hallmark tumor protein, has emerged as a focal point of interest because of its ambiguous function and mechanism in HCC prognosis. This study aimed to provide a comprehensive understanding of the role of ANXA5 in the malignant progression of human HCC cells by employing an integrative approach that combines conventional experimental methods with RNA sequencing. METHODS Differences in ANXA5 expression between HCC tissues and corresponding nontumor tissues were evaluated using immunofluorescence (n = 25). Correlation analysis was subsequently performed to assess the association between ANXA5 expression and clinicopathological features (n = 65). The role of ANXA5 in human HCC cell lines with ANXA5 gene knockout and overexpression was explored in vitro using migration and invasion assays and Ki-67 indices and in vivo based on node mice xenograft model. A tube formation assay using human umbilical vein endothelial cells (HUVECs) was conducted to demonstrate the angiogenic effects of ANXA5 in HCC. Single-cell and bulk RNA sequencing was used to further investigate the underlying mechanisms involved. RESULTS This study revealed that ANXA5 is highly expressed in patients with HCC and correlates with poor prognosis. Assays for migration, invasion, and proliferation based on ANXA5 gene knockout and overexpression systems in human HCC cell lines have demonstrated that ANXA5 enhances HCC malignancy in vitro and in vivo. Tube formation assays of HUVECs indicated that ANXA5 facilitates angiogenesis and recruits endothelial cells to HCC cells. Single-cell and bulk RNA sequencing data analysis further confirmed that ANXA5 expression in HCC is associated with hepatocyte metabolism, immune response activation, and various oncogenic signaling pathways. CONCLUSIONS This study revealed a meaningful association between elevated ANXA5 expression in tumor tissues and an unfavorable prognosis in patients with HCC. In addition, ANXA5 promotes HCC malignancy by promoting invasion and angiogenesis. Thus, ANXA5 has emerged as a promising therapeutic target for HCC and has the potential to improve patient outcomes.
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Affiliation(s)
- Jiaxi Zheng
- Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing, China
| | - Yang Wang
- Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing, China
| | - Yuheng Zhou
- Department of Medical Genetics, Center for Medical Genetics, Peking University Health Science Center, Beijing, China
| | - Zhao Li
- Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing, China
- Beijing Key Laboratory of HCC and Liver Cirrhosis, Peking University People's Hospital, Beijing, China
- Peking University Center of Liver Cancer Diagnosis and Treatment, Peking University People's Hospital, Beijing, China
- Peking University Institute of Organ Transplantation, Peking University People's Hospital, Beijing, China
| | - Li Yang
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Institutes of Biomedical Sciences, Inner Mongolia University, Hohhot, China
| | - Jie Gao
- Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing, China
- Beijing Key Laboratory of HCC and Liver Cirrhosis, Peking University People's Hospital, Beijing, China
- Peking University Center of Liver Cancer Diagnosis and Treatment, Peking University People's Hospital, Beijing, China
- Peking University Institute of Organ Transplantation, Peking University People's Hospital, Beijing, China
| | - Jiye Zhu
- Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing, China
- Beijing Key Laboratory of HCC and Liver Cirrhosis, Peking University People's Hospital, Beijing, China
- Peking University Center of Liver Cancer Diagnosis and Treatment, Peking University People's Hospital, Beijing, China
- Peking University Institute of Organ Transplantation, Peking University People's Hospital, Beijing, China
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14
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Soon GST, Callea F, Burt AD, Cook S, Terracciano L, Ercan C, Dienes HP, Goodman ZD, Roberts EA, Clouston AD, Gouw ASH, Kleiner DE, Park YN, Chung T, Schirmacher P, Tiniakos D, Dimopoulou K, Weber A, Endhardt K, Torbenson M. Steatohepatitic hepatocellular Carcinoma:A new approach to classifying morphological subtypes of hepatocellular carcinoma. Hum Pathol 2024; 149:55-65. [PMID: 38876199 DOI: 10.1016/j.humpath.2024.06.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 06/07/2024] [Accepted: 06/11/2024] [Indexed: 06/16/2024]
Abstract
Histological subtyping of hepatocellular carcinoma (HCC) is challenging in the presence of histological heterogeneity, where distinctly different morphological patterns are present within the same tumor. Current approaches rely on percent cut-offs. We hypothesized that morphologic intratumor heterogeneity is a non-random biological feature and that incorporating recurrent patterns would improve histological subtyping of HCC. Resected HCC were studied and the overall frequency of morphologic intratumor heterogeneity was 45% in 242 specimens. Steatohepatitic HCC (SH-HCC) had the highest frequency of morphologic intratumor heterogeneity (91%); this was confirmed in additional cohorts of SH-HCC from different medical centers (overall frequency of 78% in SH-HCC). Morphologic intratumor heterogeneity in SH-HCC showed distinct and recurrent patterns that could be classified as early, intermediate, and advanced. Incorporating these patterns into the definition of SH-HCC allowed successful resolution of several persistent challenges: the problem of the best cut-off for subtyping SH-HCC, the problem of the relationship between SH-HCC and scirrhous HCC, and the classification for HCC with abundant microvesicular steatosis. This approach also clarified the relationship between SH-HCC and CTNNB1 mutations, showing that CTNNB1 mutations occur late in a subset of SH-HCC. In summary, there is a high frequency of morphologic intratumor heterogeneity in HCC. Incorporating this finding into histological subtyping resolved several persistent problems with the SH-HCC subtype.
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Affiliation(s)
- Gwyneth S T Soon
- Department of Pathology, National University Hospital, Singapore
| | | | - Alastair D Burt
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, United Kingdom
| | - Sam Cook
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, United Kingdom
| | - Luigi Terracciano
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele, Milan, Italy; IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Caner Ercan
- Institute of Pathology and Medical Genetics, University Hospital Basel, Basel, Switzerland
| | - Hans-Peter Dienes
- Institute of Pathology, Meduniwien, Medical University of Vienna, 1090 Wien, Austria
| | - Zachary D Goodman
- Center for Liver Diseases, Inova Fairfax Hospital, Falls Church, VA 22042, USA
| | - Eve A Roberts
- Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, Ontario M5G1X8, Canada
| | - Andrew D Clouston
- Centre for Liver Disease Research, School of Medicine (Southern), University of Queensland, Princess Alexandra Hospital, Ipswich Rd Woolloongabba 4109, Australia
| | - Annette S H Gouw
- Department of Pathology and Medical Biology, University Medical Center Groningen, 9700 RB Groningen, the Netherlands
| | - David E Kleiner
- Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, USA
| | - Young Nyun Park
- Department of Pathology, Yonsei University College of Medicine, Seoul Korea
| | - Taek Chung
- Department of Pathology, Yonsei University College of Medicine, Seoul Korea.
| | - Peter Schirmacher
- Institute of Pathology, University Hospital, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany
| | - Dina Tiniakos
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, United Kingdom; Department of Pathology, Aretaieion Hospital, Medical School, National & Kapodistrian University of Athens, Athens, Greece
| | - Konstantina Dimopoulou
- Department of Pathology, Aretaieion Hospital, Medical School, National & Kapodistrian University of Athens, Athens, Greece
| | - Achim Weber
- Department of Pathology and Molecular Pathology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Katharina Endhardt
- Department of Pathology and Molecular Pathology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Michael Torbenson
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
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15
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Liu H, Yue L, Hong W, Zhou J. SMARCA4 (BRG1) activates ABCC3 transcription to promote hepatocellular carcinogenesis. Life Sci 2024; 347:122605. [PMID: 38642845 DOI: 10.1016/j.lfs.2024.122605] [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: 12/28/2023] [Revised: 03/08/2024] [Accepted: 04/01/2024] [Indexed: 04/22/2024]
Abstract
AIMS Hepatocellular carcinoma (HCC) is a lead cause of cancer-related deaths. In the present study we investigated the role of Brahma-related gene 1 (BRG1), a chromatin remodeling protein, in HCC the pathogenesis focusing on identifying novel transcription targets. METHODS AND MATERIALS Hepatocellular carcinogenesis was modeled in mice by diethylnitrosamine (DEN). Cellular transcriptome was evaluated by RNA-seq. RESULTS Hepatocellular carcinoma was appreciably retarded in BRG1 knockout mice compared to wild type littermates. Transcriptomic analysis identified ATP Binding Cassette Subfamily C Member 3 (ABCC3) as a novel target of BRG1. BRG1 over-expression in BRG1low HCC cells (HEP1) up-regulated whereas BRG1 depletion in BRG1high HCC cells (SNU387) down-regulated ABCC3 expression. Importantly, BRG1 was detected to directly bind to the ABCC3 promoter to activate ABCC3 transcription. BRG1 over-expression in HEP1 cells promoted proliferation and migration, both of which were abrogated by ABCC3 silencing. On the contrary, BRG1 depletion in SNU387 cells decelerated proliferation and migration, both of which were rescued by ABCC3 over-expression. Importantly, high BRG1/ABCC3 expression predicted poor prognosis in HCC patients. Mechanistically, ABCC3 regulated hepatocellular carcinogenesis possibly by influencing lysosomal homeostasis. SIGNIFICANCE In conclusion, our data suggest that targeting BRG1 and its downstream target ABCC3 can be considered as a reasonable approach for the intervention of hepatocellular carcinoma.
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Affiliation(s)
- Huimin Liu
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China
| | - Linbo Yue
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China
| | - Wenxuan Hong
- Institute of Biomedical Sciences, Fudan University, Shanghai, China.
| | - Junjing Zhou
- Department of Hepatobiliary Surgery, Affiliated Hospital of Jiangnan University, Wuxi, China.
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16
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Wang Y, Shang P, Xu C, Dong W, Zhang X, Xia Y, Sui C, Yang C. Novel genetic alterations in liver cancer distinguish distinct clinical outcomes and combination immunotherapy responses. Front Pharmacol 2024; 15:1416295. [PMID: 38948469 PMCID: PMC11211383 DOI: 10.3389/fphar.2024.1416295] [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: 04/12/2024] [Accepted: 05/27/2024] [Indexed: 07/02/2024] Open
Abstract
Introduction: Genomic profiling has revolutionized therapeutic interventions and the clinical management of liver cancer. However, pathogenetic mechanisms, molecular determinants of recurrence, and predictive biomarkers for first-line treatment (anti-PD-(L)1 plus bevacizumab) in liver cancer remain incompletely understood. Materials and methods: Targeted next-generation sequencing (tNGS) (a 603-cancer-gene panel) was applied for the genomic profiling of 232 hepatocellular carcinoma (HCC) and 22 intrahepatic cholangiocarcinoma (ICC) patients, among which 47 unresectable/metastatic HCC patients underwent anti-PD-1 plus bevacizumab therapy. Genomic alterations were estimated for their association with vascular invasion (VI), location of onset, recurrence, overall survival (OS), recurrence-free survival (RFS), and anti-PD-1 plus bevacizumab therapy response. Results: The genomic landscape exhibited that the most commonly altered genes in HCC were TP53, FAT3, PDE4DIP, KMT2C, FAT1, and MYO18A, while TP53, FAT1, FAT3, PDE4DIP, ROS1, and GALNT11 were frequently altered in ICC; notably, KRAS (18.18% vs. 1.29%) and BAP1 (13.64% vs. 1.29%) alterations were significantly more prevalent in ICC. Comparison analysis demonstrated the distinct clinicopathological/genomic characterizations between Chinese and Western HCC cohorts. Genomic profiling of HCC underlying VI showed that LDLR, MSH2, KDM5D, PDE3A, and FOXO1 were frequently altered in the VI group compared to patients without VIs. Compared to the right hepatic lobes of HCC patients, the left hepatic lobe of HCC patients had superior OS (median OS: 36.77 months vs. unreached, p < 0.05). By further comparison, Notch signaling pathway-related alterations were significantly prevalent among the right hepatic lobes of HCC patients. Of note, multivariate Cox regression analysis showed that altered RB1, NOTCH3, MGA, SYNE1, and ZFHX3, as independent prognostic factors, were significantly correlated with the OS of HCC patients. Furthermore, altered LATS1 was abundantly enriched in the HCC-recurrent group, and impressively, it was independent of clinicopathological features in predicting RFS (median RFS of altered type vs. wild-type: 5.57 months vs. 22.47 months, p < 0.01). Regarding those treated HCC patients, TMB value, altered PTPRZ1, and cell cycle-related alterations were identified to be positively associated with the objective response rate (ORR), but KMT2D alterations were negatively correlated with ORR. In addition, altered KMT2D and cell cycle signaling were significantly associated with reduced and increased time to progression-free survival (PFS), respectively. Conclusion: Comprehensive genomic profiling deciphered distinct molecular characterizations underlying VI, location of onset, recurrence, and survival time in liver cancer. The identification of novel genetic predictors of response to anti-PD-1 plus bevacizumab in HCC facilitated the development of an evidence-based approach to therapy.
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Affiliation(s)
- Yizhou Wang
- Department of Hepatic Surgery IV and Clinical Research Institute, Eastern Hepatobiliary Surgery Hospital, Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Peipei Shang
- Department of Medical Oncology, Eastern Hepatobiliary Surgery Hospital, Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Chang Xu
- Department of General Surgery, Biliary Tract Disease Institute, Biliary Tract Disease Center, and Cancer Center of Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wei Dong
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Xiaofeng Zhang
- Department of Hepatic Surgery IV and Clinical Research Institute, Eastern Hepatobiliary Surgery Hospital, Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Yong Xia
- Department of Hepatic Surgery IV and Clinical Research Institute, Eastern Hepatobiliary Surgery Hospital, Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Chengjun Sui
- Department of Special Treatment, Eastern Hepatobiliary Surgery Hospital, Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Cheng Yang
- Department of Special Treatment, Eastern Hepatobiliary Surgery Hospital, Third Affiliated Hospital of Naval Medical University, Shanghai, China
- Department of Interventional Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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17
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Peng X, Lu X, Yang D, Liu J, Wu H, Peng H, Zhang Y. A novel CD8+ T cell-related gene signature as a prognostic biomarker in hepatocellular carcinoma. Medicine (Baltimore) 2024; 103:e37496. [PMID: 38489709 PMCID: PMC10939595 DOI: 10.1097/md.0000000000037496] [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: 07/25/2023] [Revised: 12/16/2023] [Accepted: 02/14/2024] [Indexed: 03/17/2024] Open
Abstract
CD8+ T cells have great roles in tumor suppression and elimination of various tumors including hepatocellular carcinoma (HCC). Nonetheless, potential prognostic roles of CD8+ T cell-related genes (CD8Gs) in HCC remains unknown. In our study, 416 CD8Gs were identified in HCC, which were enriched in inflammatory and immune signaling pathways. Using The Cancer Genome Atlas dataset, a 5-CD8Gs risk model (KLRB1, FYN, IL2RG, FCER1G, and DGKZ) was constructed, which was verified in International Cancer Genome Consortium and gene expression omnibus datasets. Furthermore, we found that overall survival was independently correlated with the CD8Gs signature, and it was associated with immune- and cancer-related signaling pathways and immune cells infiltration. Finally, drug sensitivity data indicated that 10 chemotherapeutic drugs held promise as therapeutics for HCC patients with high-risk. In conclusion, multi-databases analysis showed that 5-CD8Gs and their signature could be an indicator to predict candidate drugs for HCC therapy.
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Affiliation(s)
- Xiaozhen Peng
- School of Public Health & Laboratory Medicine, Hunan University of Medicine, Huaihua, China
- Hunan Provincial Key Laboratory for Synthetic Biology of Traditional Chinese Medicine, Hunan University of Medicine, Huaihua, China
| | - Xingjun Lu
- School of Public Health & Laboratory Medicine, Hunan University of Medicine, Huaihua, China
| | - Daqing Yang
- School of Public Health & Laboratory Medicine, Hunan University of Medicine, Huaihua, China
| | - Jinyan Liu
- Hunan Normal University, Changsha, China
| | - Honglin Wu
- School of Public Health & Laboratory Medicine, Hunan University of Medicine, Huaihua, China
| | - Hong Peng
- Medical School, Huanghe Science & Technology College, Zhengzhou, China
| | - Yiya Zhang
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
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18
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Yan Y, Lin XS, Ming WZ, Chuan ZQ, Hui G, Juan SY, Shuang W, Yang Fan LV, Dong Z. Radiomic Analysis Based on Gd-EOB-DTPA Enhanced MRI for the Preoperative Prediction of Ki-67 Expression in Hepatocellular Carcinoma. Acad Radiol 2024; 31:859-869. [PMID: 37689559 DOI: 10.1016/j.acra.2023.07.019] [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: 06/13/2023] [Revised: 07/13/2023] [Accepted: 07/19/2023] [Indexed: 09/11/2023]
Abstract
RATIONALE AND OBJECTIVES To develop and validate a random forest model based on radiomic features in Gd-EOB-DTPA enhanced MRI for predicting the Ki-67 expression in solitary HCC. MATERIALS AND METHODS This retrospective study analyzed 258 patients with solitary HCC. Significant clinicoradiological factors were identified through univariate and multivariate analyses for distinguishing HCC with high (>20%) and low (≤20%) Ki-67 expression. Radiomic features were extracted at Gd-EOB-DTPA enhanced MRI. The recursive feature elimination (RFE) strategy was employed to screen robust radiomic features, and the Random Forest (RF) algorithm was utilized to rank radiomic features and construct prediction models. The AUC, accuracy, precision, recall, and f1-score were used to evaluate the performance of RF models. RESULTS Multivariate analysis identified serum AFP level, tumor size, growth type, and peritumoral enhancement as independent predictors for HCC with high Ki-67 expression. The clinicoradiological-radiomic model that incorporated the clinicoradiological predictors and the top ten radiomic features outperformed the clinicoradiological model in the training set (AUCs 0.876 vs. 0.780; p < 0.001), though the test set did not have a statistical significance (AUCs 0.809 vs. 0.723; p = 0.123). The addition of clinicoradiological predictors did not yield a significant improvement in the performance of radiomic features in both sets (training, p = 0.692; test, p = 0.229). Decision curve analysis further confirmed the clinical utility of the RF models. CONCLUSION The RF models based on radiomic features of Gd-EOB-DTPA enhanced MRI achieved satisfactory performance in preoperatively predicting Ki-67 expression in HCC.
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Affiliation(s)
- Yang Yan
- Department of Radiology, XinQiao Hospital, Army Medical University, Chongqing 400037, People's Republic of China (Y.Y., X.S.L., W.Z.M., Z.Q.C., G.H., S.Y.J., W.S., Z.D.)
| | - Xiao Shi Lin
- Department of Radiology, XinQiao Hospital, Army Medical University, Chongqing 400037, People's Republic of China (Y.Y., X.S.L., W.Z.M., Z.Q.C., G.H., S.Y.J., W.S., Z.D.)
| | - Wang Zheng Ming
- Department of Radiology, XinQiao Hospital, Army Medical University, Chongqing 400037, People's Republic of China (Y.Y., X.S.L., W.Z.M., Z.Q.C., G.H., S.Y.J., W.S., Z.D.)
| | - Zhang Qi Chuan
- Department of Radiology, XinQiao Hospital, Army Medical University, Chongqing 400037, People's Republic of China (Y.Y., X.S.L., W.Z.M., Z.Q.C., G.H., S.Y.J., W.S., Z.D.)
| | - Gan Hui
- Department of Radiology, XinQiao Hospital, Army Medical University, Chongqing 400037, People's Republic of China (Y.Y., X.S.L., W.Z.M., Z.Q.C., G.H., S.Y.J., W.S., Z.D.)
| | - Sun Ya Juan
- Department of Radiology, XinQiao Hospital, Army Medical University, Chongqing 400037, People's Republic of China (Y.Y., X.S.L., W.Z.M., Z.Q.C., G.H., S.Y.J., W.S., Z.D.)
| | - Wang Shuang
- Department of Radiology, XinQiao Hospital, Army Medical University, Chongqing 400037, People's Republic of China (Y.Y., X.S.L., W.Z.M., Z.Q.C., G.H., S.Y.J., W.S., Z.D.)
| | - L V Yang Fan
- Department of Pathology, XinQiao Hospital, Army Medical University, Chongqing, People's Republic of China (L.Y.F.)
| | - Zhang Dong
- Department of Radiology, XinQiao Hospital, Army Medical University, Chongqing 400037, People's Republic of China (Y.Y., X.S.L., W.Z.M., Z.Q.C., G.H., S.Y.J., W.S., Z.D.).
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19
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Cowzer D, White JB, Chou JF, Chen PJ, Kim TH, Khalil DN, El Dika IH, Columna K, Yaqubie A, Light JS, Shia J, Yarmohammadi H, Erinjeri JP, Wei AC, Jarnagin W, Do RK, Solit DB, Capanu M, Shah RH, Berger MF, Abou-Alfa GK, Harding JJ. Targeted Molecular Profiling of Circulating Cell-Free DNA in Patients With Advanced Hepatocellular Carcinoma. JCO Precis Oncol 2023; 7:e2300272. [PMID: 37769223 PMCID: PMC10581608 DOI: 10.1200/po.23.00272] [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: 05/30/2023] [Revised: 07/29/2023] [Accepted: 08/08/2023] [Indexed: 09/30/2023] Open
Abstract
PURPOSE Next-generation sequencing (NGS) of tumor-derived, circulating cell-free DNA (cfDNA) may aid in diagnosis, prognostication, and treatment of patients with hepatocellular carcinoma (HCC). The operating characteristics of cfDNA mutational profiling must be determined before routine clinical implementation. METHODS This was a single-center, retrospective study with the primary objective of defining genomic alterations in circulating cfDNA along with plasma-tissue genotype agreement between NGS of matched tumor samples in patients with advanced HCC. cfDNA was analyzed using a clinically validated 129-gene NGS assay; matched tissue-based NGS was analyzed with a US Food and Drug Administration-authorized NGS tumor assay. RESULTS Fifty-three plasma samples from 51 patients with histologically confirmed HCC underwent NGS-based cfDNA analysis. Genomic alterations were detected in 92.2% of patients, with the most commonly mutated genes including TERT promoter (57%), TP53 (47%), CTNNB1 (37%), ARID1A (18%), and TSC2 (14%). In total, 37 (73%) patients underwent paired tumor NGS, and concordance was high for mutations observed in patient-matched plasma samples: TERT (83%), TP53 (94%), CTNNB1 (92%), ARID1A (100%), and TSC2 (71%). In 10 (27%) of 37 tumor-plasma samples, alterations were detected by cfDNA analysis that were not detected in the patient-matched tumors. Potentially actionable mutations were identified in 37% of all cases including oncogenic/likely oncogenic alterations in TSC1/2 (18%), BRCA1/2 (8%), and PIK3CA (8%). Higher average variant allele fraction was associated with elevated alpha-fetoprotein, increased tumor volume, and no previous systemic therapy, but did not correlate with overall survival in treatment-naïve patients. CONCLUSION Tumor mutation profiling of cfDNA in HCC represents an alternative to tissue-based genomic profiling, given the high degree of tumor-plasma NGS concordance; however, genotyping of both blood and tumor may be required to detect all clinically actionable genomic alterations.
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Affiliation(s)
- Darren Cowzer
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Jessica B. White
- Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Joanne F. Chou
- Weill Medical College of Cornell University, New York, NY
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Pin-Jung Chen
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Tae-Hyung Kim
- Weill Medical College of Cornell University, New York, NY
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Danny N. Khalil
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Medical College of Cornell University, New York, NY
| | - Imane H. El Dika
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Medical College of Cornell University, New York, NY
| | - Katrina Columna
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Amin Yaqubie
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Joseph S. Light
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Jinru Shia
- Weill Medical College of Cornell University, New York, NY
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Hooman Yarmohammadi
- Weill Medical College of Cornell University, New York, NY
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Joseph Patrick Erinjeri
- Weill Medical College of Cornell University, New York, NY
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Alice C. Wei
- Weill Medical College of Cornell University, New York, NY
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - William Jarnagin
- Weill Medical College of Cornell University, New York, NY
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Richard K.G. Do
- Weill Medical College of Cornell University, New York, NY
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - David B. Solit
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Medical College of Cornell University, New York, NY
| | - Marinela Capanu
- Weill Medical College of Cornell University, New York, NY
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Ronak H. Shah
- Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Michael F. Berger
- Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Medical College of Cornell University, New York, NY
| | - Ghassan K. Abou-Alfa
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Medical College of Cornell University, New York, NY
| | - James J. Harding
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Medical College of Cornell University, New York, NY
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Chen R, Zhao M, An Y, Liu D, Tang Q. GBAP1 functions as a tumor promotor in hepatocellular carcinoma via the PI3K/AKT pathway. BMC Cancer 2023; 23:628. [PMID: 37407932 DOI: 10.1186/s12885-023-11107-7] [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: 10/08/2022] [Accepted: 06/23/2023] [Indexed: 07/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is common worldwide, and novel therapeutic targets and biomarkers are needed to improve outcomes. In this study, bioinformatics analyses combined with in vitro and in vivo assays were used to identify the potential therapeutic targets. Differentially expressed genes (DEG) in HCC were identified by the intersection between The Cancer Genome Atlas and International Cancer Genome Consortium data. The DEGs were evaluated by a gene set enrichment analysis as well as Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. A protein interaction network, univariate Cox regression, and Lasso regression were used to screen out hub genes correlated with survival. Increased expression of the long noncoding RNA GBAP1 in HCC was confirmed in additional datasets and its biological function was evaluated in HCC cell lines and nude mice. Among 121 DEGs, GBAP1 and PRC1 were identified as hub genes with significant prognostic value. Overexpression of GBAP1 in HCC was confirmed in 21 paired clinical tissues and liver cancer or normal cell lines. The inhibition of GBAP1 expression reduced HCC cell proliferation and promoted apoptosis by inactivating the PI3K/AKT pathway in vitro and in vivo. Therefore, GBAP1 has a pro-oncogenic function in HCC and is a candidate prognostic biomarker and therapeutic target.
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Affiliation(s)
- Rong Chen
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, Nanjing, 210009, Jiangsu Province, China.
| | - Meng Zhao
- Medical college, Henan University of Traditional Chinese Medicine, 450001, Henan Province, China
| | - Yanli An
- Jiangsu Provincial Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, 210009, Jiangsu Province, China
| | - Dongfang Liu
- Jiangsu Provincial Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, 210009, Jiangsu Province, China
| | - Qiusha Tang
- Medical School of Southeast University, Nanjing, 210009, Jiangsu Province, China
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21
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Wu Q, Yu YX, Zhang T, Zhu WJ, Fan YF, Wang XM, Hu CH. Preoperative Diagnosis of Dual-Phenotype Hepatocellular Carcinoma Using Enhanced MRI Radiomics Models. J Magn Reson Imaging 2023; 57:1185-1196. [PMID: 36190656 DOI: 10.1002/jmri.28391] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Revised: 07/27/2022] [Accepted: 07/28/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Dual-phenotype hepatocellular carcinoma (DPHCC) is highly aggressive and difficult to distinguish from hepatocellular carcinoma (HCC). PURPOSE To develop and validate clinical and radiomics models based on contrast-enhanced MRI for the preoperative diagnosis of DPHCC. STUDY TYPE Retrospective. POPULATION A total of 87 patients with DPHCC and 92 patients with non-DPHCC randomly divided into a training cohort (n = 125: 64 non-DPHCC; 61 DPHCC) and a validation cohort (n = 54: 28 non-DPHCC; 26 DPHCC). FIELD STRENGTH/SEQUENCE A 3.0 T; dynamic contrast-enhanced MRI with time-resolved T1-weighted imaging sequence. ASSESSMENT In the clinical model, the maximum tumor diameter and hepatitis B virus (HBV) were independent risk factors of DPHCC. In the radiomics model, a total of 1781 radiomics features were extracted from tumor volumes of interest (VOIs) in the arterial phase (AP) and portal venous phase (PP) images. For feature reduction and selection, Pearson correlation coefficient (PCC) and recursive feature elimination (RFE) were used. Clinical, AP, PP, and combined radiomics models were established using machine learning algorithms (support vector machine [SVM], logistic regression [LR], and logistic regression-least absolute shrinkage and selection operator [LR-LASSO]) and their discriminatory efficacy assessed and compared. STATISTICAL TESTS The independent sample t test, Mann-Whitney U test, Chi-square test, regression analysis, receiver operating characteristic curve (ROC) analysis, Pearson correlation analysis, the Delong test. A P value < 0.05 was considered statistically significant. RESULTS In the validation cohort, the combined radiomics model (area under the curve [AUC] = 0.908, 95% confidence interval [CI]: 0.831-0.985) showed the highest diagnostic performance. The AUCs of the PP (AUC = 0.879, 95% CI: 0.779-0.979) and combined radiomics models were significantly higher than that of clinical model (AUC = 0.685, 95% CI: 0.526-0.844). There were no significant differences in AUC between AP or PP radiomics model and combined radiomics model (P = 0.286, 0.180 and 0.543). CONCLUSION MRI radiomics models may be useful for discriminating DPHCC from non-DPHCC before surgery. EVIDENCE LEVEL 4 TECHNICAL EFFICACY: Stage 2.
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Affiliation(s)
- Qian Wu
- Department of Radiology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yi-Xing Yu
- Department of Radiology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Tao Zhang
- Department of Radiology, Affiliated Nantong Hospital 3 of Nantong University, Nantong, China
| | - Wen-Jing Zhu
- Department of Radiology, Affiliated Nantong Hospital 3 of Nantong University, Nantong, China
| | - Yan-Fen Fan
- Department of Radiology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xi-Ming Wang
- Department of Radiology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Chun-Hong Hu
- Department of Radiology, The First Affiliated Hospital of Soochow University, Suzhou, China
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Liu P, Kong L, Liu Y, Li G, Xie J, Lu X. A key driver to promote HCC: Cellular crosstalk in tumor microenvironment. Front Oncol 2023; 13:1135122. [PMID: 37007125 PMCID: PMC10050394 DOI: 10.3389/fonc.2023.1135122] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Accepted: 02/23/2023] [Indexed: 03/17/2023] Open
Abstract
Liver cancer is the third greatest cause of cancer-related mortality, which of the major pathological type is hepatocellular carcinoma (HCC) accounting for more than 90%. HCC is characterized by high mortality and is predisposed to metastasis and relapse, leading to a low five-year survival rate and poor clinical prognosis. Numerous crosstalk among tumor parenchymal cells, anti-tumor cells, stroma cells, and immunosuppressive cells contributes to the immunosuppressive tumor microenvironment (TME), in which the function and frequency of anti-tumor cells are reduced with that of associated pro-tumor cells increasing, accordingly resulting in tumor malignant progression. Indeed, sorting out and understanding the signaling pathways and molecular mechanisms of cellular crosstalk in TME is crucial to discover more key targets and specific biomarkers, so that develop more efficient methods for early diagnosis and individualized treatment of liver cancer. This piece of writing offers insight into the recent advances in HCC-TME and reviews various mechanisms that promote HCC malignant progression from the perspective of mutual crosstalk among different types of cells in TME, aiming to assist in identifying the possible research directions and methods in the future for discovering new targets that could prevent HCC malignant progression.
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Affiliation(s)
- Pengyue Liu
- Clinical Medical College, North China University of Science and Technology, Tangshan, China
| | - Lingyu Kong
- Department of Traditional Chinese Medicine, Affiliated Hospital of North China University of Science and Technology, Tangshan, China
| | - Ying Liu
- Department of Clinical Skills Training Center, Tangshan Gongren Hospital, Tangshan, China
| | - Gang Li
- Department of Clinical Laboratory, Tangshan Maternal and Child Health Care Hospital, Tangshan, China
| | - Jianjia Xie
- Department of Clinical Laboratory, Tangshan Maternal and Child Health Care Hospital, Tangshan, China
| | - Xin Lu
- Clinical Medical College, North China University of Science and Technology, Tangshan, China
- Department of Clinical Laboratory, Tangshan Maternal and Child Health Care Hospital, Tangshan, China
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23
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Lin DC. Large-scale genomic analyses reveal alterations and mechanisms underlying clonal evolution and immune evasion in esophageal cancer. Nat Commun 2023; 14:893. [PMID: 36807265 PMCID: PMC9938131 DOI: 10.1038/s41467-023-36557-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 11/23/2022] [Indexed: 02/19/2023] Open
Affiliation(s)
- De-Chen Lin
- Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, CA, USA.
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.
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CRISPR-based DNA methylation editing of NNT rescues the cisplatin resistance of lung cancer cells by reducing autophagy. Arch Toxicol 2023; 97:441-456. [PMID: 36336710 DOI: 10.1007/s00204-022-03404-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 10/24/2022] [Indexed: 11/08/2022]
Abstract
Cisplatin is recommended as a first-line chemotherapeutic agent against advanced non-small cell lung cancer (NSCLC), but acquired resistance substantially limits its clinical efficacy. Recently, DNA methylation has been identified as an essential contributor to chemoresistance. However, the precise DNA methylation regulatory mechanism of cisplatin resistance remains unclear. Here, we found that nicotinamide nucleotide transhydrogenase (NNT) was silenced by DNA hypermethylation in cisplatin resistance A549 (A549/DDP) cells. Also, the DNA hypermethylation of NNT was positively correlated to poor prognosis in NSCLC patients. Overexpression of NNT in A549/DDP cells could reduce their cisplatin resistance, and also suppressed their tumor malignancy such as cell proliferation and clone formation. However, NNT enhanced sensitivity of A549/DDP cells to cisplatin had little to do with its function in mediating NADPH and ROS level, but was mainly because NNT could inhibit protective autophagy in A549/DDP cells. Further investigation revealed that NNT could decrease NAD+ level, thereby inactivate SIRT1 and block the autophagy pathway, while re-activation of SIRT1 through NAD+ precursor supplementation could antagonize this effect. In addition, targeted demethylation of NNT CpG island via CRISPR/dCas9-Tet1 system significantly reduced its DNA methylation level and inhibited the autophagy and cisplatin resistance in A549/DDP cells. Thus, our study found a novel chemoresistance target gene NNT, which played important roles in cisplatin resistance of lung cancer cells. Our findings also suggested that CRISPR-based DNA methylation editing of NNT could be a potential therapeutics method in cisplatin resistance of lung cancer.
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Campani C, Zucman-Rossi J, Nault JC. Genetics of Hepatocellular Carcinoma: From Tumor to Circulating DNA. Cancers (Basel) 2023; 15:cancers15030817. [PMID: 36765775 PMCID: PMC9913369 DOI: 10.3390/cancers15030817] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 01/21/2023] [Accepted: 01/23/2023] [Indexed: 02/01/2023] Open
Abstract
Hepatocellular carcinoma (HCC) accounts for 90% of primary hepatic malignancies and is one of the major causes of cancer-related death. Over the last 15 years, the molecular landscape of HCC has been deciphered, with the identification of the main driver genes of liver carcinogenesis that belong to six major biological pathways, such as telomere maintenance, Wnt/b-catenin, P53/cell cycle regulation, oxidative stress, epigenetic modifiers, AKT/mTOR and MAP kinase. The combination of genetic and transcriptomic data composed various HCC subclasses strongly related to risk factors, pathological features and prognosis. However, translation into clinical practice is not achieved, mainly because the most frequently mutated genes are undruggable. Moreover, the results derived from the analysis of a single tissue sample may not adequately catch the intra- and intertumor heterogeneity. The analysis of circulating tumor DNA (ctDNA) is broadly developed in other types of cancer for early diagnosis, prognosis and monitoring under systemic treatment in order to identify primary and secondary mechanisms of resistance. The aim of this review is to describe recent data about the HCC molecular landscape and to discuss how ctDNA could be used in the future for HCC detection and management.
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Affiliation(s)
- Claudia Campani
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris Cité, Team «Functional Genomics of Solid Tumors», 75006 Paris, France
- Equipe labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, 75006 Paris, France
- Internal Medicine and Hepatology Unit, Department of Experimental and Clinical Medicine, University of Firenze, 50134 Firenze, Italy
| | - Jessica Zucman-Rossi
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris Cité, Team «Functional Genomics of Solid Tumors», 75006 Paris, France
- Equipe labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, 75006 Paris, France
- Hôpital Européen Georges Pompidou, APHP, 75015 Paris, France
| | - Jean-Charles Nault
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris Cité, Team «Functional Genomics of Solid Tumors», 75006 Paris, France
- Equipe labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, 75006 Paris, France
- Liver Unit, Hôpital Avicenne, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, 93000 Bobigny, France
- Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris Nord, 93000 Bobigny, France
- Correspondence: ; Tel.: +33-6-1067-9461
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Yamada S, Morine Y, Ikemoto T, Saito Y, Teraoku H, Waki Y, Nakasu C, Shimada M. Impact of apparent diffusion coefficient on prognosis of early hepatocellular carcinoma: a case control study. BMC Surg 2023; 23:6. [PMID: 36631851 PMCID: PMC9835379 DOI: 10.1186/s12893-022-01892-6] [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: 10/24/2022] [Accepted: 12/20/2022] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND We investigated the usefulness of apparent diffusion coefficients (ADC) from diffusion-weighted images (DWI) obtained using magnetic resonance imaging (MRI) for prognosis of early hepatocellular carcinoma (HCC): Barcelona Clinic Liver Cancer (BCLC) stage 0 and A. METHODS We enrolled 102 patients who had undergone surgical resection for early HCC: BCLC stage 0 and A, and calculated their minimum ADC using DWI-MRI. We divided patients into ADCHigh (n = 72) and ADCLow (n = 30) groups, and compared clinicopathological factors between the two groups. RESULTS The ADCLow group showed higher protein induced by vitamin K absence-II (PIVKA-II) levels (p = 0.02) compared with the ADCHigh group. In overall survival, the ADCLow group showed significantly worse prognosis than the ADCHigh group (p < 0.01). Univariate analysis identified multiple tumors, infiltrative growth, high PIVKA-II, and low ADC value as prognostic factors. Multivariate analysis identified infiltrative growth and low ADC value as an independent prognostic factor. CONCLUSION ADC values can be used to estimate the prognosis of early HCC.
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Affiliation(s)
- Shinichiro Yamada
- grid.412772.50000 0004 0378 2191Department of Digestive and Transplant Surgery, Tokushima University Hospital, 3-18-15 Kuramoto-cho, Tokushima City, Tokushima 770-8503 Japan
| | - Yuji Morine
- grid.412772.50000 0004 0378 2191Department of Digestive and Transplant Surgery, Tokushima University Hospital, 3-18-15 Kuramoto-cho, Tokushima City, Tokushima 770-8503 Japan
| | - Tetsuya Ikemoto
- grid.412772.50000 0004 0378 2191Department of Digestive and Transplant Surgery, Tokushima University Hospital, 3-18-15 Kuramoto-cho, Tokushima City, Tokushima 770-8503 Japan
| | - Yu Saito
- grid.412772.50000 0004 0378 2191Department of Digestive and Transplant Surgery, Tokushima University Hospital, 3-18-15 Kuramoto-cho, Tokushima City, Tokushima 770-8503 Japan
| | - Hiroki Teraoku
- grid.412772.50000 0004 0378 2191Department of Digestive and Transplant Surgery, Tokushima University Hospital, 3-18-15 Kuramoto-cho, Tokushima City, Tokushima 770-8503 Japan
| | - Yuhei Waki
- grid.412772.50000 0004 0378 2191Department of Digestive and Transplant Surgery, Tokushima University Hospital, 3-18-15 Kuramoto-cho, Tokushima City, Tokushima 770-8503 Japan
| | - Chiharu Nakasu
- grid.412772.50000 0004 0378 2191Department of Digestive and Transplant Surgery, Tokushima University Hospital, 3-18-15 Kuramoto-cho, Tokushima City, Tokushima 770-8503 Japan
| | - Mitsuo Shimada
- grid.412772.50000 0004 0378 2191Department of Digestive and Transplant Surgery, Tokushima University Hospital, 3-18-15 Kuramoto-cho, Tokushima City, Tokushima 770-8503 Japan
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Li X, Zhu G, Li Y, Huang H, Chen C, Wu D, Cao P, Shi R, Su L, Zhang R, Liu H, Chen J. LINC01798/miR-17-5p axis regulates ITGA8 and causes changes in tumor microenvironment and stemness in lung adenocarcinoma. Front Immunol 2023; 14:1096818. [PMID: 36911684 PMCID: PMC9995370 DOI: 10.3389/fimmu.2023.1096818] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Accepted: 02/09/2023] [Indexed: 02/25/2023] Open
Abstract
Integrins are closely related to the occurrence and development of tumors. ITGA8 encodes the alpha 8 subunit of the heterodimeric integrin alpha8beta1. Studies on the role of this gene in the occurrence and development of lung cancer are scarce. The examination of public databases revealed that ITGA8 expression was significantly lower in tumor tissue than that in normal tissue, especially in lung cancer, renal carcinoma, and prostate cancer. Survival analysis of patients with lung adenocarcinoma revealed that higher ITGA8 expression had better prognosis. ITGA8 was positively related to immune checkpoints and immunomodulators, whereas B cell, CD4+ T cell, CD8+ T cell, neutrophil, macrophage, and dendritic cell infiltration had the same correlation. Moreover, ITGA8 was negatively related to cancer stemness. We used an online database to predict the miRNAs and lncRNAs that regulate ITGA8 and obtained the regulatory network of ITGA8 through correlation analysis and Kaplan-Meier survival analysis. Quantitative real-time PCR and western blot analyses showed that LINC01798 regulates ITGA8 expression through miR-17-5p. Therefore, the regulatory network of ITGA8 may serve as a new therapeutic target to improve the prognosis of patients with lung cancer.
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Affiliation(s)
- Xuanguang Li
- Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Guangsheng Zhu
- Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Yongwen Li
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Hua Huang
- Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Chen Chen
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Di Wu
- Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Peijun Cao
- Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Ruifeng Shi
- Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Lianchun Su
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Ruihao Zhang
- Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Hongyu Liu
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Jun Chen
- Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
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Xu FQ, Dong MM, Wang ZF, Cao LD. Metabolic rearrangements and intratumoral heterogeneity for immune response in hepatocellular carcinoma. Front Immunol 2023; 14:1083069. [PMID: 36776894 PMCID: PMC9908004 DOI: 10.3389/fimmu.2023.1083069] [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: 10/28/2022] [Accepted: 01/09/2023] [Indexed: 01/27/2023] Open
Abstract
Liver cancer is one of the most common malignant tumors globally. Not only is it difficult to diagnose, but treatments are scarce and the prognosis is generally poor. Hepatocellular carcinoma (HCC) is the most common type of liver cancer. Aggressive cancer cells, such as those found in HCC, undergo extensive metabolic rewiring as tumorigenesis, the unique feature, ultimately causes adaptation to the neoplastic microenvironment. Intratumoral heterogeneity (ITH) is defined as the presence of distinct genetic features and different phenotypes in the same tumoral region. ITH, a property unique to malignant cancers, results in differences in many different features of tumors, including, but not limited to, tumor growth and resistance to chemotherapy, which in turn is partly responsible for metabolic reprogramming. Moreover, the different metabolic phenotypes might also activate the immune response to varying degrees and help tumor cells escape detection by the immune system. In this review, we summarize the reprogramming of glucose metabolism and tumoral heterogeneity and their associations that occur in HCC, to obtain a better understanding of the mechanisms of HCC oncogenesis.
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Affiliation(s)
- Fei-Qi Xu
- General Surgery, Cancer Center, Department of Hepatobiliary and Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China.,The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Meng-Meng Dong
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetics, The Second Hospital of Jilin University, Changchun, China
| | - Zhi-Fei Wang
- General Surgery, Cancer Center, Department of Hepatobiliary and Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Li-Dong Cao
- General Surgery, Cancer Center, Department of Hepatobiliary and Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
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29
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Gu J, Wang Z, Wang BO, Ma X. ImmuneScore of eight-gene signature predicts prognosis and survival in patients with endometrial cancer. Front Oncol 2023; 13:1097015. [PMID: 36937436 PMCID: PMC10020521 DOI: 10.3389/fonc.2023.1097015] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Accepted: 02/16/2023] [Indexed: 03/06/2023] Open
Abstract
Background Endometrial cancer (EC) is a common gynecological cancer worldwide and the sixth most common female malignant tumor. A large number of studies conducted through database mining have identified many biomarkers that may be related to survival and prognosis. However, the predictive ability of single-gene biomarkers is not sufficiently accurate. In recent years, tumors have been shown to interact closely with their microenvironment, and tumor-infiltrating immune cells in the tumor microenvironment were associated with therapeutic effects. Furthermore, sequencing technology has evolved and allowed the identification of genetic signatures that may improve prediction results. The purpose of this research was to discover the Cancer Genome Atlas (TCGA) data to evaluate new genetic features that can predict the prognosis of EC. Methods mRNA expression profiling was analyzed in patients with EC identified in the TCGA database (n = 530). Differentially expressed genes at different stages of EC were screened using the immune cell enrichment score (ImmuneScore). Univariate and multivariate Cox regression analyses was applied to evaluate genes significantly related to overall survival and establish the prognostic risk parameter formula. Kaplan-Meier survival curves and the logarithmic rank method were applied to verify the importance of risk parameters for the prognostic forecast. The accuracy of survival prediction was confirmed using the nomogram and Receiver Operating Characteristic (ROC) curve analysis. The mRNA expression of eight genes were measured by qRT-PCR. According to COX and HR values, NBAT1, a representative gene among 8 genes, was selected for CCK-8 assay, colony formation assay and transwell invasion assay to verify the effect on survival. Results Eight related genes (NBAT1, GFRA4, PTPRT, DLX4, RANBP3L, UNQ6494, KLRB1, and PRAC1) were discovered to be significantly associated with the overall survival rate. According to these eight-gene signatures, 530 patients with EC were assigned to high- and low-risk subgroups. The prognostic capability of the eight-gene signature was not influenced by other elements. Conclusions Eight related gene markers were identified using ImmuneScore, which could predict prognosis and survival in patients with EC. These findings provide a basis for understanding the application of biological information in tumors and identifying the poor prognosis of EC.
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Yang C, Zhang S, Cheng Z, Liu Z, Zhang L, Jiang K, Geng H, Qian R, Wang J, Huang X, Chen M, Li Z, Qin W, Xia Q, Kang X, Wang C, Hang H. Multi-region sequencing with spatial information enables accurate heterogeneity estimation and risk stratification in liver cancer. Genome Med 2022; 14:142. [PMID: 36527145 PMCID: PMC9758830 DOI: 10.1186/s13073-022-01143-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Accepted: 11/22/2022] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Numerous studies have used multi-region sampling approaches to characterize intra-tumor heterogeneity (ITH) in hepatocellular carcinoma (HCC). However, conventional multi-region sampling strategies do not preserve the spatial details of samples, and thus, the potential influences of spatial distribution on patient-wise ITH (represents the overall heterogeneity level of the tumor in a given patient) have long been overlooked. Furthermore, gene-wise transcriptional ITH (represents the expression pattern of genes across different intra-tumor regions) in HCC is also under-explored, highlighting the need for a comprehensive investigation. METHODS To address the problem of spatial information loss, we propose a simple and easy-to-implement strategy called spatial localization sampling (SLS). We performed multi-region sampling and sequencing on 14 patients with HCC, collecting a total of 75 tumor samples with spatial information and molecular data. Normalized diversity score and integrated heterogeneity score (IHS) were then developed to measure patient-wise and gene-wise ITH, respectively. RESULTS A significant correlation between spatial and molecular heterogeneity was uncovered, implying that spatial distribution of sampling sites did influence ITH estimation in HCC. We demonstrated that the normalized diversity score had the ability to overcome sampling location bias and provide a more accurate estimation of patient-wise ITH. According to this metric, HCC tumors could be divided into two classes (low-ITH and high-ITH tumors) with significant differences in multiple biological properties. Through IHS analysis, we revealed a highly heterogenous immune microenvironment in HCC and identified some low-ITH checkpoint genes with immunotherapeutic potential. We also constructed a low-heterogeneity risk stratification (LHRS) signature based on the IHS results which could accurately predict the survival outcome of patients with HCC on a single tumor biopsy sample. CONCLUSIONS This study provides new insights into the complex phenotypes of HCC and may serve as a guide for future studies in this field.
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Affiliation(s)
- Chen Yang
- grid.16821.3c0000 0004 0368 8293Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China ,grid.16821.3c0000 0004 0368 8293State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Senquan Zhang
- grid.16821.3c0000 0004 0368 8293Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhuoan Cheng
- grid.16821.3c0000 0004 0368 8293Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China ,grid.16821.3c0000 0004 0368 8293State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhicheng Liu
- grid.412793.a0000 0004 1799 5032Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Linmeng Zhang
- grid.16821.3c0000 0004 0368 8293State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Kai Jiang
- grid.16821.3c0000 0004 0368 8293Renji Biobank, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haigang Geng
- grid.16821.3c0000 0004 0368 8293Department of Gastrointestinal Surgery, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Ruolan Qian
- grid.16821.3c0000 0004 0368 8293State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jun Wang
- grid.16821.3c0000 0004 0368 8293State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaowen Huang
- grid.16821.3c0000 0004 0368 8293Key Laboratory of Gastroenterology and Hepatology, Division of Gastroenterology and Hepatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Mo Chen
- grid.16821.3c0000 0004 0368 8293Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhe Li
- grid.16821.3c0000 0004 0368 8293Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wenxin Qin
- grid.16821.3c0000 0004 0368 8293State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qiang Xia
- grid.16821.3c0000 0004 0368 8293Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China ,grid.16821.3c0000 0004 0368 8293State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaonan Kang
- grid.16821.3c0000 0004 0368 8293Renji Biobank, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Cun Wang
- grid.16821.3c0000 0004 0368 8293Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China ,grid.16821.3c0000 0004 0368 8293State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hualian Hang
- grid.16821.3c0000 0004 0368 8293Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China ,grid.16821.3c0000 0004 0368 8293State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Nyman SS, Ahlström H, Creusen AD, Dahlgren D, Hedeland M, Heindryckx F, Johnson U, Khaled J, Kullenberg F, Nyman R, Rorsman F, Sheikhi R, Simonsson USH, Sjögren E, Wanders A, Lennernäs H, Ebeling Barbier C. Study protocol for locoregional precision treatment of hepatocellular carcinoma with transarterial chemoembolisation (TACTida), a clinical study: idarubicin dose selection, tissue response and survival. BMJ Open 2022; 12:e065839. [PMID: 36343995 PMCID: PMC9644353 DOI: 10.1136/bmjopen-2022-065839] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) is a common cause of cancer-related death, often detected in the intermediate stage. The standard of care for intermediate-stage HCC is transarterial chemoembolisation (TACE), where idarubicin (IDA) is a promising drug. Despite the fact that TACE has been used for several decades, treatment success is unpredictable. This clinical trial has been designed believing that further improvement might be achieved by increasing the understanding of interactions between local pharmacology, tumour targeting, HCC pathophysiology, metabolomics and molecular mechanisms of drug resistance. METHODS AND ANALYSIS The study population of this single-centre clinical trial consists of adults with intermediate-stage HCC. Each tumour site will receive TACE with two different IDA doses, 10 and 15 mg, on separate occasions. Before and after each patient's first TACE blood samples, tissue and liquid biopsies, and positron emission tomography (PET)/MRI will be performed. Blood samples will be used for pharmacokinetics (PK) and liver function evaluation. Tissue biopsies will be used for histopathology analyses, and culturing of primary organoids of tumour and non-tumour tissue to measure cell viability, drug response, multiomics and gene expression. Multiomics analyses will also be performed on liquid biopsies. PET/MRI will be used to evaluate tumour viability and liver metabolism. The two doses of IDA will be compared regarding PK, antitumour effects and safety. Imaging, molecular biology and multiomics data will be used to identify HCC phenotypes and their relation to drug uptake and metabolism, treatment response and survival. ETHICS AND DISSEMINATION Participants give informed consent. Personal data are deidentified. A patient will be withdrawn from the study if considered medically necessary, or if it is the wish of the patient. The study has been approved by the Swedish Ethical Review Authority (Dnr. 2021-01928) and by the Medical Product Agency, Uppsala, Sweden. TRIAL REGISTRATION NUMBER EudraCT number: 2021-001257-31.
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Affiliation(s)
- Sofi Sennefelt Nyman
- Department of Surgical Sciences, Section of Radiology, Uppsala University, Uppsala, Sweden
| | - Håkan Ahlström
- Department of Surgical Sciences, Section of Radiology, Uppsala University, Uppsala, Sweden
| | | | - David Dahlgren
- Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
| | - Mikael Hedeland
- Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry, Uppsala University, Uppsala, Sweden
| | - Femke Heindryckx
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Ulf Johnson
- Department of Surgical Sciences, Section of Radiology, Uppsala University, Uppsala, Sweden
| | - Jaafar Khaled
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Fredrik Kullenberg
- Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
| | - Rickard Nyman
- Department of Surgical Sciences, Section of Radiology, Uppsala University, Uppsala, Sweden
| | - Fredrik Rorsman
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Reza Sheikhi
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | | | - Erik Sjögren
- Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
| | - Alkwin Wanders
- Department of Pathology, Aalborg University Hospital, Aalborg, Denmark
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Hans Lennernäs
- Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
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Ahmad M, Dhasmana A, Harne PS, Zamir A, Hafeez BB. Chemokine clouding and liver cancer heterogeneity: Does it impact clinical outcomes? Semin Cancer Biol 2022; 86:1175-1185. [PMID: 35189322 DOI: 10.1016/j.semcancer.2022.02.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Revised: 02/11/2022] [Accepted: 02/12/2022] [Indexed: 02/08/2023]
Abstract
Tumor heterogeneity is a predominant feature of hepatocellular carcinoma (HCC) that plays a crucial role in chemoresistance and limits the efficacy of available chemo/immunotherapy regimens. Thus, a better understanding regarding the molecular determinants of tumor heterogeneity will help in developing newer strategies for effective HCC management. Chemokines, a sub-family of cytokines are one of the key molecular determinants of tumor heterogeneity in HCC and are involved in cell survival, growth, migration, and angiogenesis. Herein, we provide a panoramic insight into the role of chemokines in HCC heterogeneity at genetic, epigenetic, metabolic, immune cell composition, and tumor microenvironment levels and its impact on clinical outcomes. Interestingly, our in-silico analysis data showed that expression of chemokine receptors impacts infiltration of various immune cell populations into the liver tumor and leads to heterogeneity. Thus, it is evident that aberrant chemokines clouding impacts HCC tumor heterogeneity and understanding this phenomenon in depth could be harnessed for the development of personalized medicine strategies in future.
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Affiliation(s)
- Mudassier Ahmad
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, TX 78504, United States
| | - Anupam Dhasmana
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, TX 78504, United States; Department of Biosciences and Cancer Research Institute, Himalayan Institute of Medical Sciences, Swami Rama Himalayan University, Dehradun, India
| | - Prateek Suresh Harne
- DHR Health Gastroenterology, 5520 Leonardo da Vinci Drive, Suite 100, Edinburg, TX 78539, United States
| | - Asif Zamir
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, TX 78504, United States; DHR Health Gastroenterology, 5520 Leonardo da Vinci Drive, Suite 100, Edinburg, TX 78539, United States
| | - Bilal Bin Hafeez
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, TX 78504, United States; Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, TX 78504, United States.
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Testa U, Pelosi E, Castelli G. Clinical value of identifying genes that inhibit hepatocellular carcinomas. Expert Rev Mol Diagn 2022; 22:1009-1035. [PMID: 36459631 DOI: 10.1080/14737159.2022.2154658] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/05/2022]
Abstract
INTRODUCTION Primary liver cancer is a major health problem being the sixth most frequent cancer in the world and the fourth most frequent cause of cancer-related death in the world. The most common histological type of liver cancer is hepatocellular carcinoma (HCC, 75-80%). AREAS COVERED Based on primary literature, this review provides an updated analysis of studies of genetic characterization of HCC at the level of gene mutation profiling, copy number alterations and gene expression, with definition of molecular subgroups and identification of some molecular biomarkers and therapeutic targets. EXPERT OPINION A detailed and comprehensive study of the genetic abnormalities characterizing different HCC subsets represents a fundamental tool for a better understanding of the disease heterogeneity and for the identification of subgroups of patients responding or resistant to targeted treatments and for the discovery of new therapeutic targets. It is expected that a comprehensive characterization of these tumors may provide a fundamental contribution to improve the survival of a subset of HCC patients. Immunotherapy represents a new fundamental strategy for the treatment of HCC.
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Affiliation(s)
- Ugo Testa
- Department of Oncology, Istituto Superiore Di Sanità, ROME, ITALY
| | - Elvira Pelosi
- Department of Oncology, Istituto Superiore Di Sanità, ROME, ITALY
| | - Germana Castelli
- Department of Oncology, Istituto Superiore Di Sanità, ROME, ITALY
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Pu Z, Liu J, Liu Z, Peng F, Zhu Y, Wang X, He J, Yi P, Hu X, Fan X, Chen J. STING pathway contributes to the prognosis of hepatocellular carcinoma and identification of prognostic gene signatures correlated to tumor microenvironment. Cancer Cell Int 2022; 22:314. [PMID: 36224658 PMCID: PMC9554977 DOI: 10.1186/s12935-022-02734-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 09/26/2022] [Indexed: 11/10/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) is one of the most malignant solid tumors worldwide. Recent evidence shows that the stimulator of interferon genes (STING) pathway is essential for anti-tumor immunity via inducing the production of downstream inflammatory cytokines. However, its impact on the prognosis and tumor microenvironment of HCC was still limited known. Methods We obtained gene expression profiles of HCC from GEO, TCGA, and ICGC databases, and immune-related genes (IRGs) from the ImmPort database. Multivariate Cox regression was performed to identify independent prognostic factors. Nomogram was established to predict survival probability for individual patients. Kaplan–Meier curve was used to evaluate the survival difference. Afterward, ESTIMATE, TISCH, and TIMER databases were combined to assess the immune cell infiltration. Furthermore, the qPCR, western blotting, and immunohistochemistry were done to evaluate gene expression, and in vitro cell models were built to determine cell migratory ability. Results We found that gene markers of NLRC3, STING1, TBK1, TRIM21, and XRCC6 within STING pathway were independent prognostic factors in HCC patients. Underlying the finding, a predictive nomogram was constructed in TCGA-training cohort and further validated in TCGA-all and ICGC datasets, showing credible performance. Experimentally, up-regulated TBK1 promotes the ability of HCC cell migration. Next, the survival-related immune-related co-expressed gene signatures (IRCGS) (VAV1, RHOA, and ZC3HAV1) were determined in HCC cohorts and their expression was verified in human HCC cells and clinical samples. Furthermore, survival-related IRCGS was associated with the infiltration of various immune cell subtypes in HCC, the transcriptional expression of prominent immune checkpoints, and immunotherapeutic response. Conclusion Collectively, we constructed a novel prognostic nomogram model for predicting the survival probability of individual HCC patients. Moreover, an immune-related prognostic gene signature was determined. Both might function as potential therapeutic targets for HCC treatment in the future. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-022-02734-4.
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Affiliation(s)
- Zhangya Pu
- Department of Infectious Diseases, Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, No. 87, Xiangya Rd, Kaifu District, Changsha, 410008, Hunan Province, China.,Department of Infectious Disease, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310000, Zhejiang Province, China
| | - Jinghua Liu
- Department of Hepatobiliary Surgery, Linyi People's Hospital, Linyi, Shandong, China
| | - Zelong Liu
- Division of Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China
| | - Fang Peng
- Department of Infectious Diseases, Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, No. 87, Xiangya Rd, Kaifu District, Changsha, 410008, Hunan Province, China.,NHC Key Laboratory of Cancer Proteomics, Xiangya Hospital, Central South University, Changsha, 41800, Hunan Province, China
| | - Yuanyuan Zhu
- Department of Infectious Diseases, Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, No. 87, Xiangya Rd, Kaifu District, Changsha, 410008, Hunan Province, China.,NHC Key Laboratory of Cancer Proteomics, Xiangya Hospital, Central South University, Changsha, 41800, Hunan Province, China
| | - Xiaofang Wang
- Department of Infectious Diseases, Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, No. 87, Xiangya Rd, Kaifu District, Changsha, 410008, Hunan Province, China
| | - Jiayan He
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310000, Zhejiang Province, China
| | - Panpan Yi
- Department of Infectious Diseases, Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, No. 87, Xiangya Rd, Kaifu District, Changsha, 410008, Hunan Province, China
| | - Xingwang Hu
- Department of Infectious Diseases, Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, No. 87, Xiangya Rd, Kaifu District, Changsha, 410008, Hunan Province, China.
| | - Xuegong Fan
- Department of Infectious Diseases, Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, No. 87, Xiangya Rd, Kaifu District, Changsha, 410008, Hunan Province, China.
| | - Jiang Chen
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310000, Zhejiang Province, China.
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Zhang G, Xiao Y, Zhang X, Fan W, Zhao Y, Wu Y, Wang H, Li J. Dissecting a hypoxia-related angiogenic gene signature for predicting prognosis and immune status in hepatocellular carcinoma. Front Oncol 2022; 12:978050. [PMID: 36110938 PMCID: PMC9468769 DOI: 10.3389/fonc.2022.978050] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Accepted: 08/09/2022] [Indexed: 12/12/2022] Open
Abstract
BackgroundHypoxia and angiogenesis, as prominent characteristics of malignant tumors, are implicated in the progression of hepatocellular carcinoma (HCC). However, the role of hypoxia in the angiogenesis of liver cancer is unclear. Therefore, we explored the regulatory mechanisms of hypoxia-related angiogenic genes (HRAGs) and the relationship between these genes and the prognosis of HCC.MethodsThe transcriptomic and clinical data of HCC samples were downloaded from public datasets, followed by identification of hypoxia- and angiogenesis-related genes in the database. A gene signature model was constructed based on univariate and multivariate Cox regression analyses, and validated in independent cohorts. Kaplan-Meier survival and time-dependent receiver operating characteristic (ROC) curves were generated to evaluate the model’s predictive capability. Gene set enrichment analysis (GSEA) was performed to explore signaling pathways regulated by the gene signature. Furthermore, the relationships among gene signature, immune status, and response to anti-angiogenesis agents and immune checkpoint blockade (ICB) were analyzed.ResultsThe prognostic model was based on three HRAGs (ANGPT2, SERPINE1 and SPP1). The model accurately predicted that low-risk patients would have longer overall survival than high-risk patients, consistent with findings in other cohorts. GSEA indicated that high-risk group membership was significantly associated with hypoxia, angiogenesis, the epithelial-mesenchymal transition, and activity in immune-related pathways. The high-risk group also had more immunosuppressive cells and higher expression of immune checkpoints such as PD-1 and PD-L1. Conversely, the low-risk group had a better response to anti-angiogenesis and ICB therapy.ConclusionsThe gene signature based on HRAGs was predictive of prognosis and provided an immunological perspective that will facilitate the development of personalized therapies.
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Affiliation(s)
- Guixiong Zhang
- Department of Interventional Oncology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yitai Xiao
- Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China
| | - Xiaokai Zhang
- Department of Interventional Oncology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Wenzhe Fan
- Department of Interventional Oncology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yue Zhao
- Department of Interventional Oncology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yanqin Wu
- Department of Interventional Oncology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Hongyu Wang
- Department of Interventional Oncology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jiaping Li
- Department of Interventional Oncology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- *Correspondence: Jiaping Li,
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Ong LJY, Chia S, Wong SQR, Zhang X, Chua H, Loo JM, Chua WY, Chua C, Tan E, Hentze H, Tan IB, DasGupta R, Toh YC. A comparative study of tumour-on-chip models with patient-derived xenografts for predicting chemotherapy efficacy in colorectal cancer patients. Front Bioeng Biotechnol 2022; 10:952726. [PMID: 36147524 PMCID: PMC9488115 DOI: 10.3389/fbioe.2022.952726] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 07/19/2022] [Indexed: 11/24/2022] Open
Abstract
Inter-patient and intra-tumour heterogeneity (ITH) have prompted the need for a more personalised approach to cancer therapy. Although patient-derived xenograft (PDX) models can generate drug response specific to patients, they are not sustainable in terms of cost and time and have limited scalability. Tumour Organ-on-Chip (OoC) models are in vitro alternatives that can recapitulate some aspects of the 3D tumour microenvironment and can be scaled up for drug screening. While many tumour OoC systems have been developed to date, there have been limited validation studies to ascertain whether drug responses obtained from tumour OoCs are comparable to those predicted from patient-derived xenograft (PDX) models. In this study, we established a multiplexed tumour OoC device, that consists of an 8 × 4 array (32-plex) of culture chamber coupled to a concentration gradient generator. The device enabled perfusion culture of primary PDX-derived tumour spheroids to obtain dose-dependent response of 5 distinct standard-of-care (SOC) chemotherapeutic drugs for 3 colorectal cancer (CRC) patients. The in vitro efficacies of the chemotherapeutic drugs were rank-ordered for individual patients and compared to the in vivo efficacy obtained from matched PDX models. We show that quantitative correlation analysis between the drug efficacies predicted via the microfluidic perfusion culture is predictive of response in animal PDX models. This is a first study showing a comparative framework to quantitatively correlate the drug response predictions made by a microfluidic tumour organ-on-chip (OoC) model with that of PDX animal models.
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Affiliation(s)
- Louis Jun Ye Ong
- School of Mechanical, Medical and Process Engineering, Queensland University of Technology (QUT), Brisbane, QL, Australia
- Centre for Biomedical Technologies, Queensland University of Technology (QUT), Brisbane, QL, Australia
- Department of Biomedical Engineering, National University of Singapore, Singapore, Singapore
- Institute for Health Innovation and Technology, National University of Singapore, Singapore, Singapore
| | - Shumei Chia
- Laboratory of Precision Oncology and Cancer Evolution, Genome Institute of Singapore, A*STAR, Singapore, Singapore
| | - Stephen Qi Rong Wong
- Laboratory of Precision Oncology and Cancer Evolution, Genome Institute of Singapore, A*STAR, Singapore, Singapore
- Biological Resource Centre, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Xiaoqian Zhang
- Laboratory of Precision Oncology and Cancer Evolution, Genome Institute of Singapore, A*STAR, Singapore, Singapore
| | - Huiwen Chua
- Laboratory of Precision Oncology and Cancer Evolution, Genome Institute of Singapore, A*STAR, Singapore, Singapore
| | - Jia Min Loo
- Laboratory of Precision Oncology and Cancer Evolution, Genome Institute of Singapore, A*STAR, Singapore, Singapore
| | - Wei Yong Chua
- Laboratory of Precision Oncology and Cancer Evolution, Genome Institute of Singapore, A*STAR, Singapore, Singapore
| | - Clarinda Chua
- National Cancer Centre Singapore, Singapore, Singapore
| | - Emile Tan
- Singapore General Hospital, Singapore, Singapore
| | - Hannes Hentze
- Experimental, Drug Development Centre, A*STAR, Singapore, Singapore
| | - Iain Beehuat Tan
- Laboratory of Precision Oncology and Cancer Evolution, Genome Institute of Singapore, A*STAR, Singapore, Singapore
- National Cancer Centre Singapore, Singapore, Singapore
- Duke-NUS Graduate Medical School, Singapore, Singapore
| | - Ramanuj DasGupta
- Laboratory of Precision Oncology and Cancer Evolution, Genome Institute of Singapore, A*STAR, Singapore, Singapore
- *Correspondence: Ramanuj DasGupta, ; Yi-Chin Toh,
| | - Yi-Chin Toh
- School of Mechanical, Medical and Process Engineering, Queensland University of Technology (QUT), Brisbane, QL, Australia
- Centre for Biomedical Technologies, Queensland University of Technology (QUT), Brisbane, QL, Australia
- Department of Biomedical Engineering, National University of Singapore, Singapore, Singapore
- Institute for Health Innovation and Technology, National University of Singapore, Singapore, Singapore
- *Correspondence: Ramanuj DasGupta, ; Yi-Chin Toh,
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Shi H, Duan Y, Shi J, Zhang W, Liu W, Shen B, Liu F, Mei X, Li X, Yuan Z. Role of preoperative prediction of microvascular invasion in hepatocellular carcinoma based on the texture of FDG PET image: A comparison of quantitative metabolic parameters and MRI. Front Physiol 2022; 13:928969. [PMID: 36035488 PMCID: PMC9412047 DOI: 10.3389/fphys.2022.928969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 07/13/2022] [Indexed: 11/15/2022] Open
Abstract
Objective: To investigate the role of prediction microvascular invasion (mVI) in hepatocellular carcinoma (HCC) by 18F-FDG PET image texture analysis and hybrid criteria combining PET/CT and multi-parameter MRI. Materials and methods: Ninety-seven patients with HCC who received the examinations of MRI and 18F-FDG PET/CT were retrospectively included in this study and were randomized into training and testing cohorts. The lesion image texture features of 18F-FDG PET were extracted using MaZda software. The optimal predictive texture features of mVI were selected, and the classification procedure was conducted. The predictive performance of mVI by radiomics classier in training and testing cohorts was respectively recorded. Next, the hybrid model was developed by integrating the 18F-FDG PET image texture, metabolic parameters, and MRI parameters to predict mVI through logistic regression. Furthermore, the diagnostic performance of each time was recorded. Results: The 18F-FDG PET image radiomics classier showed good predicted performance in both training and testing cohorts to discriminate HCC with/without mVI, with an AUC of 0.917 (95% CI: 0.824–0.970) and 0.771 (95% CI: 0.578, 0.905). The hybrid model, which combines radiomics classier, SUVmax, ADC, hypovascular arterial phase enhancement pattern on contrast-enhanced MRI, and non-smooth tumor margin, also yielded better predictive performance with an AUC of 0.996 (95% CI: 0.939, 1.000) and 0.953 (95% CI: 0.883, 1.000). The differences in AUCs between radiomics classier and hybrid classier were significant in both training and testing cohorts (DeLong test, both p < 0.05). Conclusion: The radiomics classier based on 18F-FDG PET image texture and the hybrid classier incorporating 18F-FDG PET/CT and MRI yielded good predictive performance, which might provide a precise prediction of HCC mVI preoperatively.
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Affiliation(s)
- Huazheng Shi
- Shanghai Universal Cloud Medical Imaging Diagnostic Center, Shanghai, China
| | - Ying Duan
- Shanghai Universal Cloud Medical Imaging Diagnostic Center, Shanghai, China
| | - Jie Shi
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China
| | - Wenrui Zhang
- Shanghai Universal Cloud Medical Imaging Diagnostic Center, Shanghai, China
| | - Weiran Liu
- Shanghai Universal Cloud Medical Imaging Diagnostic Center, Shanghai, China
| | - Bixia Shen
- Shanghai Universal Cloud Medical Imaging Diagnostic Center, Shanghai, China
| | - Fufu Liu
- Shanghai Universal Cloud Medical Imaging Diagnostic Center, Shanghai, China
| | - Xin Mei
- Shanghai Universal Cloud Medical Imaging Diagnostic Center, Shanghai, China
| | - Xiaoxiao Li
- Shanghai Universal Cloud Medical Imaging Diagnostic Center, Shanghai, China
- *Correspondence: Zheng Yuan, ; Xiaoxiao Li,
| | - Zheng Yuan
- Department of Radiology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Zheng Yuan, ; Xiaoxiao Li,
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Hu X, Zhou J, Zhang Y, Zeng Y, Jie G, Wang S, Yang A, Zhang M. Identifying potential prognosis markers in hepatocellular carcinoma via integrated bioinformatics analysis and biological experiments. Front Genet 2022; 13:942454. [PMID: 35928445 PMCID: PMC9343963 DOI: 10.3389/fgene.2022.942454] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 06/29/2022] [Indexed: 12/18/2022] Open
Abstract
Background: Hepatocellular carcinoma is one kind of clinical common malignant tumor with a poor prognosis, and its pathogenesis remains to be clarified urgently. This study was performed to elucidate key genes involving HCC by bioinformatics analysis and experimental evaluation. Methods: We identified common differentially expressed genes (DEGs) based on gene expression profile data of GSE60502 and GSE84402 from the Gene Expression Omnibus (GEO) database. Gene Ontology enrichment analysis (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, REACTOME pathway enrichment analysis, and Gene Set Enrichment Analysis (GSEA) were used to analyze functions of these genes. The protein-protein interaction (PPI) network was constructed using Cytoscape software based on the STRING database, and Molecular Complex Detection (MCODE) was used to pick out two significant modules. Hub genes, screened by the CytoHubba plug-in, were validated by Gene Expression Profiling Interactive Analysis (GEPIA) and the Human Protein Atlas (HPA) database. Then, the correlation between hub genes expression and immune cell infiltration was evaluated by Tumor IMmune Estimation Resource (TIMER) database, and the prognostic values were analyzed by Kaplan-Meier plotter. Finally, biological experiments were performed to illustrate the functions of RRM2. Results: Through integrated bioinformatics analysis, we found that the upregulated DEGs were related to cell cycle and cell division, while the downregulated DEGs were associated with various metabolic processes and complement cascade. RRM2, MAD2L1, MELK, NCAPG, and ASPM, selected as hub genes, were all correlated with poor overall prognosis in HCC. The novel RRM2 inhibitor osalmid had anti-tumor activity, including inhibiting proliferation and migration, promoting cell apoptosis, blocking cell cycle, and inducing DNA damage of HCC cells. Conclusion: The critical pathways and hub genes in HCC progression were screened out, and targeting RRM2 contributed to developing new therapeutic strategies for HCC.
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Affiliation(s)
- Xueting Hu
- Department of Intensive Care Unit, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu, China
| | - Jian Zhou
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Yan Zhang
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Yindi Zeng
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Guitao Jie
- Department of Hematology, Linyi Central Hospital, Yishui, Shandong, China
| | - Sheng Wang
- Department of Hematology, Linyi Central Hospital, Yishui, Shandong, China
| | - Aixiang Yang
- Department of Intensive Care Unit, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu, China
- *Correspondence: Aixiang Yang, ; Menghui Zhang,
| | - Menghui Zhang
- Department of Hematology, Linyi Central Hospital, Yishui, Shandong, China
- *Correspondence: Aixiang Yang, ; Menghui Zhang,
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Yan T, Yu L, Zhang N, Peng C, Su G, Jing Y, Zhang L, Wu T, Cheng J, Guo Q, Shi X, Lu Y. The advanced development of molecular targeted therapy for hepatocellular carcinoma. Cancer Biol Med 2022. [PMID: 35699406 DOI: 10.20892/j.issn.2095-3941.2021.0661.pmid:35699406;pmcid:pmc9257319] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/15/2023] Open
Abstract
Hepatocellular carcinoma (HCC), one of the most common malignant tumors in China, severely threatens the life and health of patients. In recent years, precision medicine, clinical diagnoses, treatments, and innovative research have led to important breakthroughs in HCC care. The discovery of new biomarkers and the promotion of liquid biopsy technologies have greatly facilitated the early diagnosis and treatment of HCC. Progress in targeted therapy and immunotherapy has provided more choices for precise HCC treatment. Multiomics technologies, such as genomics, transcriptomics, and metabolomics, have enabled deeper understanding of the occurrence and development mechanisms, heterogeneity, and genetic mutation characteristics of HCC. The continued promotion and accurate typing of HCC, accurate guidance of treatment, and accurate prognostication have provided more treatment opportunities and prolonged survival timelines for patients with HCC. Innovative HCC research providing an in-depth understanding of the biological characteristics of HCC will be translated into accurate clinical practices for the diagnosis and treatment of HCC.
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Affiliation(s)
- Tao Yan
- Comprehensive Liver Cancer Center, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
| | - Lingxiang Yu
- The Second Department of Hepatobiliary Surgery, Senior Department of Hepatology, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Ning Zhang
- Comprehensive Liver Cancer Center, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Caiyun Peng
- Comprehensive Liver Cancer Center, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Guodong Su
- Comprehensive Liver Cancer Center, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Yi Jing
- Comprehensive Liver Cancer Center, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Linzhi Zhang
- Comprehensive Liver Cancer Center, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Tong Wu
- Comprehensive Liver Cancer Center, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Jiamin Cheng
- Comprehensive Liver Cancer Center, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Qian Guo
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
| | | | - Yinying Lu
- Comprehensive Liver Cancer Center, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
- National Clinical Medical Research Center for Infectious Diseases, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
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Yan T, Yu L, Zhang N, Peng C, Su G, Jing Y, Zhang L, Wu T, Cheng J, Guo Q, Shi X, Lu Y. The advanced development of molecular targeted therapy for hepatocellular carcinoma. Cancer Biol Med 2022; 19:j.issn.2095-3941.2021.0661. [PMID: 35699406 PMCID: PMC9257319 DOI: 10.20892/j.issn.2095-3941.2021.0661] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 04/18/2022] [Indexed: 11/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC), one of the most common malignant tumors in China, severely threatens the life and health of patients. In recent years, precision medicine, clinical diagnoses, treatments, and innovative research have led to important breakthroughs in HCC care. The discovery of new biomarkers and the promotion of liquid biopsy technologies have greatly facilitated the early diagnosis and treatment of HCC. Progress in targeted therapy and immunotherapy has provided more choices for precise HCC treatment. Multiomics technologies, such as genomics, transcriptomics, and metabolomics, have enabled deeper understanding of the occurrence and development mechanisms, heterogeneity, and genetic mutation characteristics of HCC. The continued promotion and accurate typing of HCC, accurate guidance of treatment, and accurate prognostication have provided more treatment opportunities and prolonged survival timelines for patients with HCC. Innovative HCC research providing an in-depth understanding of the biological characteristics of HCC will be translated into accurate clinical practices for the diagnosis and treatment of HCC.
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Affiliation(s)
- Tao Yan
- Comprehensive Liver Cancer Center, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
| | - Lingxiang Yu
- The Second Department of Hepatobiliary Surgery, Senior Department of Hepatology, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Ning Zhang
- Comprehensive Liver Cancer Center, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Caiyun Peng
- Comprehensive Liver Cancer Center, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Guodong Su
- Comprehensive Liver Cancer Center, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Yi Jing
- Comprehensive Liver Cancer Center, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Linzhi Zhang
- Comprehensive Liver Cancer Center, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Tong Wu
- Comprehensive Liver Cancer Center, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Jiamin Cheng
- Comprehensive Liver Cancer Center, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Qian Guo
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
| | | | - Yinying Lu
- Comprehensive Liver Cancer Center, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
- National Clinical Medical Research Center for Infectious Diseases, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
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Lv K, Cao X, Du P, Fu JY, Geng DY, Zhang J. Radiomics for the detection of microvascular invasion in hepatocellular carcinoma. World J Gastroenterol 2022; 28:2176-2183. [PMID: 35721882 PMCID: PMC9157623 DOI: 10.3748/wjg.v28.i20.2176] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 01/09/2022] [Accepted: 04/25/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer, accounting for about 90% of liver cancer cases. It is currently the fifth most common cancer in the world and the third leading cause of cancer-related mortality. Moreover, recurrence of HCC is common. Microvascular invasion (MVI) is a major factor associated with recurrence in postoperative HCC. It is difficult to evaluate MVI using traditional imaging modalities. Currently, MVI is assessed primarily through pathological and immunohistochemical analyses of postoperative tissue samples. Needle biopsy is the primary method used to confirm MVI diagnosis before surgery. As the puncture specimens represent just a small part of the tumor, and given the heterogeneity of HCC, biopsy samples may yield false-negative results. Radiomics, an emerging, powerful, and non-invasive tool based on various imaging modalities, such as computed tomography, magnetic resonance imaging, ultrasound, and positron emission tomography, can predict the HCC-MVI status preoperatively by delineating the tumor and/or the regions at a certain distance from the surface of the tumor to extract the image features. Although positive results have been reported for radiomics, its drawbacks have limited its clinical translation. This article reviews the application of radiomics, based on various imaging modalities, in preoperative evaluation of HCC-MVI and explores future research directions that facilitate its clinical translation.
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Affiliation(s)
- Kun Lv
- Department of Radiology, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Xin Cao
- Department of Radiology, Huashan Hospital, Fudan University, Shanghai 200040, China
- Institute of Functional and Molecular Medical Imaging, Fudan University, Shanghai 200040, China
- Center for Shanghai Intelligent Imaging for Critical Brain Diseases Engineering and Technology Research, Science and Technology Commission of Shanghai Municipality, Shanghai 200040, China
- Institute of Intelligent Imaging Phenomics, International Human Phenome Institutes (Shanghai), Shanghai 200040, China
| | - Peng Du
- Department of Radiology, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Jun-Yan Fu
- Department of Radiology, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Dao-Ying Geng
- Department of Radiology, Huashan Hospital, Fudan University, Shanghai 200040, China
- Institute of Functional and Molecular Medical Imaging, Fudan University, Shanghai 200040, China
- Center for Shanghai Intelligent Imaging for Critical Brain Diseases Engineering and Technology Research, Science and Technology Commission of Shanghai Municipality, Shanghai 200040, China
- Institute of Intelligent Imaging Phenomics, International Human Phenome Institutes (Shanghai), Shanghai 200040, China
| | - Jun Zhang
- Department of Radiology, Huashan Hospital, Fudan University, Shanghai 200040, China
- Institute of Functional and Molecular Medical Imaging, Fudan University, Shanghai 200040, China
- Center for Shanghai Intelligent Imaging for Critical Brain Diseases Engineering and Technology Research, Science and Technology Commission of Shanghai Municipality, Shanghai 200040, China
- Institute of Intelligent Imaging Phenomics, International Human Phenome Institutes (Shanghai), Shanghai 200040, China
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Chen CJ, Chiu WC, Tseng YH, Lin CM, Yang HY, Yang YH, Chen PC. Aristolochic acid and the risk of cancers in patients with type 2 diabetes: Nationwide population-based cohort study. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 99:154023. [PMID: 35276591 DOI: 10.1016/j.phymed.2022.154023] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 02/12/2022] [Accepted: 02/28/2022] [Indexed: 06/14/2023]
Abstract
BACKGROUND Both aristolochic acid (AA) exposure and diabetic can increase risk of certain cancers,whetherAAexposureincreases cancer risk in diabetic patientsisunknown. The purpose of this study was to investigate the association between the use of Chinese herbal products containing AA and the risk of cancer in diabetic patients. METHODS A cohort study was conducted using the National Health Insurance Research Database in Taiwan. Patients older than 18 years who were diagnosed with diabetes between 1997 and 2010 were enrolled in our cohort. The use of Chinese herbal products containing AA was recorded from the beginning of 1997 until the ban of herbs containing AA in November 2003. Patients were individually tracked to identify cancer incidence between 1997 and 2013. Only patients who visited traditional Chinese medicine clinics between 1997 and 1 year before the end of follow-up were included in the cohort to ensure comparability. Cox proportional hazards regression was used to calculate the hazard ratio for the association between the use of Chinese herbal products containing AA and the occurrence of cancer. RESULTS Among the 430 377 male and 431 956 female patients with diabetes enrolled in our cohort, 37 554 and 31 535 cancer diagnoses were recorded during the study period, respectively. The use of AA-containing herbal products was associated with a significantly higher risk of liver, colorectum, kidney, bladder, prostate, pelvis, and ureter cancer in a dose-dependent manner. An increased risk of extrahepatic bile duct cancer in women was also associated with AA exposure at doses of more than 500 mg. CONCLUSIONS Association between AA exposure and the risk of some cancers were found in this study. AA exposure might increase risk of kidney,bladder,pelvis, ureter,liver,colorectum,andprostatecancer in all patientsandextrahepatic bile duct cancerin women.
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Affiliation(s)
- Chi-Jen Chen
- Institute of Epidemiology and Preventive Medicine, National Taiwan University College of Public Health, Taipei, Taiwan
| | - Wei-Che Chiu
- Department of Psychiatry, Cathay General Hospital, Taipei, Taiwan; School of Medicine, Fu Jen Catholic University, New Taipei, Taiwan
| | - Yao-Hsien Tseng
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; Division of Geriatrics, Puli Branch, Taichung Veterans General Hospital, Nantou, Taiwan
| | - Chien-Mu Lin
- Department of Nuclear Medicine (C.-M.L.), Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan; Department of Radiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Hsiao-Yu Yang
- Institute of Environmental and Occupational Health Sciences, National Taiwan University College of Public Health, Taipei, Taiwan; Department of Public Health, National Taiwan University College of Public Health, Taipei, Taiwan
| | - Yao-Hsu Yang
- Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Chiayi County, Taiwan; Health Informatics and Epidemiology Laboratory, Chang Gung Memorial Hospital, Chiayi County, Taiwan; School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
| | - Pau-Chung Chen
- Institute of Environmental and Occupational Health Sciences, National Taiwan University College of Public Health, Taipei, Taiwan; Department of Public Health, National Taiwan University College of Public Health, Taipei, Taiwan; Department of Environmental and Occupational Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli, Taiwan.
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Comprehensive Analysis of RAPGEF2 for Predicting Prognosis and Immunotherapy Response in Patients with Hepatocellular Carcinoma. JOURNAL OF ONCOLOGY 2022; 2022:6560154. [PMID: 35518785 PMCID: PMC9064514 DOI: 10.1155/2022/6560154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 03/30/2022] [Indexed: 11/17/2022]
Abstract
Background Hepatocellular carcinoma (HCC) is the sixth most common tumor worldwide. Additionally, deletion of RAPGEF2 plays a critical role in CNV and related to tumor immune microenvironment, whereas the prognostic potential of RAPGEF2 in HCC patient needs to be explored. Methods We looked for prognostic potential genes in HCC using a variety of R programs. Then, using the LASSO Cox regression, we thoroughly evaluated and integrated the RAPGEF2-related genes from TCGA database. Meanwhile, utilizing TCGA and ICGA databases, the link between RAPGEF2 and immunotherapy response in HCC was studied. In vivo, the effect of RAPGEF2 on tumor development and the capacity of natural killer (NK) cells to recruit were confirmed. To ascertain the connection between RAPGEF2-related genes and the prognosis of HCC, a prognostic model was created and validated. Result We demonstrated RAPGEF2 has a differential expression, and patients with deletion of RAPGEF2 gene get shorter survival in HCC. Additionally, the tissues without RAPGEF2 have a weaker ability to recruit the NK cells and response to immunotherapy. After that, we scoured the database for eight RAPGEF2-related genes linked with a better prognosis in HCC patients. Additionally, silencing RAPGEF2 accelerated tumor development in the HCC mouse model and decreased CD56+ NK cell recruitment in HCC tissues. TCGA database was used to classify patients into low- and high-risk categories based on the expression of related genes. Patients in the low-risk group had a significantly greater overall survival than those in the high-risk group (P < 0.001). Meanwhile, the low-risk group demonstrated connections with the NK cell and immunotherapy response. Finally, the prognostic nomogram showed a high sensitivity and specificity for predicting the survival of HCC patients at 1, 2, and 3 years. Conclusion The prognostic model based on RAPGEF2 and RAPGEF2-related genes showed an excellent predictive performance in terms of prognosis and immunotherapy response in HCC, therefore establishing a unique prognostic model for clinical assessment of HCC patients.
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Lin S, Xu H, Pang M, Zhou X, Pan Y, Zhang L, Guan X, Wang X, Lin B, Tian R, Chen K, Zhang X, Yang Z, Ji F, Huang Y, Wei W, Gong W, Ren J, Wang JM, Guo M, Huang J. CpG Site-Specific Methylation-Modulated Divergent Expression of PRSS3 Transcript Variants Facilitates Nongenetic Intratumor Heterogeneity in Human Hepatocellular Carcinoma. Front Oncol 2022; 12:831268. [PMID: 35480112 PMCID: PMC9035874 DOI: 10.3389/fonc.2022.831268] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 03/16/2022] [Indexed: 01/18/2023] Open
Abstract
BackgroundHepatocellular carcinoma (HCC) is one of the most lethal human tumors with extensive intratumor heterogeneity (ITH). Serine protease 3 (PRSS3) is an indispensable member of the trypsin family and has been implicated in the pathogenesis of several malignancies, including HCC. However, the paradoxical effects of PRSS3 on carcinogenesis due to an unclear molecular basis impede the utilization of its biomarker potential. We hereby explored the contribution of PRSS3 transcripts to tumor functional heterogeneity by systematically dissecting the expression of four known splice variants of PRSS3 (PRSS3-SVs, V1~V4) and their functional relevance to HCC.MethodsThe expression and DNA methylation of PRSS3 transcripts and their associated clinical relevance in HCC were analyzed using several publicly available datasets and validated using qPCR-based assays. Functional experiments were performed in gain- and loss-of-function cell models, in which PRSS3 transcript constructs were separately transfected after deleting PRSS3 expression by CRISPR/Cas9 editing.ResultsPRSS3 was aberrantly differentially expressed toward bipolarity from very low (PRSS3Low) to very high (PRSS3High) expression across HCC cell lines and tissues. This was attributable to the disruption of PRSS3-SVs, in which PRSS3-V2 and/or PRSS3-V1 were dominant transcripts leading to PRSS3 expression, whereas PRSS3-V3 and -V4 were rarely or minimally expressed. The expression of PRSS3-V2 or -V1 was inversely associated with site-specific CpG methylation at the PRSS3 promoter region that distinguished HCC cells and tissues phenotypically between hypermethylated low-expression (mPRSS3-SVLow) and hypomethylated high-expression (umPRSS3-SVHigh) groups. PRSS3-SVs displayed distinct functions from oncogenic PRSS3-V2 to tumor-suppressive PRSS3-V1, -V3 or PRSS3-V4 in HCC cells. Clinically, aberrant expression of PRSS3-SVs was translated into divergent relevance in patients with HCC, in which significant epigenetic downregulation of PRSS3-V2 was seen in early HCC and was associated with favorable patient outcome.ConclusionsThese results provide the first evidence for the transcriptional and functional characterization of PRSS3 transcripts in HCC. Aberrant expression of divergent PRSS3-SVs disrupted by site-specific CpG methylation may integrate the effects of oncogenic PRSS3-V2 and tumor-suppressive PRSS3-V1, resulting in the molecular diversity and functional plasticity of PRSS3 in HCC. Dysregulated expression of PRSS3-V2 by site-specific CpG methylation may have potential diagnostic value for patients with early HCC.
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Affiliation(s)
- Shuye Lin
- Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing, China
| | - Hanli Xu
- College of Life Sciences & Bioengineering, Beijing Jiaotong University, Beijing, China
| | - Mengdi Pang
- College of Life Sciences & Bioengineering, Beijing Jiaotong University, Beijing, China
| | - Xiaomeng Zhou
- College of Life Sciences & Bioengineering, Beijing Jiaotong University, Beijing, China
- Department of Gastroenterology and Hepatology, Chinese People’s Liberation Army of China (PLA) General Hospital, Beijing, China
| | - Yuanming Pan
- Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing, China
| | - Lishu Zhang
- College of Life Sciences & Bioengineering, Beijing Jiaotong University, Beijing, China
| | - Xin Guan
- College of Life Sciences & Bioengineering, Beijing Jiaotong University, Beijing, China
| | - Xiaoyue Wang
- College of Life Sciences & Bioengineering, Beijing Jiaotong University, Beijing, China
| | - Bonan Lin
- College of Life Sciences & Bioengineering, Beijing Jiaotong University, Beijing, China
| | - Rongmeng Tian
- College of Life Sciences & Bioengineering, Beijing Jiaotong University, Beijing, China
| | - Keqiang Chen
- Laboratory of Cancer Immunometabolism, Center for Cancer Research, National Cancer Institute, Frederick, MD, United States
| | - Xiaochen Zhang
- College of Life Sciences & Bioengineering, Beijing Jiaotong University, Beijing, China
| | - Zijiang Yang
- College of Life Sciences & Bioengineering, Beijing Jiaotong University, Beijing, China
| | - Fengmin Ji
- College of Life Sciences & Bioengineering, Beijing Jiaotong University, Beijing, China
| | - Yingying Huang
- Chinese Academy of Sciences (CAS) Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Wu Wei
- Chinese Academy of Sciences (CAS) Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Wanghua Gong
- Basic Research Program, Leidos Biomedical Research, Inc., Frederick, MD, United States
| | - Jianke Ren
- Chinese Academy of Sciences (CAS) Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Ji Ming Wang
- Laboratory of Cancer Immunometabolism, Center for Cancer Research, National Cancer Institute, Frederick, MD, United States
| | - Mingzhou Guo
- Department of Gastroenterology and Hepatology, Chinese People’s Liberation Army of China (PLA) General Hospital, Beijing, China
- *Correspondence: Jiaqiang Huang, ; Mingzhou Guo,
| | - Jiaqiang Huang
- Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing, China
- College of Life Sciences & Bioengineering, Beijing Jiaotong University, Beijing, China
- Laboratory of Cancer Immunometabolism, Center for Cancer Research, National Cancer Institute, Frederick, MD, United States
- *Correspondence: Jiaqiang Huang, ; Mingzhou Guo,
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Tang Y, Wang Y, Xu X, Sun H, Tang W. STEAP4 promoter methylation correlates with tumorigenesis of hepatocellular carcinoma. Pathol Res Pract 2022; 233:153870. [DOI: 10.1016/j.prp.2022.153870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 03/22/2022] [Accepted: 03/30/2022] [Indexed: 10/18/2022]
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He Z, Peng C, Li T, Li J. Cell Differentiation Trajectory in Liver Cirrhosis Predicts Hepatocellular Carcinoma Prognosis and Reveals Potential Biomarkers for Progression of Liver Cirrhosis to Hepatocellular Carcinoma. Front Genet 2022; 13:858905. [PMID: 35360852 PMCID: PMC8960263 DOI: 10.3389/fgene.2022.858905] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 02/24/2022] [Indexed: 12/24/2022] Open
Abstract
Most hepatocellular carcinoma (HCC) patients occur on a background of liver cirrhosis, the molecular mechanisms of liver cirrhosis and its progression to HCC remain to be fully elucidated. Single cell differentiation trajectory analysis has been used in cell classification and tumor molecular typing, which correlated with disease progression and patient prognosis. Here we use cell differentiation trajectory analysis to investigate the relevance of liver cirrhosis and HCC. Single-cell RNA sequencing (scRNA-seq) data of liver cirrhosis and bulk RNA-seq and clinical data of HCC were downloaded from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) for analysis. HCC samples were divided into three subtypes, based on differentiation-related genes (DRGs) of liver cirrhosis, each with a different expression profile and overall survival (OS). A two- DRGs (CD34 and RAMP3) based prognostic risk scoring (RS) signature was established which could differentiate OS between high-risk and low-risk groups. And expression levels of CD34 and RAMP3 were predominantly high in endothelial cells. By integrating the RS and clinicopathological features, a nomogram was constructed and can accurately predicted the 1-year, 3-years, and 5-years OS. In conclusion, cell differentiation trajectory of liver cirrhosis can predict the prognosis of HCC, and provides new perspectives on the mechanisms of progression of liver cirrhosis to HCC.
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Affiliation(s)
- Zhaobin He
- Department of Hepatobiliary Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Cheng Peng
- Department of Hepatobiliary Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Tianen Li
- Department of Hepatobiliary Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jie Li
- Department of Hepatobiliary Surgery, Shandong Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- *Correspondence: Jie Li,
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Tenofovir vs. entecavir on prognosis of hepatitis B virus-related hepatocellular carcinoma after curative resection. J Gastroenterol 2022; 57:185-198. [PMID: 35152312 DOI: 10.1007/s00535-022-01855-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 01/20/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are recommended as first-line choices regarding the treatment of chronic hepatits B. The impact of the two antiviral agents on prognosis of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after curative liver resection remains to be explored. We aimed to assess the effect of antiviral therapy with ETV or TDF after curative resection on the prognosis of patients with HBV-related HCC. METHODS A total of 1173 consecutive patients who were treated with ETV or TDF after curative liver resection for HCC were enrolled in the study. HCC recurrence, overall survival, postoperative liver function reserve, and early virologic (VR) and biochemical responses (BR) of patients were compared between the ETV and TDF groups by propensity score matching (PSM) from the date of liver resection for HCC. RESULTS No difference was observed with recurrence-free survival between TDF and ETV in the PSM cohort (hazard ratio [HR], 0.91; 95% confidence interval [CI] 0.70-1.17; P = 0.45). No difference was observed with early VR and BR between TDF and ETV in the PSM cohort. Compared with ETV, TDF therapy was associated with significantly better protection of liver function and higher overall survival rates in the PSM cohort (HR, 0.37; 95% CI 0.20-0.71; P = 0.002). After PSM, 69 (40.8%) patients in the ETV group and 63 (57.3%) patients in the TDF group had single tumor recurrence, while the TDF group had significantly more patients with single tumor recurrence in the PSM cohort (P = 0.007). CONCLUSIONS For patients who underwent curative resection for HBV-related HCC, TDF treatment had a significantly better overall survival and better protection of liver function, but no difference in the incidences of HCC recurrence than ETV treatment.
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Bai W, Cheng L, Xiong L, Wang M, Liu H, Yu K, Wang W. Identification of Prognostic Genes in Hepatocellular Carcinoma. Int J Gen Med 2022; 15:2895-2904. [PMID: 35300146 PMCID: PMC8923701 DOI: 10.2147/ijgm.s347535] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Accepted: 02/11/2022] [Indexed: 12/05/2022] Open
Abstract
Background Previous studies have demonstrated the important role of tumor stem cells (TSCs) in the development of hepatocellular carcinoma (HCC); however, TSC-related genetic markers have not been investigated. Aim The aim of the present study was to identify stem cell-related signature genes to predict the prognosis of HCC, using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Methods In total, 423 liver HCC tissue samples, including 373 tumor and 50 adjacent normal tissue samples from TCGA, and 115 primary tumor and 52 adjacent non-tumor tissue samples from the GEO GSE76427 database, were used in the present study. The non-negative matrix factorization (NMF) algorithm, t-distributed stochastic neighbor embedding (t-SNE) algorithm and Cox regression analysis were combined for model construction and validation. Results Overall, six clusters were identified using the NMF and t-SNE algorithms with 470 stem cell-related genes. The results demonstrated that patients in cluster 5 had the worst prognosis. For multivariate Cox survival analysis, 15 genes with optimal lambda values were chosen and eight genes were incorporated into the final regression model using the optimal Akaike information criterion value. Validation of the risk model using the aforementioned eight signature genes demonstrated the models strong reliability and stable predictive performance. Conclusion The results of the present study indicated that the eight-gene (Hes family BHLH transcription factor 5, KIT ligand, methyltransferase-like 3, proteasome 26S subunit non-ATPase 1, Ras-related protein Rab-10, treacle ribosome biogenesis factor 1, YTH N6-methyladenosine RNA binding protein 2 and Zinc Finger CCCH-Type Containing 13) signature constructed by the model may be reliable in predicting the prognosis of patients with HCC.
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Affiliation(s)
- Wenhui Bai
- Department of Hepatobiliary Surgery, Eastern Campus, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China
| | - Li Cheng
- Department of Intensive Care Unit, Eastern Campus, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China
| | - Liangkun Xiong
- Department of Hepatobiliary Surgery, Eastern Campus, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China
| | - Maoming Wang
- Department of Hepatobiliary Surgery, Eastern Campus, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China
| | - Hao Liu
- Department of Hepatobiliary Surgery, Eastern Campus, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China
| | - Kaihuan Yu
- Department of Hepatobiliary Surgery, Eastern Campus, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China
| | - Weixing Wang
- Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China
- Correspondence: Weixing Wang; Kaihuan Yu, Email ;
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Liu D, Li H, Dong H, Qu M, Yang L, Chen L, Li Y, Wang H, He Y. Spatial Multiomics Analysis Reveals Only Minor Genetic and Epigenetic Changes in Human Liver Cancer Stem-Like Cells Compared With Other Tumor Parenchymal Cells. Front Cell Dev Biol 2022; 10:810687. [PMID: 35223840 PMCID: PMC8863946 DOI: 10.3389/fcell.2022.810687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Accepted: 01/17/2022] [Indexed: 11/13/2022] Open
Abstract
Cancer stem cells (CSCs) usually account for a very small tumor cell population but play pivotal roles in human cancer development and recurrence. A fundamental question in cancer biology is what genetic and epigenetic changes occur in CSCs. Here we show that the in-situ global levels of DNA cytosine modifications, including 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC) and 5-formylcytosine (5fC), are similar between liver cancer stem-like (LCSL) cells and paratumor liver cells of liver cancer patients. We then developed a robust method combining immunohistochemistry, laser capture microdissection and genome sequencing with ultra-low-input cells (CIL-seq) to study the detailed genetic and DNA methylation changes in human LCSL cells. We first used clinical samples of mixed hepatocellular carcinoma-cholangiocarcinoma (HCC-CCA) with stem cell features to investigate human LCSL cells. The CIL-seq analysis of HCC-CCA and HCC patients showed that LCSL cells had strong spatial genetic and epigenetic heterogeneity. More interestingly, although the LCSL cells had some potential key changes in their genome, they had substantially fewer somatic single nucleotide variants (SNVs), copy number alterations (CNAs) and differentially methylated regions than other tumor parenchymal cells. The cluster analysis of SNVs, CNAs, DNA methylation patterns and spatial transcriptomes all clearly showed that the LCSL cells were clustered with the paratumor liver cells. Thus, spatial multiomics analysis showed that LCSL cells had only minor genetic and epigenetic changes compared with other tumor parenchymal cells. Targeting key changes in CSCs, not just changes in bulk tumor cells, should be more effective for human cancer therapy.
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Affiliation(s)
- Dan Liu
- Model Animal Research Center, Medical School, Nanjing University, Nanjing, China.,Molecular Pathology Laboratory, National Center for Liver Cancer, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Hong Li
- CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Hui Dong
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Mincheng Qu
- Model Animal Research Center, Medical School, Nanjing University, Nanjing, China.,Molecular Pathology Laboratory, National Center for Liver Cancer, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Liguang Yang
- CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Lina Chen
- CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Yixue Li
- CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Hongyang Wang
- Model Animal Research Center, Medical School, Nanjing University, Nanjing, China.,National Center for Liver Cancer and International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, Shanghai, China
| | - Yufei He
- Molecular Pathology Laboratory, National Center for Liver Cancer, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
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Wang L, Bai SH, Song SJ, Lu ZN, Huang J, Han ZG. Exposure to aristolochic acid I is associated with poor prognosis of liver cancer patients. Toxicol Res (Camb) 2022; 11:255-260. [PMID: 35237430 PMCID: PMC8882800 DOI: 10.1093/toxres/tfac002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 12/30/2021] [Accepted: 01/14/2022] [Indexed: 01/31/2023] Open
Abstract
The aristolochic acids (AAs), derived from Aristolochia and Asarum species used widely in herbal medicines, are closely associated with liver cancer. The major AA derivatives are aristolochic acid I (AAI) and II (AAII), which can bind DNA covalently to form AA-DNA adducts after metabolic activation in vivo. Among all these AA-DNA adducts, 7-(deoxyadenosine-N6-yl) aristolactam I (dA-AL-I) is the most abundant and persistent DNA lesion in patients. However, the direct evidence indicating AA exposure in human liver cancer is still missing. Here, we analyzed dA-AL-I adduct, the direct biomarker of AAI exposure, by ultra-performance liquid chromatography coupled with triple quadrupole mass spectrometry (UPLC-TQ/MS) in 209 liver cancer patients. Also, DNA samples from mice treated with/without AAI were used as positive and negative controls. dA-AL-I adduct was present in 110 of 209 (52.6%) patients, indicating that these patients were exposed to AAI prior to their clinical investigations and also had a worse prognosis. The relative high AA exposure rate and worse prognosis in our cohort of patients emphasize the significance to increase public awareness to avoid the use of herbal medicine containing AAs or their derivatives.
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Affiliation(s)
- Lan Wang
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Shi-Hao Bai
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Shu-Jin Song
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Zhao-Ning Lu
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Jian Huang
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Ze-Guang Han
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China,Correspondence author. Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
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