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Wu J, Zhang C, Zhang Y, He R, Wang Q, Zhang L, Hu J, Wan R. Prediction model establishment of prognosis factors for distant metastasis of hepatocellular carcinoma based on the SEER database. Cancer Epidemiol 2025; 94:102729. [PMID: 39675259 DOI: 10.1016/j.canep.2024.102729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/25/2024] [Revised: 12/02/2024] [Accepted: 12/09/2024] [Indexed: 12/17/2024]
Abstract
BACKGROUND Distant metastasis in hepatocellular carcinoma (HCC) is an important indicator of poor patient prognosis. Identifying patients who are at high risk of metastasis early on is essential for creating personalized treatment plans, yet currently, there is a scarcity of effective predictive tools. OBJECTIVE To investigate the effects of different factors on distant metastasis in HCC patients and to establish a clinical prediction model for predicting distant metastasis in HCC patients. METHODS Our study retrospectively examined 22,318 patients diagnosed with confirmed HCC from the SEER database. Prognostic factors for developing distant metastases in HCC patients were identified by univariate and multivariate logistic regression analyses. Utilizing data from a multivariate logistic regression analysis, we created a nomogram. Its predictive precision was evaluated by analyzing the calibration curve, the area under the curve (AUC) of the receiver operating characteristic curve, decision curve assessment (DCA), and Kaplan-Meier (KM) curve analysis of overall survival. Finally,the nomogram was visualized with an online calculator. RESULTS We identified six independent prognostic factors: ethnicity, marital status, tumor size, survival time, surgery, and radiotherapy. The nomogram constructed from these six factors showed good calibration, discrimination, and clinical application value after calibration curve analysis, receiver operating characteristic curve analysis and DCA curve analysis. Besides, KaplanMeier survival curves also demonstrated that this nomogram had predictive accuracy. CONCLUSION In this research, a nomogram model was created to accurately predict distant metastasis risk in patients with HCC. This study provides guidance for optimizing individual therapies and making better clinical decisions.
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Affiliation(s)
- Jixuan Wu
- School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China; Key Laboratory of Luzhou City for Aging Medicine, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, China
| | - Chun Zhang
- School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China; Key Laboratory of Luzhou City for Aging Medicine, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, China
| | - Youjia Zhang
- School of Public Health, Southwest Medical University, Luzhou 646000, China
| | - Rui He
- Department of Oncology, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Qin Wang
- Dazhou Vocational College of Chinese Medicine, Dazhou, Dazhou 635000, China
| | - Lei Zhang
- School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Jing Hu
- Department of Oncology, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Runlan Wan
- Department of Oncology, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan 646000, China; Key Laboratory of Luzhou City for Aging Medicine, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, China.
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Su J, Wang X, Li S, Wu X, Li M, Du F, Deng S, Shen J, Zhao Y, Xiao Z, Chen Y. Synthesis and antitumor evaluation of glycyrrhetinic acid-dithiocarbamate hybrids. Arch Pharm (Weinheim) 2025; 358:e2400421. [PMID: 39526492 DOI: 10.1002/ardp.202400421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/27/2024] [Revised: 10/05/2024] [Accepted: 10/21/2024] [Indexed: 11/16/2024]
Abstract
Glycyrrhetinic acid (GA) is a naturally occurring triterpene compound. The aim of this study was to employ the pharmacophore hybrid strategy to merge GA with various dithiocarbamates and obtain novel compounds with better antitumor activities. We present a two-step synthetic protocol wherein the GA derivative underwent reaction with carbon disulfide and various secondary amines in a one-pot manner under mild conditions, facilitating the preparation of a series of structurally novel GA-dithiocarbamate derivatives. Bioassay screening revealed that the representative compound 3c demonstrated the capacity to reduce the mitochondrial membrane potential in Hep3B and Huh-7 cells, induce nuclear apoptosis, inhibit invasion and migration, and prompt both early and late apoptosis. Furthermore, our research findings indicated that this apoptotic phenomenon may be associated with the expression of Bcl-2, Bax, Bak, PARP, and cleaved-PARP proteins. Utilizing network pharmacology for predicting core targets and signaling pathways of compound 3c for hepatocellular carcinoma (HCC) treatment involved employing molecular docking models to demonstrate high affinity between compound and target protein. In conjunction with Western blot analysis, compound 3c may impact HCC through the PI3K-AKT-mTOR pathway.
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Affiliation(s)
- Jiahong Su
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Xingyue Wang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Sha Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Fukuan Du
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Shuai Deng
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Zhangang Xiao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Yu Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, South Sichuan Institute of Translational Medicine, Luzhou, China
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Xu Z, Pang C, Xu X. Establishment of prognostic risk model related to disulfidptosis and immune infiltration in hepatocellular carcinoma. Heliyon 2024; 10:e40405. [PMID: 39687103 PMCID: PMC11647807 DOI: 10.1016/j.heliyon.2024.e40405] [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] [Academic Contribution Register] [Received: 09/13/2024] [Revised: 11/11/2024] [Accepted: 11/13/2024] [Indexed: 12/18/2024] Open
Abstract
Background Disulfidptosis is a newly discovered type of cell death. We aim to identify hub genes associated with both disulfidptosis and immune infiltration in hepatocellular carcinoma (HCC) patients, and to develop an individualized risk prediction model. Methods The TCGA-LIHC cohort was utilized as the training set to identify molecular subtypes associated with disulfidptosis and to perform immune infiltration analysis. WGCNA, univariate Cox, and LASSO algorithm were employed to select hub genes for constructing the prognostic model. ICGC-LIRI cohort was utilized as an independent testing set. Validation of the expression of hub genes was performed in vitro using qRT-PCR and Western blot. Results Cluster 1 was identified as the disulfidptosis associated molecular subtype, characterized by higher expression of disulfidptosis related genes (DRGs) and immune infiltration levels. ANXA2, MSC, and ST6GALNAC4 were identified as hub genes for calculating the risk score. The high-risk group were more likely to benefit from immunotherapy, targeted therapy and chemotherapy. A prognostic model was developed combining clinicopathological factors with satisfactory predictive accuracy. The hub genes were found upregulated in HCC cell line. Conclusions Our findings provide valuable theoretical support for prognostic prediction and the evaluation of therapeutic outcomes in relation to disulfidptosis and immune infiltration in HCC, highlighting the importance of conducting in-depth research on disulfidptosis-related mechanisms.
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Affiliation(s)
- Zhe Xu
- Department of Breast and Thyroid Surgery, South China Hospital, Medical School, Shenzhen University, Shenzhen, 518116, PR China
| | - Chong Pang
- Department of Hepatobiliary Pancreatic Surgery, South China Hospital, Medical School, Shenzhen University, Shenzhen, 518116, PR China
| | - Xundi Xu
- Department of Hepatobiliary Pancreatic Surgery, South China Hospital, Medical School, Shenzhen University, Shenzhen, 518116, PR China
- Department of General Surgery, The Second Xiangya Hospital of Central South University, Changsha, PR China
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Yao J, Zhang LJ, Zhou Z, Hua MF. NK-92 cells activated by IL-2 inhibit the progression of endometriosis in vitro. J OBSTET GYNAECOL 2024; 44:2372682. [PMID: 39034630 DOI: 10.1080/01443615.2024.2372682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/03/2023] [Accepted: 06/20/2024] [Indexed: 07/23/2024]
Abstract
BACKGROUND Interleukin (IL)-2 is a key cytokine capable of modulating the immune response by activating natural killer (NK) cells. This study was recruited to explore the therapeutic potential of IL-2-activated NK-92 cells in endometriosis in vitro. METHODS Ectopic endometrial stromal cells (EESCs) were isolated and co-cultured with IL-2-activated NK-92 cells at varying effector-to-target (E:T) ratios (1:0 [Control], 1:1, 1:3, and 1:9). The viability, cytotoxicity, and cell surface antigen expression of IL-2-activated NK-92 cells were assessed. The viability, apoptosis, invasion, and migration ability of EESCs co-cultured with NK-92 cells at different ratios were evaluated. The apoptosis-related proteins, invasion and migration-related proteins as well as MEK/ERK pathway were examined via western blot. Each experiment was repeated three times. RESULTS IL-2 activation enhanced NK-92 cytotoxicity in a concentration-dependent manner. Co-culturing EESCs with IL-2-activated NK-92 cells at E:T ratios of 1:1, 1:3, and 1:9 reduced EESC viability by 20%, 45%, and 70%, respectively, compared to the control group. Apoptosis rates in EESCs increased in correlation with the NK-92 cell proportion, with the highest rate observed at a 1:9 ratio. Moreover, EESC invasion and migration were significantly inhibited by IL-2-activated NK-92 cells, with a 60% reduction in invasion and a 50% decrease in migration at the 1:9 ratio. Besides, the MEK/ERK signalling pathway was down-regulated in EESCs by IL-2-activated NK-92 cells. CONCLUSION IL-2-activated NK-92 cells exhibit potent cytotoxic effects against EESCs. They promote EESC apoptosis and inhibit viability, invasion, and migration through modulating the MEK/ERK signalling pathway.
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Affiliation(s)
- Jun Yao
- Department of Gynecology, Lianyungang Maternal and Child Health Hospital, Lianyungang, Jiangsu, China
| | - Li-Jiao Zhang
- Department of Obstetrics, Lianyungang Maternal and Child Health Hospital, Lianyungang, Jiangsu, China
| | - Zhe Zhou
- Department of Gynecology, Lianyungang Maternal and Child Health Hospital, Lianyungang, Jiangsu, China
| | - Mao-Fang Hua
- Department of Gynecology, Lianyungang Maternal and Child Health Hospital, Lianyungang, Jiangsu, China
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Wang J, Li Y, Deng L, Zha Y, Zhang S. FTO suppresses cardiac fibrosis after myocardial infarction via m 6A-mediated epigenetic modification of EPRS. Mol Med 2024; 30:213. [PMID: 39538146 PMCID: PMC11562098 DOI: 10.1186/s10020-024-00985-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/22/2024] [Accepted: 11/03/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Cardiac fibrosis is common in myocardial infarction (MI), leading to progressive cardiac dysfunction. Studies suggested that the abnormal N6-methyladenosine (m6A) modification induced by fat mass and obesity protein (FTO) is vital in MI. However, the effects of FTO on post-infarction cardiac fibrosis have not been detected. METHODS Western blot and quantitative real-time PCR were performed to detect the expression of FTO in the fibrotic tissue of rats. The functions of FTO on collagen biosynthesis were analyzed in vitro and in vivo. The underlying targets of FTO were selected through RNA-seq with m6A-seq. The following dual luciferase reporter assay and RNA stability assay were conducted to investigate the mechanisms of FTO-mediated m6A regulation. RESULTS The expression of FTO was decreased in the fibrotic tissue of post-infarction rats. The HIF-1 signal pathway was enriched after MI. HIF-1α could bind to the promoter of FTO and inhibit its expression. Functionally, FTO inhibited collagen synthesis after MI in vitro and in vivo. Mechanistically, EPRS was selected as the underlying target of FTO-induced m6A regulation. IGF2BP3 recognized and bound to the m6A sites of EPRS mRNA, which improved its stability. EPRS was required for cardiac fibrosis induced by FTO silencing. CONCLUSIONS FTO, identified as a cardioprotective factor, suppressed collagen synthesis in post-infarction cardiac fibrosis via m6A modification, which provided a new therapeutic strategy for cardiac fibrosis.
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Affiliation(s)
- Jian Wang
- Department of Emergency, Renji Hospital, Affiliated Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, People's Republic of China
| | - Yanyan Li
- Department of Cardiology, Xinhua Hospital, Affiliated Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People's Republic of China
| | - Lijie Deng
- Department of Emergency, Renji Hospital, Affiliated Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, People's Republic of China
| | - Yafang Zha
- Department of Emergency, Renji Hospital, Affiliated Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, People's Republic of China
| | - Song Zhang
- Department of Emergency, Renji Hospital, Affiliated Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, People's Republic of China.
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Yao G, Yang Z. Glypican-3 knockdown inhibits the cell growth, stemness, and glycolysis development of hepatocellular carcinoma cells under hypoxic microenvironment through lactylation. Arch Physiol Biochem 2024; 130:546-554. [PMID: 37131292 DOI: 10.1080/13813455.2023.2206982] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 12/30/2022] [Revised: 03/09/2023] [Accepted: 04/19/2023] [Indexed: 05/04/2023]
Abstract
CONTEXT Hepatocellular carcinoma (HCC) is a common malignant tumour in China. Glypican-3 (GPC3) is reported to be closely related to the occurrence and development of various tumours. OBJECTIVE This study aimed to explore the role of GPC3 in HCC. MATERIALS AND METHODS The cell behaviours were investigated using Cell Counting Kit-8 (CCK-8), Traswell, and sphere formation assays. The protein and mRNA expression levels were detected using western blot and Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR) assays. RESULTS The results showed that GPC3 knockdown decreased the cell viability and stemness, glucose uptake, lactate production, and extracellular acidification rate (ECAR), while increased the oxygen consumption rate (OCR) in hypoxia-treated HCC cells. Additionally, GPC3 knockdown decreased the global lactylation and c-myc lactylation, which further decreased the protein stability and expressions of c-myc. DISCUSSION AND CONCLUSION GPC3-mediated lactylation modification may be a new direction in HCC treatment in the future.
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Affiliation(s)
- Gebing Yao
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Xi'an Medical University, Xi'an, China
| | - Zihua Yang
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Xi'an Medical University, Xi'an, China
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Gopalakrishnan K, Kannan B, Pandi C, Pandi A, Ramasubramanian A, Jayaseelan VP, Arumugam P. Aberrant expression of VASP serves as a potential prognostic biomarker and therapeutic target for oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol 2024; 138:391-402. [PMID: 38816308 DOI: 10.1016/j.oooo.2024.05.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/08/2024] [Revised: 03/16/2024] [Accepted: 05/05/2024] [Indexed: 06/01/2024]
Abstract
OBJECTIVE To address the molecular markers linked to the development and progression of oral squamous cell carcinoma (OSCC), we sought to analyze the expression of vasodilator-stimulated phosphoproteins (VASP) in OSCC samples. STUDY DESIGN This study used 51 OSCC patients and The Cancer Genome Atlas-Head and Neck Squamous Cell Carcinoma (TCGA-HNSC) dataset to analyze VASP expression. The association between VASP mRNA expression and HNSCC clinicopathological features, tumor infiltration, functional roles, and gene co-expression of VASP also were evaluated. RESULTS Our study observed increased VASP mRNA expression in OSCC tumor tissues compared to normal tissues, supported by TCGA-HNSC dataset analysis. Elevated VASP levels correlated with advanced tumor stage, higher grade, nodal metastasis, and poor survival, indicating its potential as a prognostic marker. Protein analysis and immunohistochemistry confirmed these findings, and in silico analysis revealed VASP involvement in key cancer-related processes and its correlation with IL8, RAP1A expression, and tumor infiltration levels. CONCLUSIONS In conclusion, VASP emerges as a promising diagnostic and prognostic marker for OSCC within HNSCC, emphasizing the importance of exploring its regulatory mechanisms and therapeutic applications. The revealed pathways present avenues for targeted treatment in OSCC. Despite limitations, this study provides valuable insights with potential implications for improving patient outcomes.
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Affiliation(s)
- Karpakavinayakam Gopalakrishnan
- Saveetha Medical College and Hospital, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai, TN, India
| | - Balachander Kannan
- Molecular Biology Lab, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai, TN, India
| | - Chandra Pandi
- Molecular Biology Lab, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai, TN, India
| | - Anitha Pandi
- Clinical Genetics Lab, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai, TN, India
| | - Abilasha Ramasubramanian
- Department of Oral Pathology, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai, TN, India
| | - Vijayashree Priyadharsini Jayaseelan
- Clinical Genetics Lab, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai, TN, India
| | - Paramasivam Arumugam
- Molecular Biology Lab, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai, TN, India.
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Tan C, Qin G, Wang QQ, Li KM, Zhou YC, Yao SK. Comprehensive serum proteomics profiles and potential protein biomarkers for the early detection of advanced adenoma and colorectal cancer. World J Gastrointest Oncol 2024; 16:2971-2987. [PMID: 39072170 PMCID: PMC11271786 DOI: 10.4251/wjgo.v16.i7.2971] [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] [Academic Contribution Register] [Received: 11/10/2023] [Revised: 03/08/2024] [Accepted: 05/15/2024] [Indexed: 07/12/2024] Open
Abstract
BACKGROUND The majority of colorectal cancer (CRC) cases develop from precursor advanced adenoma (AA). With the development of proteomics technologies, blood protein biomarkers have potential applications in the early screening of AA and CRC in the general population. AIM To identify serum protein biomarkers for the early screening of AA and CRC. METHODS We collected 43 serum samples from 8 normal controls (NCs), 19 AA patients and 16 CRC patients at China-Japan Friendship Hospital. Quantitative proteomic analysis was performed using liquid chromatography-mass spectrometry/mass spectrometry and data independent acquisition, and differentially expressed proteins (DEPs) with P-values < 0.05 and absolute fold changes > 1.5 were screened out, followed by bioinformatics analysis. Prognosis was further analyzed based on public databases, and proteins expression in tissues were validated by immunohistochemistry. RESULTS A total of 2132 proteins and 17365 peptides were identified in the serum samples. There were 459 upregulated proteins and 118 downregulated proteins in the NC vs AA group, 289 and 180 in the NC vs CRC group, and 52 and 248 in the AA vs CRC group, respectively. Bioinformatic analysis revealed that these DEPs had different functions and participated in extensive signaling pathways. We also identified DIAPH1, VASP, RAB11B, LBP, SAR1A, TUBGCP5, and DOK3 as important proteins for the progression of AA and CRC. Furthermore, VASP (P < 0.01), LBP (P = 0.01), TUBGCP5 (P < 0.01), and DOK3 (P < 0.01) were associated with a poor prognosis. In addition, we propose that LBP and VASP may be more promising protein biomarkers for the early screening of colorectal tumors. CONCLUSION Our study elucidated the serum proteomic profiles of AA and CRC patients, and the identified proteins, such as LBP and VASP, may contribute to the early detection of AA and CRC.
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Affiliation(s)
- Chang Tan
- Graduate School, Peking University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China
| | - Geng Qin
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Qian-Qian Wang
- Graduate School, Peking University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China
| | - Kai-Min Li
- School of Biological Science and Medical Engineering, Beihang University, Beijing 100191, China
| | - Yuan-Chen Zhou
- Graduate School, Peking University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China
| | - Shu-Kun Yao
- Graduate School, Peking University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
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Liu C, Li K, Ding W, Tang X, Wu Z, Zhu X, Gong W, Zhao H. LINC01535 promotes hepatocellular carcinoma proliferation and metastasis by regulating the miR-214-3p/VASP axis. J Cancer 2024; 15:3809-3824. [PMID: 38911365 PMCID: PMC11190762 DOI: 10.7150/jca.91756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/31/2023] [Accepted: 05/02/2024] [Indexed: 06/25/2024] Open
Abstract
Background: Emerging evidence has indicated that long noncoding RNAs (lncRNAs) are associated with the development and progression of several carcinomas, including hepatocellular carcinoma (HCC). However, the role of LINC01535 in HCC is still unknown. Materials and methods: In this study, RNA-seq, CCK-8, colony formation, wound healing, Transwell and tumor xenograft assays were used to explore the function of LINC01535 in the proliferation and metastasis of HCC in vitro and in vivo. Fluorescence in situ hybridization (FISH) assay, bioinformatics analysis, dual-luciferase assay, quantitative real-time polymerase chain reaction (qRT-PCR), and western blot analysis were used to reveal the interactions of LINC01535, miR-214-3p and VASP. Results: LINC01535 was overexpressed in HCC tissues and HCC cell lines. Gain- and loss-of-function studies revealed that LINC01535 could promote HCC cell proliferation, migration and invasion both in vitro and in vivo. In addition, upregulation of LINC01535 significantly decreased the expression of microRNA-214-3p (miR-214-3p), which was found closely associated with suppressing tumor progression. Moreover, VASP was identified as a direct downstream target gene of miR-214-3p. LINC01535 positively regulated VASP expression by sponging miR-214-3p, and VASP overexpression activated the PI3K/AKT signaling pathway and stimulated epithelial-to-mesenchymal transition (EMT) in HCC. Conclusions: Our study first found that LINC01535 promoted HCC progression by regulating its downstream target, the miR-214-3p/VASP axis, via the PI3K/AKT signaling pathway. The function and novel regulatory mechanism of LINC01535 may provide a valuable target for the diagnosis and treatment of HCC patients.
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Affiliation(s)
- Chunjiang Liu
- Department of General Surgery, Shaoxing People's Hospital, Shaoxing, 312000, China
| | - Kuan Li
- Department of Hepatobiliary Surgery, Kunshan Hospital of Traditional Chinese Medicine, Suzhou, 215000, China
| | - Wenzhou Ding
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, China
| | - Xiaoqi Tang
- Department of General Surgery, Shaoxing People's Hospital, Shaoxing, 312000, China
| | - Zhifeng Wu
- Department of General Surgery, Shaoxing People's Hospital, Shaoxing, 312000, China
| | - Xin Zhu
- Department of General Surgery, Shaoxing People's Hospital, Shaoxing, 312000, China
| | - Wanwan Gong
- Department of Hepatopancreatobiliary Surgery, Jiangnan University Medical Center, Wuxi, 214002, China
| | - Hui Zhao
- Department of Hepatopancreatobiliary Surgery, Jiangnan University Medical Center, Wuxi, 214002, China
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Tan L, Zhang H, Ding Y, Huang Y, Sun D. CRTAC1 identified as a promising diagnosis and prognostic biomarker in lung adenocarcinoma. Sci Rep 2024; 14:11223. [PMID: 38755183 PMCID: PMC11099150 DOI: 10.1038/s41598-024-61804-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/01/2024] [Accepted: 05/09/2024] [Indexed: 05/18/2024] Open
Abstract
CRTAC1, one of the pyroptosis-related genes, has been identified as a protective factor in certain kinds of cancer, such as gastric adenocarcinoma and bladder cancer. The study aimed to investigate the role of CRTAC1 in lung adenocarcinoma (LUAD). LUAD datasets were obtained from Gene Expression Omnibus (GEO) database and The Cancer Genome Atlas (TCGA), pyroptosis-related genes from GeneCard. Limma package used to find differentially expressed genes (DEGs), least absolute shrinkage and selection operator (LASSO) regression and weighted genes co-expression network analysis (WGCNA) to identify CRTAC1 as hub gene. CRTAC1 expression was confirmed in a real-world cohort using quantitative polymerase chain reaction (qPCR) and Western Blot (WB) analyses. Cellular experiments were conducted to investigate CRTAC1's potential oncogenic mechanisms. CRTAC1 mRNA expression was significantly lower in LUAD tissues (p < 0.05) and showed high accuracy in diagnosing LUAD. Reduced CRTAC1 expression was associated with a poor prognosis. Higher CRTAC1 expression correlated with increased immune cell infiltration. Individuals with high CRTAC1 expression showed increased drug sensitivity. Additionally, qPCR and WB analyses showed that CRTAC1 expression was lower in tumor tissue compared to adjacent normal tissue at both the RNA and protein levels. Upregulation of CRTAC1 significantly inhibited LUAD cell proliferation, invasion, and migration in cellular experiments. CRTAC1 has the potential to serve as a diagnostic and prognostic biomarker in LUAD.
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Affiliation(s)
- Lin Tan
- Tianjin Medical University Graduate School, Tianjin, China
- Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital), Qingdao, China
| | - Han Zhang
- Tianjin Medical University Graduate School, Tianjin, China
- Clinical School of Thoracic, Tianjin Medical University, Tianjin, China
| | - Yun Ding
- Tianjin Medical University Graduate School, Tianjin, China
- Clinical School of Thoracic, Tianjin Medical University, Tianjin, China
| | - Yangyun Huang
- Tianjin Medical University Graduate School, Tianjin, China
- Clinical School of Thoracic, Tianjin Medical University, Tianjin, China
| | - Daqiang Sun
- Tianjin Chest Hospital, Tianjin University, Tianjin, China.
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Zhou H, Zhou X, Zhu R, Zhao Z, Yang K, Shen Z, Sun H. A ferroptosis-related signature predicts the clinical diagnosis and prognosis, and associates with the immune microenvironment of lung cancer. Discov Oncol 2024; 15:163. [PMID: 38743344 PMCID: PMC11093956 DOI: 10.1007/s12672-024-01032-x] [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] [Academic Contribution Register] [Received: 10/20/2023] [Accepted: 05/10/2024] [Indexed: 05/16/2024] Open
Abstract
Targeting ferroptosis-related pathway is a potential strategy for treatment of lung cancer (LC). Consequently, exploration of ferroptosis-related markers is important for treating LC. We collected LC clinical data and mRNA expression profiles from TCGA and GEO database. Ferroptosis-related genes (FRGs) were obtained through FerrDB database. Expression analysis was performed to obtain differentially expressed FRGs. Diagnostic and prognostic models were constructed based on FRGs by LASSO regression, univariate, and multivariate Cox regression analysis, respectively. External verification cohorts GSE72094 and GSE157011 were used for validation. The interrelationship between prognostic risk scores based on FRGs and the tumor immune microenvironment was analyzed. Immunocytochemistry, Western blotting, and RT-qPCR detected the FRGs level. Eighteen FRGs were used for diagnostic models, 8 FRGs were used for prognostic models. The diagnostic model distinguished well between LC and normal samples in training and validation cohorts of TCGA. The prognostic models for TCGA, GSE72094, and GSE157011 cohorts significantly confirmed lower overall survival (OS) in high-risk group, which demonstrated excellent predictive properties of the survival model. Multivariate Cox regression analysis further confirmed risk score was an independent risk factor related with OS. Immunoassays revealed that in high-risk group, a significantly higher proportion of Macrophages_M0, Neutrophils, resting Natural killer cells and activated Mast cells and the level of B7H3, CD112, CD155, B7H5, and ICOSL were increased. In conclusion, diagnostic and prognostic models provided superior diagnostic and predictive power for LC and revealed a potential link between ferroptosis and TIME.
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Affiliation(s)
- Hua Zhou
- Department of Oncology Radiotherapy, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, Yunnan, China
| | - Xiaoting Zhou
- Medical School, Kunming University of Science and Technology, Kunming, 650031, Yunnan, China
| | - Runying Zhu
- Department of Oncology Radiotherapy, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, Yunnan, China
| | - Zhongquan Zhao
- Department of Oncology Radiotherapy, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, Yunnan, China
| | - Kang Yang
- Department of Thoracic Surgery, First Affiliated Hospital of Kunming Medical University, No.295 Xichang Rd, Kunming, 650032, Yunnan, China
| | - Zhenghai Shen
- Department of Thoracic Surgery, Yunnan Cancer Hospital, Kunming, 650118, Yunnan, China
| | - Hongwen Sun
- Department of Thoracic Surgery, First Affiliated Hospital of Kunming Medical University, No.295 Xichang Rd, Kunming, 650032, Yunnan, China.
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Li X, Cong J, Zhou X, Gao W, Li W, Yang Q, Li X, Liu Z, Luo A. JunD-miR494-CUL3 axis promotes radioresistance and metastasis by facilitating EMT and restraining PD-L1 degradation in esophageal squamous cell carcinoma. Cancer Lett 2024; 587:216731. [PMID: 38369005 DOI: 10.1016/j.canlet.2024.216731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/14/2023] [Revised: 02/05/2024] [Accepted: 02/10/2024] [Indexed: 02/20/2024]
Abstract
Therapy resistance and metastatic progression jointly determine the fatal outcome of cancer, therefore, elucidating their crosstalk may provide new opportunities to improve therapeutic efficacy and prevent recurrence and metastasis in esophageal squamous cell carcinoma (ESCC). Here, we have established radioresistant ESCC cells with the remarkable metastatic capacity, and identified miR-494-3p (miR494) as a radioresistant activator. Mechanistically, we demonstrated that cullin 3 (CUL3) is a direct target of miR494, which is transcriptionally regulated by JunD, and highlighted that JunD-miR494-CUL3 axis promotes radioresistance and metastasis by facilitating epithelial-mesenchymal transition (EMT) and restraining programmed cell death 1 ligand 1 (PD-L1) degradation. In clinical specimens, miR494 is significantly up-regulated and positively associated with T stage and lymph node metastasis in ESCC tissues and serum. Notably, patients with higher serum miR494 expression have poor prognosis, and patients with higher CUL3 expression have more conventional dendritic cells (cDCs) and plasmacytoid DCs (pDCs), less cancer-associated fibroblasts (CAF2/4), and tumor endothelial cells (TEC2/3) infiltration than patients with lower CUL3 expression, suggesting that CUL3 may be involved in tumor microenvironment (TME). Overall, miR494 may serve as a potential prognostic predictor and therapeutic target, providing a promising strategy for ESCC treatment.
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Affiliation(s)
- Xin Li
- State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Ji Cong
- State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Xuantong Zhou
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Thoracic Surgery II, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Wenyan Gao
- State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Wenxin Li
- State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Qi Yang
- State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Xinyue Li
- State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Zhihua Liu
- State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
| | - Aiping Luo
- State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
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13
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Xing Y, Hou Y, Fan T, Gao R, Feng X, Li B, Pang J, Guo W, Shu T, Li J, Yang J, Mao Q, Luo Y, Qi X, Yang P, Liang C, Zhao H, Chen W, Wang J, Wang C. Endothelial phosphodiesterase 4B inactivation ameliorates endothelial-to-mesenchymal transition and pulmonary hypertension. Acta Pharm Sin B 2024; 14:1726-1741. [PMID: 38572107 PMCID: PMC10985131 DOI: 10.1016/j.apsb.2024.01.012] [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] [Academic Contribution Register] [Received: 08/09/2023] [Revised: 12/13/2023] [Accepted: 01/05/2024] [Indexed: 04/05/2024] Open
Abstract
Pulmonary hypertension (PH) is a fatal disorder characterized by pulmonary vascular remodeling and obstruction. The phosphodiesterase 4 (PDE4) family hydrolyzes cyclic AMP (cAMP) and is comprised of four subtypes (PDE4A-D). Previous studies have shown the beneficial effects of pan-PDE4 inhibitors in rodent PH; however, this class of drugs is associated with side effects owing to the broad inhibition of all four PDE4 isozymes. Here, we demonstrate that PDE4B is the predominant PDE isozyme in lungs and that it was upregulated in rodent and human PH lung tissues. We also confirmed that PDE4B is mainly expressed in the lung endothelial cells (ECs). Evaluation of PH in Pde4b wild type and knockout mice confirmed that Pde4b is important for the vascular remodeling associated with PH. In vivo EC lineage tracing demonstrated that Pde4b induces PH development by driving endothelial-to-mesenchymal transition (EndMT), and mechanistic studies showed that Pde4b regulates EndMT by antagonizing the cAMP-dependent PKA-CREB-BMPRII axis. Finally, treating PH rats with a PDE4B-specific inhibitor validated that PDE4B inhibition has a significant pharmacological effect in the alleviation of PH. Collectively, our findings indicate a critical role for PDE4B in EndMT and PH, prompting further studies of PDE4B-specific inhibitors as a therapeutic strategy for PH.
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Affiliation(s)
- Yanjiang Xing
- State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
- Haihe Laboratory of Cell Ecosystem, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300051, China
| | - Yangfeng Hou
- State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Tianfei Fan
- State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu 610044, China
| | - Ran Gao
- State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Xiaohang Feng
- State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Bolun Li
- State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Junling Pang
- State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Wenjun Guo
- State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Ting Shu
- State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
- Haihe Laboratory of Cell Ecosystem, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300051, China
| | - Jinqiu Li
- State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Jie Yang
- State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Qilong Mao
- State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Ya Luo
- State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Xianmei Qi
- State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Peiran Yang
- State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Chaoyang Liang
- Department of Lung Transplantation, National Center for Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, China–Japan Friendship Hospital, Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing 100029, China
| | - Hongmei Zhao
- The State Key Laboratory of Complex, Severe, and Rare Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Department of Pathophysiology, Peking Union Medical College, Beijing 100005, China
| | - Wenhui Chen
- Department of Lung Transplantation, National Center for Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, China–Japan Friendship Hospital, Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing 100029, China
| | - Jing Wang
- State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
- Haihe Laboratory of Cell Ecosystem, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300051, China
| | - Chen Wang
- State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
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14
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Chen J, He F, Peng H, Guo J. The underlying mechanism and targeted therapy strategy of miRNAs cross-regulating EMT process through multiple signaling pathways in hepatocellular carcinoma. Front Mol Biosci 2024; 11:1378386. [PMID: 38584703 PMCID: PMC10995332 DOI: 10.3389/fmolb.2024.1378386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/29/2024] [Accepted: 03/04/2024] [Indexed: 04/09/2024] Open
Abstract
The consistent notion holds that hepatocellular carcinoma (HCC) initiation, progression, and clinical treatment failure treatment failure are affected by the accumulation of various genetic and epigenetic alterations. MicroRNAs (miRNAs) play an irreplaceable role in a variety of physiological and pathological states. meanwhile, epithelial-mesenchymal transition (EMT) is a crucial biological process that controls the development of HCC. miRNAs regulate the intermediation state of EMTor mesenchymal-epithelial transition (MTE)thereby regulating HCC progression. Notably, miRNAs regulate key HCC-related molecular pathways, including the Wnt/β-catenin pathway, PTEN/PI3K/AKT pathway, TGF-β pathway, and RAS/MAPK pathway. Therefore, we comprehensively reviewed how miRNAs produce EMT effects by multiple signaling pathways and their potential significance in the pathogenesis and treatment response of HCC. emphasizing their molecular pathways and progression in HCC initiation. Additionally, we also pay attention to regulatory mechanisms that are partially independent of signaling pathways. Finally, we summarize and propose miRNA-targeted therapy and diagnosis and defense strategies forHCC. The identification of the mechanism leading to the activation of EMT programs during HCC disease processes also provides a new protocol for the plasticity of distinct cellular phenotypes and possible therapeutic interventions. Consequently, we summarize the latest progress in this direction, with a promising path for further insight into this fast-moving field.
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Affiliation(s)
- Juan Chen
- Department of Pathology, Bishan Hospital of Chongqing Medical University, Chongqing, China
| | - Fuguo He
- Department of Pathology, Bishan Hospital of Chongqing Medical University, Chongqing, China
| | - Hong Peng
- Department of Gastroenterology, Bishan Hospital of Chongqing Medical University, Chongqing, China
| | - Jinjun Guo
- Department of Gastroenterology, Bishan Hospital of Chongqing Medical University, Chongqing, China
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15
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Zong S, Huang G, Pan B, Zhao S, Ling C, Cheng B. A Hypoxia-Related miRNA-mRNA Signature for Predicting the Response and Prognosis of Transcatheter Arterial Chemoembolization in Hepatocellular Carcinoma. J Hepatocell Carcinoma 2024; 11:525-542. [PMID: 38496249 PMCID: PMC10944249 DOI: 10.2147/jhc.s454698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/13/2023] [Accepted: 02/28/2024] [Indexed: 03/19/2024] Open
Abstract
Purpose Transcatheter arterial chemoembolization (TACE) is commonly used in the treatment of hepatocellular carcinoma (HCC). However, not all patients respond to this treatment. TACE typically leads to hypoxia in the tumor microenvironment. Therefore, we aimed to construct a prognostic model based on hypoxia-related differentially expressed microRNA (miRNAs) in hepatocellular carcinoma (HCC) and to investigate the potential target mRNAs for predicting TACE response. Methods The hypoxia-related miRNAs (HRMs) were identified in liver cancer cells, then global test was performed to further select the miRNAs which were associated with recurrence and vascular invasion. A prognostic model was constructed based on multivariate Cox regression analysis; qRT-PCR analysis was used to validate the differentially expressed miRNAs in HCC cell lines under hypoxic condition. We further identified the putative target genes of the miRNAs and investigate the relationship between the target genes and TACE response, immune cells infiltration. Results We established a HRMs prognostic model for HCC patients, containing two miRNAs (miR-638, miR-501-5p), the patients with high-HRMs score showed worse survival in discovery and validation cohort; qRT-PCR analysis confirmed that these two miRNAs are up-regulated in hepatoma cells under hypoxic condition. Furthermore, four putative target genes of these two miRNAs were identified (ADH1B, CTH, FTCD, RCL1), which were significantly associated with TACE response, immune score, immunosuppressive immune cells infiltration, PDCD1 and CTLA4. Conclusion The HCC-HRMs signature may be utilized as a promising prognostic factor and may have implications for guiding TACE and immune therapy.
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Affiliation(s)
- Shaoqi Zong
- Oncology Department of Traditional Chinese Medicine, The First Affiliated Hospital of Naval Medical University, Shanghai, 200043, People’s Republic of China
- Department of Oncology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, People’s Republic of China
| | - Guokai Huang
- Oncology Department of Traditional Chinese Medicine, The First Affiliated Hospital of Naval Medical University, Shanghai, 200043, People’s Republic of China
- Faculty of Traditional Chinese Medicine, Naval Medical University, Shanghai, 200043, People’s Republic of China
| | - Bo Pan
- Oncology Department of Traditional Chinese Medicine, The First Affiliated Hospital of Naval Medical University, Shanghai, 200043, People’s Republic of China
| | - Shasha Zhao
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, People’s Republic of China
| | - Changquan Ling
- Oncology Department of Traditional Chinese Medicine, The First Affiliated Hospital of Naval Medical University, Shanghai, 200043, People’s Republic of China
- Faculty of Traditional Chinese Medicine, Naval Medical University, Shanghai, 200043, People’s Republic of China
| | - Binbin Cheng
- Oncology Department of Traditional Chinese Medicine, The First Affiliated Hospital of Naval Medical University, Shanghai, 200043, People’s Republic of China
- Faculty of Traditional Chinese Medicine, Naval Medical University, Shanghai, 200043, People’s Republic of China
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16
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Wu J, Wu Y, Chen S, Guo Q, Shao Y, Liu C, Lin K, Wang S, Zhu J, Chen X, Ju X, Xia L, Wu X. PARP1-stabilised FOXQ1 promotes ovarian cancer progression by activating the LAMB3/WNT/β-catenin signalling pathway. Oncogene 2024; 43:866-883. [PMID: 38297082 DOI: 10.1038/s41388-024-02943-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/06/2023] [Revised: 01/03/2024] [Accepted: 01/08/2024] [Indexed: 02/02/2024]
Abstract
Metastasis is an important factor that causes ovarian cancer (OC) to become the most lethal malignancy of the female reproductive system, but its molecular mechanism is not fully understood. In this study, through bioinformatics analysis, as well as analysis of tissue samples and clinicopathological characteristics and prognosis of patients in our centre, it was found that Forkhead box Q1 (FOXQ1) was correlated with metastasis and prognosis of OC. Through cell function experiments and animal experiments, the results show that FOXQ1 can promote the progression of ovarian cancer in vivo and in vitro. Through RNA-seq, chromatin immunoprecipitation sequencing (ChIP-seq), Kyoto Encyclopedia of Genes and Genomes (KEGG), gene set enrichment analysis (GSEA), Western blotting (WB), quantitative real-time polymerase chain reaction (qRT‒PCR), immunohistochemistry (IHC), luciferase assay, and ChIP-PCR, it was demonstrated that FOXQ1 can mediate the WNT/β-catenin pathway by targeting the LAMB promoter region. Through coimmunoprecipitation (Co-IP), mass spectrometry (MS), ubiquitination experiments, and immunofluorescence (IF), the results showed that PARP1 could stabilise FOXQ1 expression via the E3 ubiquitin ligase Hsc70-interacting protein (CHIP). Finally, the whole mechanism pathway was verified by animal drug combination experiments and clinical specimen prognosis analysis. In summary, our results suggest that PARP1 can promote ovarian cancer progression through the LAMB3/WNT/β-catenin pathway by stabilising FOXQ1 expression.
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Affiliation(s)
- Jiangchun Wu
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
| | - Yong Wu
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
| | - Siyu Chen
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
| | - Qinhao Guo
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
| | - Yang Shao
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Chaohua Liu
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
- Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Kailin Lin
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Simin Wang
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
| | - Jun Zhu
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
| | - Xiaojun Chen
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
| | - Xingzhu Ju
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
| | - Lingfang Xia
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
| | - Xiaohua Wu
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China.
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17
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Jiang H, Su W, Wang H, Luo C, Wang Y, Zhang L, Luo L, Lu Z, Shen D, Su G. DPY30 knockdown suppresses colorectal carcinoma progression via inducing Raf1/MST2-mediated apoptosis. Heliyon 2024; 10:e24807. [PMID: 38314299 PMCID: PMC10837565 DOI: 10.1016/j.heliyon.2024.e24807] [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] [Academic Contribution Register] [Received: 09/22/2023] [Revised: 01/11/2024] [Accepted: 01/15/2024] [Indexed: 02/06/2024] Open
Abstract
Colorectal Carcinoma (CRC) is one of the most common malignant tumors of the digestive tract, with a high mortality rate. DPY30 is one of the core subunits of the histone methyltransferase complex, which was involved in many cancer processes. However, the role of DPY30 in the occurrence and progression of CRC remains unclear. In this study, we sought to evaluate the role and mechanism of DPY30 in CRC cells apoptosis. Here, we identified that knockdown of DPY30 significantly inhibited the HT29 and HCT116 cells proliferation in vitro. Moreover, the knockdown of DPY30 significantly increased the apoptosis rate and promoted the expression of apoptosis-related proteins in CRC cells. Meanwhile, DPY30 knockdown promoted CRC cells apoptosis through endogenous programmed death and in a caspase activation-dependent manner. Furthermore, RNA-seq analysis revealed that the action of DPY30 is closely related to the apoptosis biological processes, and screened its potential effectors Raf1. Mechanistically, DPY30 downregulation promotes MST2-induced apoptosis by inhibiting Raf1 transcriptional activity through histone H3 lysine 4 trimethylation (H3K4me3). In vivo experiments showed that DPY30 was correlated with Raf1 in nude mouse subcutaneous xenografts tissues significantly. Clinical colorectal specimens further confirmed that overexpression of DPY30 in malignant tissues was significantly correlated with Raf1 level. The vital role of the DPY30/Raf1/MST2 signaling axis in the cell death and survival rate of CRC cells was disclosed, which provides potential new targets for early diagnosis and clinical treatment of CRC.
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Affiliation(s)
- HaiFeng Jiang
- Department of Colorectal Tumor Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, Fujian Province, China
- Department of Critical Care Medicine, Second People's Hospital of Yibin City, Yibin, 644000, Sichuan Province, China
| | - WeiChao Su
- Department of Colorectal Tumor Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, Fujian Province, China
- Xiamen Xianyue Hospital, Xianyue Hospital Affiliated with Xiamen Medical College, Fujian Psychiatric Center, Fujian Clinical Research Center for Mental Disorders, Xiamen, 361012, China
| | - HaiXing Wang
- Department of Endoscopy Center, The First Affiliated Hospital of Xiamen University, Xiamen, 361003, China
| | - ChunYing Luo
- Department of Pathology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, 533000, China
| | - YaTao Wang
- Department of Colorectal Tumor Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, Fujian Province, China
| | - LinJun Zhang
- Xiamen Cell Therapy Research Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, China
| | - LingTao Luo
- Department of Colorectal Tumor Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, Fujian Province, China
| | - ZeBin Lu
- Department of Clinical Medicine, Fujian Medical University, Fuzhou, 350122, China
| | - DongYan Shen
- Xiamen Cell Therapy Research Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, China
| | - GuoQiang Su
- Department of Colorectal Tumor Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, Fujian Province, China
- Department of Pathology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, 533000, China
- Department of Clinical Medicine, Fujian Medical University, Fuzhou, 350122, China
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18
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Li Z, Wei R, Yao S, Meng F, Kong L. HIF-1A as a prognostic biomarker related to invasion, migration and immunosuppression of cervical cancer. Heliyon 2024; 10:e24664. [PMID: 38298716 PMCID: PMC10828096 DOI: 10.1016/j.heliyon.2024.e24664] [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] [Academic Contribution Register] [Received: 11/07/2023] [Revised: 01/09/2024] [Accepted: 01/11/2024] [Indexed: 02/02/2024] Open
Abstract
Background The incidence of cervical cancer ranks second among malignant tumors in women, exerting a significant impact on their quality of life and overall well-being. The hypoxic microenvironment plays a pivotal role in the initiation and progression of tumorigenesis. The present study aims to investigate the fundamental genes and pathways associated with the hypoxia-inducible factor (HIF-1A) in cervical cancer, aiming to identify potential downstream targets for diagnostic and therapeutic purposes. Methods We obtained dataset GSE63514 from the Comprehensive Gene Expression Database (GEO). The dataset comprised of 24 patients in the normal group and 28 patients in the tumor group. Gene set difference analysis (GSVA) and gene set enrichment analysis (GSEA) were used to identify the genes related to HIF-1A expression and the specific signaling pathways involved.The association between HIF-1A and tumor immune infiltration was examined in the TCGA dataset. The WGCAN network was constructed to identify key genes within the blue module, and subsequent gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted to determine the pathways and functional annotations associated with HIF-1A. The protein interaction network of the HIF-1A gene was obtained from the STRING database and visualized using Cytoscape in the meantime.The function of HIF-1A and its related gene expression were verified in vivo. Results HIF-1A was a risk factor in both univariate and multivariate Cox regression analysis of cervical cancer patients. A total of 344 genes significantly correlated with the expression of HIF-1A were identified through correlation analysis, and the genes exhibiting the strongest correlation were obtained. The major signaling pathways involved in HIF-1A encompass TNF-α/NF-κB, PI3K/AKT/MTOR, TGF-β, JAK-STAT, and various other signaling cascades. Reinforced by qRT-PCR, we identified Integrin beta-1 (ITGB1), C-C motif chemokine ligand 2 (CCL2), striatin 3 (STRN3), and endothelin-1 (EDN1) as pivotal downstream genes influenced by HIF-1A. HIF-1A is associated with immune infiltration of natural killer (NK) cells, mast cells, CD4+T cells, M0 macrophages, neutrophils, follicular helper T cells, CD8+T cells, and regulatory T cells (Treg). HIF-1A is associated with sensitivity to chemotherapy drugs. The identification of the HIF-1A pathway and its function primarily focuses on cytoplasmic translation, aerobic respiration, cellular respiration, oxidative phosphorylation, thermogenesis, among others. The results of in vivo experiments have confirmed that HIF-1A plays a crucial role in promoting the migration and invasion of cervical cancer cells. Moreover, the overexpression of HIF-1A led to an upregulation in the expressions of ITGB1, CCL2, STRN3, and EDN1. Conclusions The role of HIF-1A in cervical cancer was determined through a combination of bioinformatics analysis and experimental validation. The genes potentially implicated in the tumorigenesis mechanism of HIF-1A were identified. These findings has the potential to enhance our comprehension of the progression of cervical cancer and offer promising therapeutic targets for its clinical management.
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Affiliation(s)
- Zhenyu Li
- Department of Anesthesiology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Ran Wei
- Department of Anesthesiology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Shunyu Yao
- Department of Anesthesiology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Fang Meng
- Department of Oncology &Hematology, Xishan People's Hospital of Wuxi City, Wuxi, China
| | - Lingsuo Kong
- Department of Anesthesiology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
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Jia X, Chen S, Hou X, Zhuang Q, Tan N, Zhang M, Wang J, Xing X, Xiao Y. Development and Validation of Serum Markers as Noninvasive Diagnostic Methods for Achalasia. Clin Transl Gastroenterol 2024; 15:e00651. [PMID: 37787436 PMCID: PMC10810595 DOI: 10.14309/ctg.0000000000000651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 06/20/2023] [Accepted: 09/25/2023] [Indexed: 10/04/2023] Open
Abstract
INTRODUCTION Currently, the diagnosis of achalasia mainly relies on invasive or radioactive examinations. This study aimed to develop a noninvasive diagnostic method for achalasia based on specific serum markers. METHODS Serum levels of profilin-1, galectin-10, immunoglobulin heavy variable 3-9, vasodilator-stimulated phosphoprotein, and transgelin-2 were measured in patients with achalasia and controls by enzyme-linked immunosorbent assay. The diagnostic values and thresholds were determined by the receiver operating characteristic curve analysis. Then, patients with dysphagia were prospectively enrolled to validate the ability of these molecules for achalasia diagnosing. RESULTS A total of 142 patients with achalasia and 50 nonachalasia controls (healthy volunteers and patients with reflux esophagitis) were retrospectively included. The serum levels of profilin-1, galectin-10, and transgelin-2 in patients with achalasia were significantly higher than those in healthy volunteers and patients with reflux esophagitis ( P all < 0.001). Profilin-1, galectin-10, and transgelin-2 were of good performance in diagnosing achalasia, with optimal thresholds of 2,171.2, 33.9, and 1,630.6 pg/mL, respectively. Second, 40 patients with dysphagia were prospectively enrolled to the validation of achalasia. For profilin-1, the positive predictive value, negative predictive value, sensitivity, and specificity were 100.0%, 64.5%, 45.0%, and 100.0%, respectively. The figures for transgelin-2 were 65.5%, 90.9%, 95.0%, and 50.0%. When both increased, the positive predictive value reached to 100.0%. When both indexes were normal, the negative predictive value was 100.0%. DISCUSSION Profilin-1 and transgelin-2 were promising biomarkers for achalasia diagnosis and performed better in combination. Further multicenter studies are necessary to verify their application as preliminary screening tools for achalasia.
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Affiliation(s)
- Xingyu Jia
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangdong, China
| | - Songfeng Chen
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangdong, China
| | - Xun Hou
- Gastrointestinal Surgery Center, The First Affiliated Hospital of Sun Yat-sen University, Guangdong, China
| | - Qianjun Zhuang
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangdong, China
| | - Niandi Tan
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangdong, China
| | - Mengyu Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangdong, China
| | - Jinhui Wang
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangdong, China
| | - Xiangbin Xing
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangdong, China
| | - Yinglian Xiao
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangdong, China
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Liu Y, Peng C, Ahad F, Ali Zaidi SA, Muluh TA, Fu Q. Advanced Strategies of CAR-T Cell Therapy in Solid Tumors and Hematological Malignancies. Recent Pat Anticancer Drug Discov 2024; 19:557-572. [PMID: 38213150 DOI: 10.2174/0115748928277331231218115402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/18/2023] [Revised: 10/30/2023] [Accepted: 11/10/2023] [Indexed: 01/13/2024]
Abstract
Chimeric antigen receptor T-cells, known as CAR-T cells, represent a promising breakthrough in the realm of adoptive cell therapy. These T-cells are genetically engineered to carry chimeric antigen receptors that specifically target tumors. They have achieved notable success in the treatment of blood-related cancers, breathing new life into this field of medical research. However, numerous obstacles limit chimeric antigen receptors T-cell therapy's efficacy, such as it cannot survive in the body long. It is prone to fatigue and exhaustion, leading to difficult tumor elimination and repeated recurrence, affecting solid tumors and hematological malignancies. The challenges posed by solid tumors, especially in the context of the complex solid-tumor microenvironment, require specific strategies. This review outlines recent advancements in improving chimeric antigen receptors T-cell therapy by focusing on the chimeric antigen receptors protein, modifying T-cells, and optimizing the interaction between T-cells and other components within the tumor microenvironment. This article aims to provide an extensive summary of the latest discoveries regarding CAR-T cell therapy, encompassing its application across various types of human cancers. Moreover, it will delve into the obstacles that have emerged in recent times, offering insights into the challenges faced by this innovative approach. Finally, it highlights novel therapeutic options in treating hematological and solid malignancies with chimeric antigen receptors T-cell therapies.
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Affiliation(s)
- Yangjie Liu
- Department of Pharmacy, Luzhou People's Hospital, Luzhou 646000, Sichuan, PRC China
| | - Cao Peng
- Department of Pharmacy, Luzhou People's Hospital, Luzhou 646000, Sichuan PRC China
| | - Faiza Ahad
- Shenzhen University Medical School, Shenzhen University, Shenzhen 518060, China
| | - Syed Aqib Ali Zaidi
- Shenzhen University Medical School, Shenzhen University, Shenzhen 518060, China
| | - Tobias Achu Muluh
- Shenzhen University Medical School, Shenzhen University, Shenzhen 518060, China
| | - Qiuxia Fu
- Department of Pharmacy, Luzhou People's Hospital, Luzhou 646000, Sichuan PRC China
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Wang X, Yin L, Chai M, Kou B, Liu X, Wang X. Hu-Qi-Zheng-Xiao Decoction Inhibits the Metastasis of Hepatocellular Carcinoma Cells by Suppressing the HIF-1α Signaling Pathway to Inhibit EMT, LCSC, and Angiogenic Process. Integr Cancer Ther 2024; 23:15347354231226126. [PMID: 38385348 PMCID: PMC10893843 DOI: 10.1177/15347354231226126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/01/2023] [Revised: 10/28/2023] [Accepted: 12/27/2023] [Indexed: 02/23/2024] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a common clinical malignant tumor of the digestive system. Hu-Qi-Zheng-Xiao (HQZX) decoction has been clinically found to prolong the survival of patients with hepatocellular carcinoma and improve the quality of patients' survival, but its antitumor biological mechanism is still unclear. METHODS A nude mouse hollow fiber hepatocellular carcinoma model was constructed to analyze the in vivo efficacy of HQZX decoction against 7 different hepatocellular carcinoma cells. The subcutaneous graft tumor model was again validated. In vitro, the effect of HQZX decoction on the growth and metastasis of the cell line with the highest growth inhibition was evaluated. The cell line with the best efficacy response screened was again used to construct a hollow fiber hepatocellular carcinoma model and hollow fiber conduit cells were extracted to detect the expression of HIF-1α, VEGF, EMT-related molecules, LCSCs-related molecules, and to observe the density of the subcutaneous vascular network of hollow fiber conduits. The liver metastasis model of splenic injection was constructed to observe the effect of HQZX decoction on tumor metastasis. RESULTS The hollow fiber hepatocellular carcinoma model was evaluated for the efficacy of HQZX decoction, and it was found to have the highest growth inhibition of LM3-luc cells. In vitro, the CCK8 assay revealed that HQZX decoction could inhibit tumor migration and invasion and promote apoptosis. In addition, the mechanism study of extracting cells from hollow fiber tubes found that HQZX decoction could inhibit metastasis-associated HIF-1α, VEGF, EMT-related molecules, and LCSCs-related molecules expression. capillary network around subcutaneous fiber tubes was reduced in the HQZX decoction gavage group of mice. It inhibited tumor metastasis in nude mice. CONCLUSIONS HQZX decoction inhibited the growth of a variety of hepatocellular carcinoma cells. HQZX decoction suppressed the expression of metastasis-associated VEGF, EMT-related molecules, and LCSCs-related molecules and inhibited tumor angiogenesis and growth and metastasis, which may be related to the inhibition of the HIF-1α signaling pathway. It reveals that HQZX decoction may be a promising herbal compound for anti-HCC therapy, and also reveals the accurate feasibility of the hollow fiber hepatocellular carcinoma model for in vivo pharmacodynamic evaluation and mechanism study.
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Affiliation(s)
- Xuejing Wang
- Department of Integrated Traditional Chinese and Western Medicine, Beijing Youan Hospital, Capital Medical University, Beijing, People’s Republic of China
- Beijing Institute of Hepatology, Beijing, People’s Republic of China
| | - Ling Yin
- Beijing Institute of Hepatology, Beijing, People’s Republic of China
| | - Mengyin Chai
- Beijing Institute of Hepatology, Beijing, People’s Republic of China
| | - Buxin Kou
- Beijing Institute of Hepatology, Beijing, People’s Republic of China
| | - Xiaoni Liu
- Beijing Institute of Hepatology, Beijing, People’s Republic of China
| | - Xiaojun Wang
- Department of Integrated Traditional Chinese and Western Medicine, Beijing Youan Hospital, Capital Medical University, Beijing, People’s Republic of China
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Gui J, Zhou H, Wan H, Yang D, Liu Q, Zhu L, Mi Y. The Role of Vasodilator-stimulated Phosphoproteins in the Development of Malignant Tumors. Curr Cancer Drug Targets 2024; 24:477-489. [PMID: 37962042 PMCID: PMC11092557 DOI: 10.2174/0115680096262439231023110106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/15/2023] [Revised: 08/06/2023] [Accepted: 09/06/2023] [Indexed: 11/15/2023]
Abstract
Vasodilator-stimulated phosphoprotein (VASP) is an actin-binding protein that includes three structural domains: Enabled/VASP homolog1 (EVH1), EVH2, and proline-rich (PRR). VASP plays an important role in various cellular behaviors related to cytoskeletal regulation. More importantly, VASP plays a key role in the progression of several malignant tumors and is associated with malignant cell proliferation, invasion, and metastasis. Here, we have summarized current studies on the impact of VASP on the development of several malignant tumors and their mechanisms. This study provides a new theoretical basis for clinical molecular diagnosis and molecular targeted therapy.
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Affiliation(s)
- Jiandong Gui
- Wuxi School of Medicine, Jiangnan University, 1800 Lihudadao, Wuxi, 214122, Jiangsu Province, China
- Department of Urology, Affiliated Hospital of Jiangnan University, 1000 Hefeng Road, Wuxi, 214122, Jiangsu Province, China
| | - Hangsheng Zhou
- Wuxi School of Medicine, Jiangnan University, 1800 Lihudadao, Wuxi, 214122, Jiangsu Province, China
- Department of Urology, Affiliated Hospital of Jiangnan University, 1000 Hefeng Road, Wuxi, 214122, Jiangsu Province, China
| | - Hongyuan Wan
- Wuxi School of Medicine, Jiangnan University, 1800 Lihudadao, Wuxi, 214122, Jiangsu Province, China
- Department of Urology, Affiliated Hospital of Jiangnan University, 1000 Hefeng Road, Wuxi, 214122, Jiangsu Province, China
| | - Dongjie Yang
- Department of Urology, Affiliated Hospital of Jiangnan University, 1000 Hefeng Road, Wuxi, 214122, Jiangsu Province, China
| | - Qing Liu
- Department of Urology, Affiliated Hospital of Jiangnan University, 1000 Hefeng Road, Wuxi, 214122, Jiangsu Province, China
- Huadong Sanatorium, 67 Dajishan, Wuxi 214122, Jiangsu Province, China
| | - Lijie Zhu
- Department of Urology, Affiliated Hospital of Jiangnan University, 1000 Hefeng Road, Wuxi, 214122, Jiangsu Province, China
| | - Yuanyuan Mi
- Department of Urology, Affiliated Hospital of Jiangnan University, 1000 Hefeng Road, Wuxi, 214122, Jiangsu Province, China
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Zhang Q, Lin B, Chen H, Ye Y, Huang Y, Chen Z, Li J. Lipid metabolism-related gene expression in the immune microenvironment predicts prognostic outcomes in renal cell carcinoma. Front Immunol 2023; 14:1324205. [PMID: 38090559 PMCID: PMC10712371 DOI: 10.3389/fimmu.2023.1324205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/19/2023] [Accepted: 11/15/2023] [Indexed: 12/18/2023] Open
Abstract
Background Rates of renal cell carcinoma (RCC) occurrence and mortality are steadily rising. In an effort to address this issue, the present bioinformatics study was developed with the goal of identifying major lipid metabolism biomarkers and immune infiltration characteristics associated with RCC cases. Methods The Cancer Genome Atlas (TCGA) and E-MTAB-1980 were used to obtain matched clinical and RNA expression data from patients diagnosed with RCC. A LASSO algorithm and multivariate Cox regression analyses were employed to design a prognostic risk model for these patients. The tumor immune microenvironment (TIME) in RCC patients was further interrogated through ESTIMATE, TIMER, and single-cell gene set enrichment analysis (ssGSEA) analyses. Gene Ontology (GO), KEGG, and GSEA enrichment approaches were further employed to gauge the mechanistic basis for the observed results. Differences in gene expression and associated functional changes were then validated through appropriate molecular biology assays. Results Through the approach detailed above, a risk model based on 8 genes associated with RCC patient overall survival and lipid metabolism was ultimately identified that was capable of aiding in the diagnosis of this cancer type. Poorer prognostic outcomes in the analyzed RCC patients were associated with higher immune scores, lower levels of tumor purity, greater immune cell infiltration, and higher relative immune status. In GO and KEGG enrichment analyses, genes that were differentially expressed between risk groups were primarily related to the immune response and substance metabolism. GSEA analyses additionally revealed that the most enriched factors in the high-risk group included the stable internal environment, peroxisomes, and fatty acid metabolism. Subsequent experimental validation in vitro and in vivo revealed that the most significantly differentially expressed gene identified herein, ALOX5, was capable of suppressing RCC tumor cell proliferation, invasivity, and migration. Conclusion In summary, a risk model was successfully established that was significantly related to RCC patient prognosis and TIME composition, offering a robust foundation for the development of novel targeted therapeutic agents and individualized treatment regimens. In both immunoassays and functional analyses, dysregulated lipid metabolism was associated with aberrant immunological activity and the reprogramming of fatty acid metabolic activity, contributing to poorer outcomes.
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Affiliation(s)
- Qian Zhang
- Department of Rehabilitation Medicine, Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Bingbiao Lin
- Department of Urology, Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
- Department of Radiotherapy, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Huikun Chen
- Department of Urology, Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Yinyan Ye
- Department of Rehabilitation Medicine, Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Yijie Huang
- Department of Rehabilitation Medicine, Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Zhen Chen
- Department of Rehabilitation Medicine, Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Jun Li
- Department of Urology, Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
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Wei G, Li C, Jia X, Xie J, Tang Z, Jin M, Chen Q, Sun Y, He S, Li X, Chen Y, Zheng H, Liao W, Liao Y, Bin J, Huang S. Extracellular vesicle-derived CircWhsc1 promotes cardiomyocyte proliferation and heart repair by activating TRIM59/STAT3/Cyclin B2 pathway. J Adv Res 2023; 53:199-218. [PMID: 36587763 PMCID: PMC10658329 DOI: 10.1016/j.jare.2022.12.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/13/2022] [Revised: 12/22/2022] [Accepted: 12/26/2022] [Indexed: 12/31/2022] Open
Abstract
INTRODUCTION Extracellular vesicles (EVs)-mediated cell-to-cell communication is crucial for hypoxia-induced cell proliferation and tissue repair, but its function in endogenous cardiac regeneration is still unknown. OBJECTIVES Herein, we aimed to determine whether hypoxia-inducible circWhsc1 in endothelial EVs promoted cardiomyocyte (CM) proliferation and cardiac regeneration. METHODS RNA-sequence data was used to identify EV circRNAs that were involved into endogenous cardiac regeneration. Quantitative polymerase chain reactions were conducted to determine circRNA expression in tissue, cells and EVs. Gain- and loss-of-function assays were performed to explore the function of EV-derived circWhsc1 during cardiac regeneration. Western blotting and RNA pulldown assays were used to investigate its underlying mechanism. RESULTS We found that circWhsc1 was enriched in neonatal mouse hearts, particularly in cardiac ECs, and was further upregulated both in ECs and EC-derived EVs under hypoxic conditions. When cocultured with hypoxia-preconditioned neonatal ECs or their secreted EVs, both neonatal and adult CMs exhibited an increased proliferation rate and G2/M ratio, which could be attenuated by knockdown of circWhsc1 in ECs. In vivo, EC-restricted overexpression of circWhsc1 and EV-mediated delivery of circWhsc1 induced CM proliferation, alleviated cardiac fibrosis and restored cardiac function following myocardial infarction in adult mice. Mechanistic studies revealed that EV-derived circWhsc1 activated TRIM59 by enhancing its phosphorylation, thereby reinforcing the binding of TRIM59 to STAT3, phosphorylating STAT3 and inducing CM proliferation. CONCLUSION The current study demonstrated that hypoxia-inducible circWhsc1 in EC-derived EVs induces CM proliferation and heart regeneration. EC-CM communication mediated by EV-derived circWhsc1 might represent a prospective therapeutic target for inducing cardiac repair post-myocardial infarction.
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Affiliation(s)
- Guoquan Wei
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China
| | - Chuling Li
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China
| | - Xiaoqian Jia
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China
| | - Jingfang Xie
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China
| | - Zhenquan Tang
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China
| | - Ming Jin
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China
| | - Qiqi Chen
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China
| | - Yili Sun
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China
| | - Sisi He
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China
| | - Xinzhong Li
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China
| | - Yanmei Chen
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China
| | - Hao Zheng
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China
| | - Wangjun Liao
- Department of Oncology, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China
| | - Yulin Liao
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China
| | - Jianping Bin
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China.
| | - Senlin Huang
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China.
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Jia W, Liang S, Lin W, Li S, Yuan J, Jin M, Nie S, Zhang Y, Zhai X, Zhou L, Ling C, Cheng B, Ling C. Hypoxia-induced exosomes facilitate lung pre-metastatic niche formation in hepatocellular carcinoma through the miR-4508-RFX1-IL17A-p38 MAPK-NF-κB pathway. Int J Biol Sci 2023; 19:4744-4762. [PMID: 37781522 PMCID: PMC10539707 DOI: 10.7150/ijbs.86767] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/03/2023] [Accepted: 08/26/2023] [Indexed: 10/03/2023] Open
Abstract
Background: Hypoxia plays an important role in the lung metastasis of hepatocellular carcinoma (HCC). However, the process by which hypoxia promotes the formation of a pre-metastatic niche (PMN) and its underlying mechanism remain unclear. Methods: Exosomes derived from normoxic and hypoxic HCC cells were collected to induce fibroblast activation in vitro and PMN formation in vivo. The micro RNA (miR) profiles of the exosomes were sequenced to identify differentially expressed miRNAs. Gain- and loss-of-function analyses were performed to investigate miR-4508 function. Dual-luciferase, western blotting, and real-time reverse transcription-PCR analyses were used to identify the direct targets of miR-4508 and its downstream signaling pathways. To demonstrate the roles of hypoxic tumor-derived exosomes (H-TDEs) and miR-4508 in the lung metastasis of liver cancer, H22 tumor cells were injected through the tail vein of mice. Blood plasma-derived exosomes from patients with HCC who underwent transarterial chemoembolization (TACE) were applied to determine clinical correlations. Results: We demonstrated that H-TDEs activated lung fibroblasts and facilitated PMN formation, thereby promoting lung metastasis in mice. Screening for upregulated exosomal miRNAs revealed that miR-4508 and its target, regulatory factor X1 (RFX1), were involved in H-TDE-induced lung PMN formation. Moreover, miR-4508 was significantly upregulated in plasma exosomes derived from patients with HCC after TACE. We confirmed that the p38 MAPK-NF-κB signaling pathway is involved in RFX1 knockdown-induced fibroblast activation and PMN formation. In addition, IL17A, a downstream target of RFX1, was identified as a link between RFX1 knockdown and p38 MAPK activation in fibroblasts. Conclusion: Hypoxia enhances the release of TDEs enriched with miR-4508, thereby promoting lung PMN formation by targeting the RFX1-IL17A-p38 MAPK-NF-κB pathway. These findings highlight a novel mechanism underlying hypoxia-induced pulmonary metastasis of HCC.
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Affiliation(s)
- Wentao Jia
- Oncology Department of Traditional Chinese Medicine, the First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
- Faculty of Traditional Chinese Medicine, Naval Medical University, Shanghai, 200043, China
| | - Shufang Liang
- Oncology Department of Traditional Chinese Medicine, the First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Wanfu Lin
- Faculty of Traditional Chinese Medicine, Naval Medical University, Shanghai, 200043, China
| | - Shu Li
- Department of Gastroenterology, Baoshan Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201900, China
| | - Jiaying Yuan
- Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Mingming Jin
- Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China
| | - Shuchang Nie
- Oncology Department of Traditional Chinese Medicine, the First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
- Faculty of Traditional Chinese Medicine, Naval Medical University, Shanghai, 200043, China
| | - Ya'ni Zhang
- Oncology Department of Traditional Chinese Medicine, the First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
- Faculty of Traditional Chinese Medicine, Naval Medical University, Shanghai, 200043, China
| | - Xiaofeng Zhai
- Oncology Department of Traditional Chinese Medicine, the First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
- Faculty of Traditional Chinese Medicine, Naval Medical University, Shanghai, 200043, China
| | - Liping Zhou
- State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology (Ministry of Education), School of Life Sciences, Fudan University, Shanghai, 200438, China
| | - Changquan Ling
- Oncology Department of Traditional Chinese Medicine, the First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
- Faculty of Traditional Chinese Medicine, Naval Medical University, Shanghai, 200043, China
| | - Binbin Cheng
- Oncology Department of Traditional Chinese Medicine, the First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
- Faculty of Traditional Chinese Medicine, Naval Medical University, Shanghai, 200043, China
| | - Chen Ling
- State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology (Ministry of Education), School of Life Sciences, Fudan University, Shanghai, 200438, China
- Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
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Sin SQ, Mohan CD, Goh RMWJ, You M, Nayak SC, Chen L, Sethi G, Rangappa KS, Wang L. Hypoxia signaling in hepatocellular carcinoma: Challenges and therapeutic opportunities. Cancer Metastasis Rev 2023; 42:741-764. [PMID: 36547748 DOI: 10.1007/s10555-022-10071-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 07/15/2022] [Accepted: 11/25/2022] [Indexed: 12/24/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers with a relatively high cancer-related mortality. The uncontrolled proliferation of HCC consumes a significant amount of oxygen, causing the development of a hypoxic tumor microenvironment (TME). Hypoxia-inducible factors (HIFs), crucial regulators in the TME, activate several cancer hallmarks leading to the hepatocarcinogenesis of HCC and resistance to current therapeutics. As such, HIFs and their signaling pathways have been explored as potential therapeutic targets for the future management of HCC. This review discusses the current understanding of the structure and function of HIFs and their complex relationship with the various cancer hallmarks. To address tumor hypoxia, this review provides an insight into the various potential novel therapeutic agents for managing HCC, such as hypoxia-activated prodrugs, HIF inhibitors, nanomaterials, antisense oligonucleotides, and natural compounds, that target HIFs/hypoxic signaling pathways in HCC. Because of HCC's relatively high incidence and mortality rates in the past decades, greater efforts should be put in place to explore novel therapeutic approaches to improve the outcome for HCC patients.
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Affiliation(s)
- Shant Qinxiang Sin
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | | | | | - Mingliang You
- Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou Cancer Institute, Hangzhou, 31002, China
- Affiliated Hangzhou Cancer Hospital, Zhejiang University School of Medicine, Hangzhou, 31002, China
| | - Siddaiah Chandra Nayak
- Department of Studies in Biotechnology, University of Mysore, Manasagangotri, Mysore, 570006, India
| | - Lu Chen
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
- Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Gautam Sethi
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | | | - Lingzhi Wang
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
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Liu L, Han L, Dong L, He Z, Gao K, Chen X, Guo JC, Zhao Y. The hypoxia-associated genes in immune infiltration and treatment options of lung adenocarcinoma. PeerJ 2023; 11:e15621. [PMID: 37576511 PMCID: PMC10414028 DOI: 10.7717/peerj.15621] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/23/2023] [Accepted: 06/01/2023] [Indexed: 08/15/2023] Open
Abstract
Background Lung adenocarcinoma (LUAD) is a common lung cancer with a poor prognosis under standard chemotherapy. Hypoxia is a crucial factor in the development of solid tumors, and hypoxia-related genes (HRGs) are closely associated with the proliferation of LUAD cells. Methods In this study, LUAD HRGs were screened, and bioinformatics analysis and experimental validation were conducted. The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases were used to gather LUAD RNA-seq data and accompanying clinical information. LUAD subtypes were identified by unsupervised cluster analysis, and immune infiltration analysis of subtypes was conducted by GSVA and ssGSEA. Cox regression and LASSO regression analyses were used to obtain prognosis-related HRGs. Prognostic analysis was used to evaluate HRGs. Differences in enrichment pathways and immunotherapy were observed between risk groups based on GSEA and the TIDE method. Finally, RT-PCR and in vitro experiments were used to confirm prognosis-related HRG expression in LUAD cells. Results Two hypoxia-associated subtypes of LUAD were distinguished, demonstrating significant differences in prognostic analysis and immunological characteristics between subtypes. A prognostic model based on six HRGs (HK1, PDK3, PFKL, SLC2A1, STC1, and XPNPEP1) was developed for LUAD. HK1, SLC2A1, STC1, and XPNPEP1 were found to be risk factors for LUAD. PDK3 and PFKL were protective factors in LUAD patients. Conclusion This study demonstrates the effect of hypoxia-associated genes on immune infiltration in LUAD and provides options for immunotherapy and therapeutic strategies in LUAD.
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Affiliation(s)
- Liu Liu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Lina Han
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Lei Dong
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Zihao He
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Kai Gao
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Xu Chen
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Jin-Cheng Guo
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Yi Zhao
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
- The Research Center for Ubiquitous Computing Systems (CUbiCS), Institute of Computing Technology, Chinese Academy of Sciences, Beijing, China
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28
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Urzì O, Gasparro R, Costanzo E, De Luca A, Giavaresi G, Fontana S, Alessandro R. Three-Dimensional Cell Cultures: The Bridge between In Vitro and In Vivo Models. Int J Mol Sci 2023; 24:12046. [PMID: 37569426 PMCID: PMC10419178 DOI: 10.3390/ijms241512046] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/20/2023] [Revised: 07/19/2023] [Accepted: 07/21/2023] [Indexed: 08/13/2023] Open
Abstract
Although historically, the traditional bidimensional in vitro cell system has been widely used in research, providing much fundamental information regarding cellular functions and signaling pathways as well as nuclear activities, the simplicity of this system does not fully reflect the heterogeneity and complexity of the in vivo systems. From this arises the need to use animals for experimental research and in vivo testing. Nevertheless, animal use in experimentation presents various aspects of complexity, such as ethical issues, which led Russell and Burch in 1959 to formulate the 3R (Replacement, Reduction, and Refinement) principle, underlying the urgent need to introduce non-animal-based methods in research. Considering this, three-dimensional (3D) models emerged in the scientific community as a bridge between in vitro and in vivo models, allowing for the achievement of cell differentiation and complexity while avoiding the use of animals in experimental research. The purpose of this review is to provide a general overview of the most common methods to establish 3D cell culture and to discuss their promising applications. Three-dimensional cell cultures have been employed as models to study both organ physiology and diseases; moreover, they represent a valuable tool for studying many aspects of cancer. Finally, the possibility of using 3D models for drug screening and regenerative medicine paves the way for the development of new therapeutic opportunities for many diseases.
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Affiliation(s)
- Ornella Urzì
- Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D), Section of Biology and Genetics, University of Palermo, 90133 Palermo, Italy; (O.U.); (R.G.); (E.C.); (R.A.)
| | - Roberta Gasparro
- Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D), Section of Biology and Genetics, University of Palermo, 90133 Palermo, Italy; (O.U.); (R.G.); (E.C.); (R.A.)
| | - Elisa Costanzo
- Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D), Section of Biology and Genetics, University of Palermo, 90133 Palermo, Italy; (O.U.); (R.G.); (E.C.); (R.A.)
| | - Angela De Luca
- IRCCS Istituto Ortopedico Rizzoli, SC Scienze e Tecnologie Chirurgiche, 40136 Bologna, Italy; (A.D.L.); (G.G.)
| | - Gianluca Giavaresi
- IRCCS Istituto Ortopedico Rizzoli, SC Scienze e Tecnologie Chirurgiche, 40136 Bologna, Italy; (A.D.L.); (G.G.)
| | - Simona Fontana
- Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D), Section of Biology and Genetics, University of Palermo, 90133 Palermo, Italy; (O.U.); (R.G.); (E.C.); (R.A.)
| | - Riccardo Alessandro
- Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D), Section of Biology and Genetics, University of Palermo, 90133 Palermo, Italy; (O.U.); (R.G.); (E.C.); (R.A.)
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Lu S, Liu X, Wu C, Zhang J, Stalin A, Huang Z, Tan Y, Wu Z, You L, Ye P, Fu C, Zhang X, Wu J. Identification of an immune-related 6-lncRNA panel with a good performance for prognostic prediction in hepatocellular carcinoma by integrated bioinformatics analysis. Medicine (Baltimore) 2023; 102:e33990. [PMID: 37478241 PMCID: PMC10662904 DOI: 10.1097/md.0000000000033990] [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] [Academic Contribution Register] [Received: 12/16/2022] [Accepted: 05/23/2023] [Indexed: 07/23/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most malignant tumors with a poor prognosis. The long non-coding RNA (lncRNA) has been found to have great potential as a prognostic biomarker or therapeutic target for cancer patients. However, the prognostic value and tumor immune infiltration of lncRNAs in HCC has yet to be fully elucidated. To identify prognostic biomarkers of lncRNA in HCC by integrated bioinformatics analysis and explore their functions and relationship with tumor immune infiltration. The prognostic risk assessment model for HCC was constructed by comprehensively using univariate/multivariate Cox regression analysis, Kaplan-Meier survival analysis, and the least absolute shrinkage and selection operator regression analysis. Subsequently, the accuracy, independence, and sensitivity of our model were evaluated, and a nomogram for individual prediction in the clinic was constructed. Tumor immune microenvironment (TIME), immune checkpoints, and human leukocyte antigen alleles were compared in high- and low-risk patients. Finally, the functions of our lncRNA signature were examined using Gene Ontology, Kyoto Encyclopedia of Genes and Genomes enrichment analysis, and gene set enrichment analysis. A 6-lncRNA panel of HCC consisting of RHPN1-AS1, LINC01224, CTD-2510F5.4, RP1-228H13.5, LINC01011, and RP11-324I22.4 was eventually identified, and show good performance in predicting the survivals of patients with HCC and distinguishing the immunomodulation of TIME of high- and low-risk patients. Functional analysis also suggested that this 6-lncRNA panel may play an essential role in promoting tumor progression and immune regulation of TIME. In this study, 6 potential lncRNAs were identified as the prognostic biomarkers in HCC, and the regulatory mechanisms involved in HCC were initially explored.
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Affiliation(s)
- Shan Lu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Xinkui Liu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Chao Wu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Jingyuan Zhang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Antony Stalin
- Institute of Fundamental and Frontier Sciences, University of Electronic Science and Technology of China, Chengdu, China
| | - Zhihong Huang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Yingying Tan
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Zhishan Wu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Leiming You
- Department of Immunology and Microbiology, School of Life Science, Beijing University of Chinese Medicine, Beijing, China
| | - Peizhi Ye
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Changgeng Fu
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiaomeng Zhang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Jiarui Wu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
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Hu W, Shen J, Tao Y, Dong D, Lu S, Li L, Sun D, Fan M, Xu C, Shen W, Yu C, Cheng H. CCDC85C suppresses colorectal cancer cells proliferation and metastasis through activating GSK-3β and promoting β-catenin degradation. Cell Signal 2023:110799. [PMID: 37433398 DOI: 10.1016/j.cellsig.2023.110799] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/21/2023] [Revised: 06/20/2023] [Accepted: 07/05/2023] [Indexed: 07/13/2023]
Abstract
Coiled-coil domain-containing 85C (CCDC85C) is a member of the DIPA family and contains a pair of conserved coiled-coil motifs, which was found to be related to a therapeutic target for colorectal cancer, however, its biological effects require further elucidation. This study aimed to determine the effect of CCDC85C on Colorectal Cancer (CRC) progression and to explore the related mechanism. pLV-PURO plasmid was used to construct CCDC85C-overexpressing cells while CRISPR-CasRx was used to construct CCDC85C knockdown cells. Effects of CCDC85C on cell proliferation, cycle and migration were examined using cell counting kit-8 assay, flow cytometry, wound healing assay and transwell assay. Immunofluorescence staining, immunoprecipitation, Western blot, co-immunoprecipitation and qPCR were performed to explore the mechanism. The overexpression of CCDC85C inhibited the proliferation and migration of HCT-116 and RKO cells in vitro and in vivo, but its knockdown promoted the proliferation of HCT-116 and RKO cells in vitro. Moreover, co-immunoprecipitation experiment confirmed that CCDC85C binding with GSK-3β in RKO cells. Excess CCDC85C promoted phosphorylation and ubiquitination of β-catenin. Our results suggested that CCDC85C binds to GSK-3β to promote its activity and facilitates ubiquitination of β-catenin. β-catenin degradation is responsible for the inhibitory effect of CCDC85C on CRC cell proliferation and migration.
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Affiliation(s)
- Wenlong Hu
- The First Clinical Medical College, Nanjing University of Chinese Medicine, No. 155, Hanzhong Road, Qinhuai District, Nanjing, Jiangsu Province, China; Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, 138 Xianlin Avenue, Qixia District, Nanjing, Jiangsu Province, China; Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Qixia District, Nanjing, Jiangsu Province, China
| | - Jie Shen
- Institute of Literature in Chinese Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Qixia District, Nanjing, Jiangsu Province, China
| | - Yu Tao
- The First Clinical Medical College, Nanjing University of Chinese Medicine, No. 155, Hanzhong Road, Qinhuai District, Nanjing, Jiangsu Province, China; Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, 138 Xianlin Avenue, Qixia District, Nanjing, Jiangsu Province, China; Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Qixia District, Nanjing, Jiangsu Province, China
| | - Dan Dong
- The First Clinical Medical College, Nanjing University of Chinese Medicine, No. 155, Hanzhong Road, Qinhuai District, Nanjing, Jiangsu Province, China; Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, 138 Xianlin Avenue, Qixia District, Nanjing, Jiangsu Province, China; Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Qixia District, Nanjing, Jiangsu Province, China
| | - Sicheng Lu
- The First Clinical Medical College, Nanjing University of Chinese Medicine, No. 155, Hanzhong Road, Qinhuai District, Nanjing, Jiangsu Province, China; Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, 138 Xianlin Avenue, Qixia District, Nanjing, Jiangsu Province, China; Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Qixia District, Nanjing, Jiangsu Province, China
| | - Liu Li
- The First Clinical Medical College, Nanjing University of Chinese Medicine, No. 155, Hanzhong Road, Qinhuai District, Nanjing, Jiangsu Province, China; Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, 138 Xianlin Avenue, Qixia District, Nanjing, Jiangsu Province, China; Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Qixia District, Nanjing, Jiangsu Province, China
| | - Dongdong Sun
- The First Clinical Medical College, Nanjing University of Chinese Medicine, No. 155, Hanzhong Road, Qinhuai District, Nanjing, Jiangsu Province, China; Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, 138 Xianlin Avenue, Qixia District, Nanjing, Jiangsu Province, China; Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Qixia District, Nanjing, Jiangsu Province, China
| | - Minmin Fan
- The First Clinical Medical College, Nanjing University of Chinese Medicine, No. 155, Hanzhong Road, Qinhuai District, Nanjing, Jiangsu Province, China; Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, 138 Xianlin Avenue, Qixia District, Nanjing, Jiangsu Province, China; Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Qixia District, Nanjing, Jiangsu Province, China
| | - Changliang Xu
- The First Clinical Medical College, Nanjing University of Chinese Medicine, No. 155, Hanzhong Road, Qinhuai District, Nanjing, Jiangsu Province, China; Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, 138 Xianlin Avenue, Qixia District, Nanjing, Jiangsu Province, China; Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Qixia District, Nanjing, Jiangsu Province, China
| | - Weixing Shen
- The First Clinical Medical College, Nanjing University of Chinese Medicine, No. 155, Hanzhong Road, Qinhuai District, Nanjing, Jiangsu Province, China; Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, 138 Xianlin Avenue, Qixia District, Nanjing, Jiangsu Province, China; Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Qixia District, Nanjing, Jiangsu Province, China.
| | - Chengtao Yu
- The First Clinical Medical College, Nanjing University of Chinese Medicine, No. 155, Hanzhong Road, Qinhuai District, Nanjing, Jiangsu Province, China; Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, 138 Xianlin Avenue, Qixia District, Nanjing, Jiangsu Province, China; Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Qixia District, Nanjing, Jiangsu Province, China.
| | - Haibo Cheng
- The First Clinical Medical College, Nanjing University of Chinese Medicine, No. 155, Hanzhong Road, Qinhuai District, Nanjing, Jiangsu Province, China; Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, 138 Xianlin Avenue, Qixia District, Nanjing, Jiangsu Province, China; Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Qixia District, Nanjing, Jiangsu Province, China.
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Jiang Y, Zhu Z, Wang B, Yuan Y, Zhang Q, Li Y, Du Y, Gong P. Neuronal TRPV1-CGRP axis regulates bone defect repair through Hippo signaling pathway. Cell Signal 2023:110779. [PMID: 37336315 DOI: 10.1016/j.cellsig.2023.110779] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/06/2023] [Revised: 06/13/2023] [Accepted: 06/16/2023] [Indexed: 06/21/2023]
Abstract
Transient receptor potential vanilloid type 1 (TRPV1) is highly expressed on sensory neurons where it serves as a polymodal receptor for detecting physical and chemical stimuli. However, the role of TRPV1 in bone metabolism remains largely unclear. This study aimed to investigate the underlying mechanism of neuronal TRPV1 in regulating bone defect repair. In vivo experiment verified that TRPV1 activation could trigger dorsal root ganglion (DRG) producing the neuropeptide calcitonin gene-related peptide (CGRP) in mice. The accelerated bone healing of femoral defect in this process was observed compared to the control group (p < 0.05). Conversely, Trpv1 knockdown led to the reduced CGRP expression in DRG and nerves innervating femur bone tissue, following impaired bone formation and osteogenic capability in the defect region (p < 0.05), which could be rescued by local CGRP treatment. In vitro, results revealed that TRPV1 function in DRG neurons contributed essentially to the regulation of osteoblast physiology through affecting the production and secretion of CGRP. The capsaicin-activated neuronal TRPV1-CGRP axis could enhance the proliferation, migration and differentiation of osteoblasts (p < 0.05). Furthermore, we found that the promoting role of neuronal TRPV1 in osteogenesis were associated with Hippo signaling pathway, reflected by the phosphorylation protein level of large tumor suppressor 1 (LATS1), MOB kinase activator 1 (MOB1) and Yes-associated protein (YAP), as well as the subcellular location of YAP. Our study clarified the effects and intrinsic mechanisms of neuronal TRPV1 on bone defect repair, which might offer us a therapeutic implication for bone disorders.
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Affiliation(s)
- Yixuan Jiang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China; Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Zhanfeng Zhu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China; Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Bin Wang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China; Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ying Yuan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Qin Zhang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yanxi Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yu Du
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China; Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ping Gong
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China; Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
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Li C, Cui X, Li Y, Guo D, He S. Identification of ferroptosis and drug resistance related hub genes to predict the prognosis in Hepatocellular Carcinoma. Sci Rep 2023; 13:8681. [PMID: 37248280 DOI: 10.1038/s41598-023-35796-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/07/2022] [Accepted: 05/24/2023] [Indexed: 05/31/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Currently, overcoming the drug resistance in HCC is a critical challenge and ferroptosis has emerged as a promising therapeutic option for cancer. We aim to construct a new gene signature related to ferroptosis and drug resistance to predict the prognosis in HCC. The RNA-seq data of HCC patients was obtained from the Cancer Genome Atlas database. Using least absolute shrinkage and selection operator cox regression, Kaplan-Meier analysis, and differential analysis, we constructed a prognostic model consisting of six hub genes (TOP2A, BIRC5, VEGFA, HIF1A, FTH1, ACSL3) related to ferroptosis and drug resistance in HCC. Functional enrichment, pathway enrichment and GSEA analysis were performed to investigate the potential molecular mechanism, and construction of PPI, mRNA-miRNA, mRNA-RBP, mRNA-TF and mRNA-drugs interaction networks to predict its interaction with different molecules. Clinical prognostic characteristics were revealed by univariate, multivariate cox regression analysis and nomogram. We also analyzed the relationship between the signature, immune checkpoints, and drug sensitivity. The expression of the gene signature was detected in HCC cell lines and HPA database. Our prognostic model classified patients into high and low-risk groups based on the risk scores and found the expression level of the genes was higher in the high-risk group than the low-risk group, demonstrating that high expression of the hub genes was associated with poor prognosis in HCC. ROC analysis revealed its high diagnostic efficacy in both HCC and normal tissues. The proportional hazards model and calibration analysis confirmed that the model's prediction was most accurate for 1- and 3-years survival. QRT-PCR showed the high expression level of the gene signature in HCC. Our study built a novel gene signature with good potential to predict the prognosis of HCC, which may provide new therapeutic targets and molecular mechanism for HCC diagnosis and treatment.
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Affiliation(s)
- Chengjun Li
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Xiaomeng Cui
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Yarui Li
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Dan Guo
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Shuixiang He
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China.
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Wu S, Sun Z, Guo Z, Li P, Mao Q, Tang Y, Chen H, Peng H, Wang S, Cao Y. The effectiveness of blood-activating and stasis-transforming traditional Chinese medicines (BAST) in lung cancer progression-a comprehensive review. JOURNAL OF ETHNOPHARMACOLOGY 2023; 314:116565. [PMID: 37172918 DOI: 10.1016/j.jep.2023.116565] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 02/18/2023] [Revised: 04/20/2023] [Accepted: 04/29/2023] [Indexed: 05/15/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Blood-activating and stasis-transforming traditional Chinese medicines (BAST) are a class of herbs that have the effect of dilating blood vessels and dispersing stagnation. Modern pharmaceutical research has demonstrated that they are capable of improving hemodynamics and micro-flow, resist thrombosis and promote blood flow. BAST contain numerous active ingredients, which can theoretically regulate multiple targets at the same time and have a wide range of pharmacological effects in the treatment of diseases including human cancers. Clinically, BAST have minimal side effects and can be used in combination with Western medicine to improve patients' quality of life, lessen adverse effects and minimize the risk of recurrence and metastasis of cancers. AIM OF THE REVIEW We aimed to summarize the research progression of BAST on lung cancer in the past five years and present a prospect for the future. Particularly, this review further analyzes the effects and molecular mechanisms that BAST inhibit the invasion and metastasis of lung cancer. MATERIALS AND METHODS Relevant studies about BSAT were collected from PubMed and Web of science. RESULTS Lung cancer is one of the malignant tumors with the highest mortality rate. Most patients with lung cancer are diagnosed at an advanced stage and are highly susceptible to metastasis. Recent studies have shown that BAST, a class of traditional Chinese medicine (TCM) with the function of opening veins and dispersing blood stasis, significantly improve hemodynamics and microcirculation, prevent thrombosis and promote blood flow, and thereby inhibiting the invasion and metastasis of lung cancer. In the current review, we analyzed 51 active ingredients extracted from BAST. It was found that BAST and their active ingredients contribute to the prevention of invasion and metastasis of lung cancer through multiple mechanisms, such as regulation of EMT process, specific signaling pathway and metastasis-related genes, tumor blood vessel formation, immune microenvironment and inflammatory response of tumors. CONCLUSIONS BSAT and its active ingredients have showed promising anticancer activity and significantly inhibit the invasion and metastasis of lung cancer. A growing number of studies have realized their potential clinical significance in the therapy of lung cancer, which will provide substantial evidences for the development of new TCM for lung cancer therapy.
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Affiliation(s)
- Siqi Wu
- The First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Zhe Sun
- The First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Zehuai Guo
- The First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Peiqin Li
- The First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Qianqian Mao
- The First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Yang Tang
- The First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Hongyu Chen
- The First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Huiting Peng
- The First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Sisi Wang
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Yang Cao
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
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Jiang H, Wang S, Liu Y, Zheng C, Chen L, Zheng K, Xu Z, Dai Y, Jin H, Cheng Z, Zou C, Fu L, Liu K, Ma X. Targeting EFNA1 suppresses tumor progression via the cMYC-modulated cell cycle and autophagy in esophageal squamous cell carcinoma. Discov Oncol 2023; 14:64. [PMID: 37160815 PMCID: PMC10169935 DOI: 10.1007/s12672-023-00664-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 02/15/2023] [Accepted: 04/19/2023] [Indexed: 05/11/2023] Open
Abstract
PURPOSE Esophageal squamous cell carcinoma (ESCC) remains one of the most common causes of cancer death due to the lack of effective therapeutic options. New targets and the targeted drugs are required to be identified and developed. METHODS Highly expressed genes in ESCA were identified using the edgeR package from public datasets. Immunostaining assay verified the high expression level of EFNA1 in ESCC. CCK-8, colony formation and wound healing assays were performed to examine the role of EFNA1 and EPHA2 in ESCC progression. Cell cycle was analyzed by flow cytometry and autophagy activation was determined by autophagolysosome formation using transmission electron microscopy. The small molecule targeting to EFNA1 was identified by molecular docking and the anti-tumor effects were verified by in vitro and in vivo models with radiation treatment. RESULTS EFNA1 was highly expressed in esophageal cancer and significantly associated with poor prognosis. Downregulation of EFNA1 remarkably inhibited cell proliferation and migration. Furthermore, decreased EFNA1 significantly suppressed the expression of cMYC along with its representative downstream genes involved in cell cycle, and activated autophagy. Similar effects on ESCC progression were obtained from knockdown of the corresponding receptor, EPHA2. The potential small molecule targeting to EFNA1, salvianolic acid A (SAA), could significantly suppress ESCC progression and increase the sensitivity to radiotherapy. CONCLUSION We revealed that EFNA1 facilitated the ESCC progression via the possible mechanism of activating cMYC-modulated cell proliferation and suppressing autophagy, and identified SAA as a potential drug targeting EFNA1, providing new options for the future treatments for ESCC patients.
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Affiliation(s)
- Houxiang Jiang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, 241001, Anhui, China
- Anhui Province Clinical Research Center for Critical Respiratory Medicine, Wuhu, 241001, Anhui, China
| | - Shaoxiang Wang
- School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen, 518060, China
| | - Ying Liu
- Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College of Jinan University), Shenzhen, 518020, Guangdong, China
| | - Chaopan Zheng
- Department of Otolaryngology, Shenzhen People's Hospital (The Second Clinical Medical College of Jinan University), Shenzhen, 518020, Guangdong, China
| | - Lipeng Chen
- Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College of Jinan University), Shenzhen, 518020, Guangdong, China
| | - Kai Zheng
- School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen, 518060, China
| | - Zhenyu Xu
- Precision Medicine Center, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, 241001, Anhui, China
| | - Yong Dai
- Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College of Jinan University), Shenzhen, 518020, Guangdong, China
| | - Hongtao Jin
- Department of Pathology, Shenzhen People's Hospital (The Second Clinical Medical College of Jinan University), Shenzhen, 518020, Guangdong, China
| | - Zhiqiang Cheng
- Department of Pathology, Shenzhen People's Hospital (The Second Clinical Medical College of Jinan University), Shenzhen, 518020, Guangdong, China
| | - Chang Zou
- Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College of Jinan University), Shenzhen, 518020, Guangdong, China
- School of Medicine, Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen, 518172, Guangdong, China
| | - Li Fu
- Department of Pharmacology, Shenzhen University School of Medicine, Shenzhen, 518060, Guangdong, China.
| | - Kaisheng Liu
- Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College of Jinan University), Shenzhen, 518020, Guangdong, China.
| | - Xiaoshi Ma
- Department of Urology, Shenzhen People's Hospital (The Second Clinical Medical College of Jinan University), Shenzhen, 518020, Guangdong, China.
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Liu X, Geng X, Shi Y, Liang J, Zhao L. Biomimetic oxygen-boosted hybrid membrane nanovesicles as the treatment strategy for ischemic stroke with the concept of the neurovascular unit. BIOMATERIALS ADVANCES 2023; 148:213379. [PMID: 36934713 DOI: 10.1016/j.bioadv.2023.213379] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 11/22/2022] [Revised: 02/19/2023] [Accepted: 03/06/2023] [Indexed: 06/18/2023]
Abstract
The pathogenesis of ischemic cerebrovascular disease has revealed that ischemic stroke often leads to deprivation of oxygen, blood-brain barrier (BBB) damage and enhanced inflammatory activation, eventually causing severe brain tissue damage. Herein, we prepared hybrid membrane nanovesicles (YC-1@[RBC-PL] NVs) composed of red blood cell (RBC) membrane and platelet (PL) membrane encapsulating hypoxia inducible factor-1α (HIF-1α) inhibitor YC-1 for contributing to the protection of the neurovascular unit (NVU) in ischemic stroke. YC-1@[RBC-PL] NVs targeted the ischemic brain by the thrombus targeting properties of PL membrane and relieved the hypoxia inside ischemic brain in the presence of YC-1 and catalase in YC-1@[RBC-PL] NVs. Finally, YC-1@[RBC-PL] NVs attenuated ischemic injury to NVU by reducing infarct volume, preserving BBB integrity, and blocking activation of astrocyte and microglia in a middle cerebral artery occlusion/reperfusion (MCAO/R) model.
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Affiliation(s)
- Xintong Liu
- School of Pharmacy, Jinzhou Medical University, Jinzhou 121000, PR China
| | - Xinrong Geng
- School of Pharmacy, Jinzhou Medical University, Jinzhou 121000, PR China
| | - Yijie Shi
- School of Pharmacy, Jinzhou Medical University, Jinzhou 121000, PR China.
| | - Jia Liang
- Life Science Institution, Jinzhou Medical University, Jinzhou 121000, PR China.
| | - Liang Zhao
- School of Pharmacy, Jinzhou Medical University, Jinzhou 121000, PR China.
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Kim S, Park S, Moon EH, Kim GJ, Choi J. Hypoxia disrupt tight junctions and promote metastasis of oral squamous cell carcinoma via loss of par3. Cancer Cell Int 2023; 23:79. [PMID: 37095487 PMCID: PMC10123966 DOI: 10.1186/s12935-023-02924-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/05/2023] [Accepted: 04/10/2023] [Indexed: 04/26/2023] Open
Abstract
BACKGROUND Oral squamous cell carcinoma (OSCC) is a highly malignant tumor that is frequently associated with lymph node metastasis, resulting in poor prognosis and survival in patients. In the tumor microenvironment, hypoxia plays an important role in regulating cellular responses such as progressive and rapid growth and metastasis. In these processes, tumor cells autonomously undergo diverse transitions and acquire functions. However, hypoxia-induced transition of OSCC and the involvement of hypoxia in OSCC metastasis remain unclear. Therefore, in this study, we aimed to elucidate the mechanism of hypoxia-induced OSCC metastasis and particularly, its impact on tight junctions (TJs). METHODS The expression of hypoxia-inducible factor 1-alpha (HIF-1α) was detected in tumor tissues and adjacent normal tissues from 29 patients with OSCC using reverse transcription quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and immunohistochemistry (IHC). The migration and invasion abilities of OSCC cell lines treated with small interfering (si)RNA targeting HIF-1α or cultured in hypoxic conditions were analyzed using Transwell assays. The effect of HIF-1α expression on in vivo tumor metastasis of OSCC cells was evaluated using lung metastasis model. RESULTS HIF-1α was overexpressed in patients with OSCC. OSCC metastasis was correlated with HIF-1α expression in OSCC tissues. Hypoxia increased the migration and invasion abilities of OSCC cell lines by regulating the expression and localization of partitioning-defective protein 3 (Par3) and TJs. Furthermore, HIF-1α silencing effectively decreased the invasion and migration abilities of OSCC cell lines and restored TJ expression and localization via Par3. The expression of HIF-1α was positively regulated the OSCC metastasis in vivo. CONCLUSIONS Hypoxia promotes OSCC metastasis by regulating the expression and localization of Par3 and TJ proteins. HIF-1α positively correlates to OSCC metastasis. Lastly, HIF-1α expression could regulate the expression of Par3 and TJs in OSCC. This finding may aid in elucidating the molecular mechanisms of OSCC metastasis and progression and developing new diagnostic and therapeutic approaches for OSCC metastasis.
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Affiliation(s)
- Shihyun Kim
- Department of Oral Pathology, College of Dentistry, Gangneung-Wonju National University, 7 Jukheon-gil, Gangneung- si, Gangwon-do, 25457, Republic of Korea
| | - Suyeon Park
- Department of Oral Pathology, College of Dentistry, Gangneung-Wonju National University, 7 Jukheon-gil, Gangneung- si, Gangwon-do, 25457, Republic of Korea
| | - Eun-Hye Moon
- Institute of Lee Gil Ya Cancer and Diabetes, Gachon University, Incheon, 21999, Republic of Korea
| | - Gi Jin Kim
- Department of Biomedical Science, CHA University, Seongnam, Gyeonggi-do, 13488, Republic of Korea
| | - Jongho Choi
- Department of Oral Pathology, College of Dentistry, Gangneung-Wonju National University, 7 Jukheon-gil, Gangneung- si, Gangwon-do, 25457, Republic of Korea.
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Niu ZS, Wang WH, Niu XJ. Recent progress in molecular mechanisms of postoperative recurrence and metastasis of hepatocellular carcinoma. World J Gastroenterol 2022; 28:6433-6477. [PMID: 36569275 PMCID: PMC9782839 DOI: 10.3748/wjg.v28.i46.6433] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 08/13/2022] [Revised: 10/31/2022] [Accepted: 11/21/2022] [Indexed: 12/08/2022] Open
Abstract
Hepatectomy is currently considered the most effective option for treating patients with early and intermediate hepatocellular carcinoma (HCC). Unfortunately, the postoperative prognosis of patients with HCC remains unsatisfactory, predominantly because of high postoperative metastasis and recurrence rates. Therefore, research on the molecular mechanisms of postoperative HCC metastasis and recurrence will help develop effective intervention measures to prevent or delay HCC metastasis and recurrence and to improve the long-term survival of HCC patients. Herein, we review the latest research progress on the molecular mechanisms underlying postoperative HCC metastasis and recurrence to lay a foundation for improving the understanding of HCC metastasis and recurrence and for developing more precise prevention and intervention strategies.
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Affiliation(s)
- Zhao-Shan Niu
- Laboratory of Micromorphology, School of Basic Medicine, Qingdao University, Qingdao 266071, Shandong Province, China
| | - Wen-Hong Wang
- Department of Pathology, School of Basic Medicine, Qingdao University, Qingdao 266071, Shandong Province, China
| | - Xiao-Jun Niu
- Department of Internal Medicine, Qingdao Shibei District People's Hospital, Qingdao 266033, Shandong Province, China
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Zhang Z, Hu Y, Chen Y, Chen Z, Zhu Y, Chen M, Xia J, Sun Y, Xu W. Immunometabolism in the tumor microenvironment and its related research progress. Front Oncol 2022; 12:1024789. [PMID: 36387147 PMCID: PMC9659971 DOI: 10.3389/fonc.2022.1024789] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/22/2022] [Accepted: 10/10/2022] [Indexed: 07/30/2023] Open
Abstract
The tumor immune microenvironment has been a research hot spot in recent years. The cytokines and metabolites in the microenvironment can promote the occurrence and development of tumor in various ways and help tumor cells get rid of the surveillance of the immune system and complete immune escape. Many studies have shown that the existence of tumor microenvironment is an important reason for the failure of immunotherapy. The impact of the tumor microenvironment on tumor is a systematic study. The current research on this aspect may be only the tip of the iceberg, and a relative lack of integrity, may be related to the heterogeneity of tumor. This review mainly discusses the current status of glucose metabolism and lipid metabolism in the tumor microenvironment, including the phenotype of glucose metabolism and lipid metabolism in the microenvironment; the effects of these metabolic methods and their metabolites on three important immune cells Impact: regulatory T cells (Tregs), tumor-associated macrophages (TAM), natural killer cells (NK cells); and the impact of metabolism in the targeted microenvironment on immunotherapy. At the end of this article,the potential relationship between Ferroptosis and the tumor microenvironment in recent years is also briefly described.
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Affiliation(s)
- Ziheng Zhang
- Medical School, Shaoxing University, Shaoxing, China
| | - Yajun Hu
- Medical School, Shaoxing University, Shaoxing, China
| | - Yuefeng Chen
- Medical School, Shaoxing University, Shaoxing, China
| | - Zhuoneng Chen
- Medical School, Shaoxing University, Shaoxing, China
| | - Yexin Zhu
- Medical School, Shaoxing University, Shaoxing, China
| | - Mingmin Chen
- Medical School, Shaoxing University, Shaoxing, China
| | - Jichu Xia
- Medical School, Shaoxing University, Shaoxing, China
| | - Yixuan Sun
- Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, Xianning, China
| | - Wenfang Xu
- Department of Clinical Laboratory, Shaoxing University affiliated Hospital, Shaoxing, China
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Yu Q, Chen Z, Liu M, Meng Y, Li X, Li B, Du J. Exploring the potential targets of Sanshimao formula for hepatocellular carcinoma treatment by a method of network pharmacology combined with molecular biology. JOURNAL OF ETHNOPHARMACOLOGY 2022; 297:115531. [PMID: 35840058 DOI: 10.1016/j.jep.2022.115531] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 01/15/2022] [Revised: 06/24/2022] [Accepted: 07/08/2022] [Indexed: 06/15/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The Sanshimao (SSM) formula is an effective prescription for hepatocellular carcinoma (HCC) therapy in the clinical setting. This prescription is made up of four herbals, Maorenshen, Shijianchuan, Shishangbai and Shidachuan, which are used for detoxification and removing blood stasis. However, its mechanism in the treatment of HCC remains ambiguous. AIM OF THE STUDY To explore the potential targets of SSM against HCC by network pharmacology analysis and verify the data using molecular biological methods. MATERIALS AND METHODS We screened active components and potential targets by data mining, constructed a network, and performed functional analysis and pathway enrichment to explore the therapeutic targets of SSM for HCC treatment. Then, the effects of SSM on HCC cells were studied to validate the data from network pharmacology analysis. RESULTS Eighty-eight common targets were obtained by mapping 932 HCC-related genes, and 325 targets corresponded to 11 active components of SSM. They were enriched in various biological processes, such as the response to inorganic substances, response to toxic substances and apoptotic signalling pathway, and multi-pathways involved pathways in cancer, EGFR tyrosine kinase inhibitor resistance, and AGE-RAGE signalling pathway in diabetic complications, as evaluated by the analysis of advanced functions and pathways. TP53, JUN, HSP90AA1, EGFR, AR and MAPK1 might be the core targets closely related to the effects of SSM on HCC according to PPI analysis. Treatment with SSM decreased cell viability and migration, promoted apoptosis and inhibited the EGFR/FAK/AKT signalling pathway. CONCLUSION This research preliminarily indicates that SSM treats HCC via multiple components and pathways. EGFR/FAK/AKT are promising therapeutic targets of SSM for HCC treatment. This provides objective evidence for further mechanistic research and the future development and clinical application of SSM in HCC patients.
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Affiliation(s)
- Qin Yu
- Department of Traditional Chinese Medicine, the First Affiliated Hospital of Naval Military Medical University, Shanghai, China; Department of Oncology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhe Chen
- Department of Rehabilitation Medicine, the First Affiliated Hospital of Naval Military Medical University, Shanghai, China
| | - Minglin Liu
- Department of Traditional Chinese Medicine, the First Affiliated Hospital of Naval Military Medical University, Shanghai, China
| | - Yongbin Meng
- Department of Traditional Chinese Medicine, the First Affiliated Hospital of Naval Military Medical University, Shanghai, China
| | - Xiaoyan Li
- Department of Traditional Chinese Medicine, the First Affiliated Hospital of Naval Military Medical University, Shanghai, China
| | - Bai Li
- Department of Rehabilitation Medicine, the First Affiliated Hospital of Naval Military Medical University, Shanghai, China.
| | - Juan Du
- Department of Traditional Chinese Medicine, the First Affiliated Hospital of Naval Military Medical University, Shanghai, China.
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Yang X, Wang Y, Zhao J, Rong H, Chen Y, Xiong M, Ye X, Yu S, Hu H. Coordinated regulation of BACH1 and mitochondrial metabolism through tumor-targeted self-assembled nanoparticles for effective triple negative breast cancer combination therapy. Acta Pharm Sin B 2022; 12:3934-3951. [PMID: 36213532 PMCID: PMC9532561 DOI: 10.1016/j.apsb.2022.06.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/08/2022] [Revised: 05/30/2022] [Accepted: 06/04/2022] [Indexed: 11/29/2022] Open
Abstract
The poor prognosis of triple negative breast cancer (TNBC) results from a lack of approved targeted therapies coupled with aggressive proliferation and metastasis, which is associated with high recurrence and short overall survival. Here we developed a strategy by employing tumor-targeted self-assembled nanoparticles to coordinately regulate BACH1 (BTB domain and CNC homology 1) and mitochondrial metabolism. The BACH1 inhibitor hemin and mitochondria function inhibitor berberine derivative (BD) were used to prepare nanoparticles (BH NPs) followed by the modification of chondroitin sulfate (CS) on the surface of BH NPs to achieve tumor targeting (CS/BH NPs). CS/BH NPs were found to be able to inhibit tumor migration and invasion by significantly decreasing the amounts of tumor cell metabolites, glycolysis and metastasis-associated proteins, which were related to the inhibition of BACH1 function. Meanwhile, decreased mitochondrial membrane potential, activated caspase 3/9 and increased ROS production demonstrated coordinated regulation of BACH1 and mitochondrial metabolism. In a xenograft mice model of breast cancer, CS/BH NPs significantly inhibited tumor growth and metastasis due to the synergetic effect of hemin and BD without showing obvious toxicities for major organs. In sum, the results of efficacy and safety experiments suggest potential clinical significance of the prepared self-assembled CS/BH nanoparticles for the treatment of TNBC.
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Affiliation(s)
- Xuan Yang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Yalong Wang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Junke Zhao
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Hehui Rong
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Yujun Chen
- The First Affiliated Hospital of Guangxi Medical University, Nanning 530000, China
| | - Mengting Xiong
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Xiaoxing Ye
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Shihui Yu
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
- Guangdong Provincial Key Laboratory of Chiral Molecules and Drug Discovery, Sun Yat-sen University, Guangzhou 510006, China
| | - Haiyan Hu
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
- Guangdong Provincial Key Laboratory of Chiral Molecules and Drug Discovery, Sun Yat-sen University, Guangzhou 510006, China
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Li H, Sun X, Li J, Liu W, Pan G, Mao A, Liu J, Zhang Q, Rao L, Xie X, Sheng X. Hypoxia induces docetaxel resistance in triple-negative breast cancer via the HIF-1α/miR-494/Survivin signaling pathway. Neoplasia 2022; 32:100821. [PMID: 35985176 PMCID: PMC9403568 DOI: 10.1016/j.neo.2022.100821] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/26/2022] [Revised: 06/30/2022] [Accepted: 07/06/2022] [Indexed: 11/24/2022]
Abstract
Cytotoxic chemotherapy is the major strategy to prevent and reduce triple-negative breast cancer (TNBC) progression and metastasis. Hypoxia increases chemoresistance and is associated with a poor prognosis for patients with cancer. Based on accumulating evidence, microRNAs (miRNAs) play an important role in acquired drug resistance. However, the role of miRNAs in hypoxia-induced TNBC drug resistance remains to be clarified. Here, we found that hypoxia induced TNBC docetaxel resistance by decreasing the miR-494 level. Modulating miR-494 expression altered the sensitivity of TNBC cells to DTX under hypoxic conditions. Furthermore, we identified Survivin as a direct miR-494 target. Hypoxia upregulated survivin expression. In a clinical study, the HIF-1α/miR-494/Survivin signaling pathway was also active in primary human TNBC, and miR-494 expression negatively correlated with HIF-1α and survivin expression. Finally, in a xenograft model, both miR-494 overexpression and the HIF-1α inhibitor PX-478 increased the sensitivity of TNBC to DTX by suppressing the HIF-1α/miR-494/Survivin signaling pathway in vivo. In conclusion, treatments targeting the HIF-1α/miR-494/Survivin signaling pathway potentially reverse hypoxia-induced drug resistance in TNBC.
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Affiliation(s)
- Hongchang Li
- Department of General Surgery, Institute of Fudan Minhang Academic Health System, Minhang Hospital, Fudan University. 170 Xinsong Rd, Shanghai, China
| | - Xianhao Sun
- Department of General Surgery, Institute of Fudan Minhang Academic Health System, Minhang Hospital, Fudan University. 170 Xinsong Rd, Shanghai, China
| | - Jindong Li
- Department of General Surgery, Institute of Fudan Minhang Academic Health System, Minhang Hospital, Fudan University. 170 Xinsong Rd, Shanghai, China
| | - Weiyan Liu
- Department of General Surgery, Institute of Fudan Minhang Academic Health System, Minhang Hospital, Fudan University. 170 Xinsong Rd, Shanghai, China
| | - Gaofeng Pan
- Department of General Surgery, Institute of Fudan Minhang Academic Health System, Minhang Hospital, Fudan University. 170 Xinsong Rd, Shanghai, China
| | - Anwei Mao
- Department of General Surgery, Institute of Fudan Minhang Academic Health System, Minhang Hospital, Fudan University. 170 Xinsong Rd, Shanghai, China
| | - Jiazhe Liu
- Department of General Surgery, Institute of Fudan Minhang Academic Health System, Minhang Hospital, Fudan University. 170 Xinsong Rd, Shanghai, China
| | - Qing Zhang
- Department of General Surgery, Institute of Fudan Minhang Academic Health System, Minhang Hospital, Fudan University. 170 Xinsong Rd, Shanghai, China
| | - Longhua Rao
- Department of General Surgery, Institute of Fudan Minhang Academic Health System, Minhang Hospital, Fudan University. 170 Xinsong Rd, Shanghai, China.
| | - Xiaofeng Xie
- Department of General Surgery, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Rd, Shanghai, China.
| | - Xia Sheng
- Department of Pathology, Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University. 170 Xinsong Rd, Shanghai, China.
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Nayak A, Warrier NM, Kumar P. Cancer Stem Cells and the Tumor Microenvironment: Targeting the Critical Crosstalk through Nanocarrier Systems. Stem Cell Rev Rep 2022; 18:2209-2233. [PMID: 35876959 PMCID: PMC9489588 DOI: 10.1007/s12015-022-10426-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Accepted: 07/10/2022] [Indexed: 11/25/2022]
Abstract
The physiological state of the tumor microenvironment (TME) plays a central role in cancer development due to multiple universal features that transcend heterogeneity and niche specifications, like promoting cancer progression and metastasis. As a result of their preponderant involvement in tumor growth and maintenance through several microsystemic alterations, including hypoxia, oxidative stress, and acidosis, TMEs make for ideal targets in both diagnostic and therapeutic ventures. Correspondingly, methodologies to target TMEs have been investigated this past decade as stratagems of significant potential in the genre of focused cancer treatment. Within targeted oncotherapy, nanomedical derivates-nanocarriers (NCs) especially-have emerged to present notable prospects in enhancing targeting specificity. Yet, one major issue in the application of NCs in microenvironmental directed therapy is that TMEs are too broad a spectrum of targeting possibilities for these carriers to be effectively employed. However, cancer stem cells (CSCs) might portend a solution to the above conundrum: aside from being quite heavily invested in tumorigenesis and therapeutic resistance, CSCs also show self-renewal and fluid clonogenic properties that often define specific TME niches. Further scrutiny of the relationship between CSCs and TMEs also points towards mechanisms that underly tumoral characteristics of metastasis, malignancy, and even resistance. This review summarizes recent advances in NC-enabled targeting of CSCs for more holistic strikes against TMEs and discusses both the current challenges that hinder the clinical application of these strategies as well as the avenues that can further CSC-targeting initiatives. Central role of CSCs in regulation of cellular components within the TME.
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Affiliation(s)
- Aadya Nayak
- Department of Biotechnology, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| | - Neerada Meenakshi Warrier
- Department of Biotechnology, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| | - Praveen Kumar
- Department of Biotechnology, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India.
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Wang J, Jin Z, Wu G, Deng Z, Wang J, Xu B, Zhu H, Guo Y, Wen Z. Construction of a 3-mRNA hypoxia prognostic model to evaluate immune microenvironment in hepatocellular carcinoma. Medicine (Baltimore) 2022; 101:e30589. [PMID: 36181125 PMCID: PMC9524961 DOI: 10.1097/md.0000000000030589] [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] [Academic Contribution Register] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Hypoxia is a key factor in the development of hepatocellular carcinoma (HCC), which is the most common primary liver cancer with poor prognosis. The current study aimed to identify the potential prognostic biomarkers of the hypoxia-associated gene signature in patients with HCC, and to further explore the relationship between hypoxia and immune infiltration. METHODS After the determination of differentially expressed genes (DEGs) using the HCC transcriptome data of The Cancer Genome Atlas database and hypoxia-related gene set, the prognosis-associated genes were identified using univariate Cox regression analysis. Then, the hypoxia prognosis model was established via multivariate Cox regression analysis, with functional annotation conducted using Gene Set Enrichment Analysis. CIBERSORT was utilized to analyze the degree of tumor immune invasion, and an International Cancer Genome Consortium cohort to verify the reliability of the prognosis model. Expression levels of hypoxia-associated genes were detected by real-time quantitative polymerase chain reaction in HCC samples. RESULTS 3 genes (ENO1, SAP30, and STC2) constructed the hypoxia prognosis model. The patients were subdivided into 2 groups based on median risk score, with a high hypoxic score indicating poor prognosis of HCC. The hypoxia signature could be employed as an independent prognostic factor in HCC. In addition, the proportion of macrophages was higher in the high-risk group. CONCLUSION The hypoxia-associated signature could be a potential prognostic marker of HCC and provides a different perspective for immunotherapy of HCC.
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Affiliation(s)
- Jue Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Zongrui Jin
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Guolin Wu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Zhenfeng Deng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Jilong Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Banghao Xu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Hai Zhu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Ya Guo
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Zhang Wen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- *Correspondence: Zhang Wen, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Shuangyong Road 6#, Nanning, Guangxi 530021, China (e-mail: )
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A Regulatory Network Analysis of the Importance of USP15 in Breast Cancer Metastasis and Prognosis. JOURNAL OF ONCOLOGY 2022; 2022:1427726. [PMID: 36213818 PMCID: PMC9536986 DOI: 10.1155/2022/1427726] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Academic Contribution Register] [Received: 07/06/2022] [Revised: 08/04/2022] [Accepted: 08/18/2022] [Indexed: 11/17/2022]
Abstract
Background Ubiquitin-specific protease15(USP15), is the 16th identified protease in the USP family and is a key protein in tumorigenesis. However, the predictive value and regulatory mechanism of USP15 in breast cancer are unclear. Methods The GEPIA, UALCAN, GeneMANIA, and STRING databases were applied to explore the expression of USP15 in breast cancer and associated proteins. In addition, the TIMER database was evaluated for immune infiltration patterns. Moreover, protein immunoblotting assay, cell scratching assay, small compartment invasion assay, 3D stromal gel assay, immunoprecipitation assay, and immunohistochemistry (IHC) were used to USP15 regulatory mechanisms in breast cancer. Results In BRCA, several databases, including GEPIA and UALCAN, describe the upregulation of total protein levels and USP15 phosphorylation. In addition, the expression of USP15 was significantly correlated with gender and clinical stage. Overall survival (OS) was lower in patients with high USP15 expression. Functional network analysis showed that USP15 is involved in tumor-associated pathways, DNA replication, and cell cycle signaling through TGFβRI. In addition, USP15 expression was positively correlated with immune infiltration, including immune score, mesenchymal score, and several tumor-infiltrating lymphocytes (TIL). In addition, IHC results further confirmed the high expression of USP15 in breast cancer and its prognostic potential. Conclusions These findings demonstrate that high USP15 expression indicates poor prognosis in BRCA and reveal potential regulatory networks and the positive relationship with immune infiltration. Thus, USP15 may be an attractive predictor for BRCA.
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Zhu N, Chen X, Zhao J, Fang L, Yao Y, Zhou F, Tao L, Xu Q. Hypoxia-induced LINC00674 facilitates hepatocellular carcinoma progression by activating the NOX1/mTOR signaling pathway. J Cancer 2022; 13:3177-3188. [PMID: 36118523 PMCID: PMC9475361 DOI: 10.7150/jca.76458] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/23/2022] [Accepted: 08/11/2022] [Indexed: 11/25/2022] Open
Abstract
The hypoxic tumor microenvironment, a fundamental feature of solid tumors, drives hepatocellular carcinoma (HCC) progression through regulating the transcriptional activities of protein-coding and noncoding genes. However, long noncoding RNA (lncRNA)-mediated HCC progression in hypoxic microenvironment remains largely unknown yet. In this study, we found that LINC00674 was upregulated under hypoxic conditions in a HIF-1-dependent manner, and the occupancy of HIF-1 to HRE of LINC00674 gene promoter was essential for its transcription. In addition, LINC00674 level was increased in HCC cell lines and tissues. Clinically, statistical analysis showed that LINC00674 expression was significantly associated with tumor size, venous infiltration, tumor stage and poor prognosis of HCC. Functionally, loss-of-function assays revealed that LINC00674 knockdown inhibited the migration, proliferation and invasion of HCC cells. Furthermore, LINC00674 silencing prominently repressed the mTOR signaling pathway. LINC00674 overexpression-enhanced HCC cell proliferation, migration and invasion were markedly abolished by an mTOR inhibitor rapamycin. NADPH oxidase 1 (NOX1) was positively regulated by LINC00674 in HCC cells. NOX1 knockdown markedly reversed LINC00674-upregulated the p-mTOR level and HCC cells' malignant behaviors. Finally, we found that LINC00674 knockdown attenuated the growth of HCC cells in vivo. Our finding demonstrated that LINC00674 was a new HIF-1 target gene, and hypoxia-induced LINC00674 exerted a pro-proliferative and pro-metastatic role in HCC, possibly by activating the NOX1/mTOR signaling pathway. This study suggested LINC00674 as a promising therapeutic target for HCC.
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Affiliation(s)
- Ning Zhu
- The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 310014, China
| | - Xiaohong Chen
- Department of Pediatrics, Central Hospital of Haining, Zhejiang Provincial People's Hospital Haining Hospital, Haining 314400, China
| | - Junjun Zhao
- The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 310014, China.,Graduate Department, Bengbu Medical College, Bengbu 233030, China
| | - Lijuan Fang
- Department of Laboratory, Hangzhou Ninth People's Hospital, Hangzhou 310014, China
| | - Yingmin Yao
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Feifei Zhou
- Department of traditional Chinese Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 310014, China
| | - Liang Tao
- Department of General Surgery, Central Hospital of Haining, Zhejiang Provincial People's Hospital Haining Hospital, Haining 314400, China
| | - Qiuran Xu
- The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 310014, China
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Wu J, Wu Y, Guo Q, Chen S, Wang S, Wu X, Zhu J, Ju X. SPOP promotes cervical cancer progression by inducing the movement of PD-1 away from PD-L1 in spatial localization. J Transl Med 2022; 20:384. [PMID: 36042498 PMCID: PMC9429754 DOI: 10.1186/s12967-022-03574-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/07/2022] [Accepted: 08/04/2022] [Indexed: 12/20/2022] Open
Abstract
Background Metastasis is a major obstacle in the treatment of cervical cancer (CC), and SPOP-mediated regulatory effects are involved in metastasis. However, the mechanisms have not been fully elucidated. Methods Proteomic sequencing and SPOP immunohistochemistry (IHC) were performed for the pelvic lymph node (pLN)-positive and non-pLN groups of CC patients. The corresponding patients were stratified by SPOP expression level for overall survival (OS) and relapse-free survival (RFS) analysis. In vitro and in vivo tests were conducted to verify the causal relationship between SPOP expression and CC metastasis. Multiplex immunofluorescence (m-IF) and the HALO system were used to analyse the mechanism, which was further verified by in vitro experiments. Results SPOP is upregulated in CC with pLN metastasis and negatively associated with patient outcome. In vitro and in vivo, SPOP promotes CC proliferation and metastasis. According to m-IF and HALO analysis, SPOP may promote CC metastasis by promoting the separation of PD-1 from PD-L1. Finally, it was further verified that SPOP can achieve immune tolerance by promoting the movement of PD-1 away from PD-L1 in spatial location and function. Conclusion This study shows that SPOP can inhibit the immune microenvironment by promoting the movement of PD-1 away from PD-L1, thereby promoting pLN metastasis of CC and resulting in worse OS and RFS.
The SPOP is associated with pelvic lymph node (pLN) metastasis and prognosis in cervical cancer (CC) patients. This paper discusses the potential mechanism of pLN metastasis of CC from the perspective of spatial location. This is a multi-cross study, including clinical data, tissue microarray (TMA), multicolor immunofluorescence (m-IF), spatial immunolocalization, in vitro and in vivo functional and mechanism research fusion, from clinical to basic and clinical research.
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Affiliation(s)
- Jiangchun Wu
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.,Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, People's Republic of China
| | - Yong Wu
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.,Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, People's Republic of China
| | - Qinhao Guo
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.,Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, People's Republic of China
| | - Siyu Chen
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.,Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, People's Republic of China
| | - Simin Wang
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.,Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, People's Republic of China
| | - Xiaohua Wu
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. .,Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, People's Republic of China.
| | - Jun Zhu
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. .,Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, People's Republic of China.
| | - Xingzhu Ju
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. .,Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, People's Republic of China.
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Cai G, Zhu J, Ning D, Li G, Zhang Y, Xiong Y, Liang J, Yu C, Chen X, Liang H, Ding Z. A Novel hepatocellular carcinoma specific hypoxic related signature for predicting prognosis and therapeutic responses. Front Immunol 2022; 13:997316. [PMID: 36059442 PMCID: PMC9428591 DOI: 10.3389/fimmu.2022.997316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/18/2022] [Accepted: 07/29/2022] [Indexed: 12/24/2022] Open
Abstract
Hypoxia is an important feature of the tumor microenvironment(TME) and is closely associated with cancer metastasis, immune evasion, and drug resistance. However, the precise role of hypoxia in hepatocellular carcinoma(HCC), as well as its influence on the TME, and drug sensitivity remains unclear. We found the excellent survival prediction value of Hypoxia_DEGs_Score model. In hypoxic HCC, somatic mutation, copy number variation, and DNA methylation were closely related to hypoxic changes and affected tumorigenesis, progression, metastasis, and drug resistance. In HCC, aggravated hypoxic stress was found to be accompanied by an immune exclusion phenotype and increased infiltration of immunosuppressive cells. In the validation cohort, patients with high Hypoxia_DEGs_Score were found to have worse immunotherapeutic outcomes and prognoses, and may benefit from drugs against cell cycle signaling pathways rather than those inhibiting the PI3K/mTOR pathway. Hypoxia_DEGs_Score has an excellent predictive capability of changes in the TME, the efficacy of immunotherapy, and the response of drugs. Therefore, Hypoxia_DEGs_Score can help develop personalized immunotherapy regimens and improve the prognosis of HCC patients.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Zeyang Ding
- *Correspondence: Zeyang Ding, ; Huifang Liang,
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Chen S, Liu R, Wang H, Liu Q. Hypoxia-driven miR-1307-3p promotes hepatocellular carcinoma cell proliferation and invasion by modulating DAB2 interacting protein. Pathol Res Pract 2022; 237:154066. [PMID: 35985237 DOI: 10.1016/j.prp.2022.154066] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 04/22/2022] [Revised: 08/05/2022] [Accepted: 08/07/2022] [Indexed: 10/15/2022]
Abstract
Hypoxia is a common feature of the solid tumor microenvironment that is presented as poor clinical outcomes in multiple tumor types, including HCC. Hypoxia stabilizes HIF-1α/HIF-2α, which then moves into the nucleus and binds with HIF-1β to form a transcription complex, thereby promoting the transcription of target genes, including mRNAs, miRNAs and lncRNAs to exert their biological functions. Here, through a series of functional assay, including hypoxia culture, MTT, colony-formation, Transwell, qRT-PCR and western blot, we confirmed that miR-1307-3p, as a novel hypoxia-responsive factor, can be directly transcribed by HIF-1α rather than HIF-2α. Hypoxia-driven miR-1307-3p facilitated proliferation and invasion of HCC cells via repressing DAB2IP. Moreover, under hypoxia microenvironment, DAB2IP, as a direct target of miR-1307-3p, was down-regulated to activate AKT/mTOR signaling to further maintain the expression level of HIF-1α, thereby forming a feedback loop between HIF-1α/miR-1307-3p and DAB2IP. Targeting miR-1307-3p/DAB2IP axis also modulated tumor growth and metastasis in vivo. In summary, there exists a feedback loop between HIF-1α/miR-1307-3p and DAB2IP in HCC. Targeting a vicious feedback loop between HIF-1α/miR-1307-3p and DAB2IP may be a promising strategy to combat HCC.
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Affiliation(s)
- Shuangjiang Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, Shaanxi 710061, China; Department of General Surgery, Ankang People's Hospital, Ankang, Shaanxi 725000, China
| | - Runkun Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, Shaanxi 710061, China
| | - Hao Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, Shaanxi 710061, China
| | - Qingguang Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, Shaanxi 710061, China.
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Shi Y, Shang J, Li Y, Zhong D, Zhang Z, Yang Q, Lai C, Feng T, Yao Y, Huang X. ITGA5 and ITGB1 contribute to Sorafenib resistance by promoting vasculogenic mimicry formation in hepatocellular carcinoma. Cancer Med 2022; 12:3786-3796. [PMID: 35946175 PMCID: PMC9939139 DOI: 10.1002/cam4.5110] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/14/2022] [Revised: 05/05/2022] [Accepted: 05/24/2022] [Indexed: 11/08/2022] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is labeled with high mortality and tolerance to chemotherapy. Sorafenib has been the first-line treatment option in HCC patients for past decades, while the therapeutic effect was limited in almost HCC patients. METHODS In this study, we analyzed public omics data of HCC patients with different responses to Sorafenib treatment. To confirm the role of integrins A5 and B1 (ITGA5 and ITGB1) in Sorafenib resistance, we generated the Sorafenib-resistant (Sor-R) cell lines and cells overexpressing ITGA5 or ITGB1. Hypoxia level was measured using Hypoxy probe by flow cytometry, while vasculogenic mimicry was detected and quantified by CD31 and periodic acid schiff staining. RESULTS Hypoxia was upregulated in non-responsive patients, accompanied with genes involved in encoding extracellular matrix components and angiogenesis such as ITGA5 and ITGB1. Sor-R hepatoma cell lines were constructed to measure expression and role of candidate genes. ITGA5 and ITGB1 were augmented in Sor-R cells. Upregulation of ITGA5 or ITGB1 reduced the sensitivity to Sorafenib in HepG2 and Huh7 cells, aggravated the hypoxic condition and resulted in formation of vascular mimicry. CONCLUSIONS These findings suggested that hypoxia associated vascular mimicry account for non-response to Sorafenib treatment in HCC patients. ITGA5 and ITGB1 may serve as effective predictors of HCC patients' outcome after Sorafenib treatment, which also provides a new target for HCC patients resistant to Sorafenib.
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Affiliation(s)
- Ying Shi
- Department of Hepatobiliary‐Pancreatic Surgery, Cell Transplantation Center, Sichuan Provincial People's HospitalUniversity of Electronic Science and Technology of ChinaChengduSichuanChina,School of MedicineChengduSichuanChina,Sichuan Translational Medicine Research Hospital, Chinese Academy of SciencesChengduSichuanChina
| | - Jin Shang
- Department of Hepatobiliary‐Pancreatic Surgery, Cell Transplantation Center, Sichuan Provincial People's HospitalUniversity of Electronic Science and Technology of ChinaChengduSichuanChina,School of MedicineChengduSichuanChina,Sichuan Translational Medicine Research Hospital, Chinese Academy of SciencesChengduSichuanChina
| | - Yan Li
- Department of Hepatobiliary‐Pancreatic Surgery, Cell Transplantation Center, Sichuan Provincial People's HospitalUniversity of Electronic Science and Technology of ChinaChengduSichuanChina,School of MedicineChengduSichuanChina,Sichuan Translational Medicine Research Hospital, Chinese Academy of SciencesChengduSichuanChina
| | - Deyuan Zhong
- Department of Hepatobiliary‐Pancreatic Surgery, Cell Transplantation Center, Sichuan Provincial People's HospitalUniversity of Electronic Science and Technology of ChinaChengduSichuanChina,School of MedicineChengduSichuanChina,Sichuan Translational Medicine Research Hospital, Chinese Academy of SciencesChengduSichuanChina
| | - Zilong Zhang
- Department of Hepatobiliary‐Pancreatic Surgery, Cell Transplantation Center, Sichuan Provincial People's HospitalUniversity of Electronic Science and Technology of ChinaChengduSichuanChina,School of MedicineChengduSichuanChina,Sichuan Translational Medicine Research Hospital, Chinese Academy of SciencesChengduSichuanChina
| | - Qinyan Yang
- Department of Hepatobiliary‐Pancreatic Surgery, Cell Transplantation Center, Sichuan Provincial People's HospitalUniversity of Electronic Science and Technology of ChinaChengduSichuanChina,Sichuan Translational Medicine Research Hospital, Chinese Academy of SciencesChengduSichuanChina
| | - Chunyou Lai
- Department of Hepatobiliary‐Pancreatic Surgery, Cell Transplantation Center, Sichuan Provincial People's HospitalUniversity of Electronic Science and Technology of ChinaChengduSichuanChina,Sichuan Translational Medicine Research Hospital, Chinese Academy of SciencesChengduSichuanChina
| | - Tianhang Feng
- Department of Hepatobiliary‐Pancreatic Surgery, Cell Transplantation Center, Sichuan Provincial People's HospitalUniversity of Electronic Science and Technology of ChinaChengduSichuanChina,School of MedicineChengduSichuanChina,Sichuan Translational Medicine Research Hospital, Chinese Academy of SciencesChengduSichuanChina
| | - Yutong Yao
- Department of Hepatobiliary‐Pancreatic Surgery, Cell Transplantation Center, Sichuan Provincial People's HospitalUniversity of Electronic Science and Technology of ChinaChengduSichuanChina,School of MedicineChengduSichuanChina,Sichuan Translational Medicine Research Hospital, Chinese Academy of SciencesChengduSichuanChina
| | - Xiaolun Huang
- Department of Hepatobiliary‐Pancreatic Surgery, Cell Transplantation Center, Sichuan Provincial People's HospitalUniversity of Electronic Science and Technology of ChinaChengduSichuanChina,School of MedicineChengduSichuanChina,Sichuan Translational Medicine Research Hospital, Chinese Academy of SciencesChengduSichuanChina
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Xi Y, Shen Y, Wu D, Zhang J, Lin C, Wang L, Yu C, Yu B, Shen W. CircBCAR3 accelerates esophageal cancer tumorigenesis and metastasis via sponging miR-27a-3p. Mol Cancer 2022; 21:145. [PMID: 35840974 PMCID: PMC9284725 DOI: 10.1186/s12943-022-01615-8] [Citation(s) in RCA: 65] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/21/2022] [Accepted: 06/30/2022] [Indexed: 02/10/2023] Open
Abstract
RATIONALE Circular RNAs (circRNAs) have been demonstrated to contribute to esophageal cancer progression. CircBCAR3 (hsa_circ_0007624) is predicted to be differentially expressed in esophageal cancer by bioinformatics analysis. We investigated the oncogenic roles and biogenesis of circBCAR3 in esophageal carcinogenesis. METHODS Functions of circBCAR3 on cancer cell proliferation, migration, invasion, and ferroptosis were explored using the loss-of-function assays. A xenograft mouse model was used to reveal effects of circBCAR3 on xenograft growth and lung metastasis. The upstream and downstream mechanisms of circBCAR3 were investigated by bioinformatics analysis and confirmed by RNA immunoprecipitation and luciferase reporter assays. The dysregulated genes in hypoxia-induced esophageal cancer cells were identified using RNA-seq. RESULTS CircBCAR3 was highly expressed in esophageal cancer tissues and cells and its expression was increased by hypoxia in vitro. Silencing of circBCAR3 repressed the proliferation, migration, invasion, and ferroptosis of esophageal cancer cells in vitro, as well as inhibited the growth and metastasis of esophageal xenograft in mice in vivo. The hypoxia-induced promotive effects on esophageal cancer cell migration and ferroptosis were rescued by circBCAR3 knockdown. Mechanistically, circBCAR3 can interact with miR-27a-3p by the competitive endogenous RNA mechanism to upregulate transportin-1 (TNPO1). Furthermore, our investigation indicated that splicing factor quaking (QKI) is a positive regulator of circBCAR3 via targeting the introns flanking the hsa_circ_0007624-formed exons in BCAR3 pre-mRNA. Hypoxia upregulates E2F7 to transcriptionally activate QKI. CONCLUSION Our research demonstrated that splicing factor QKI promotes circBCAR3 biogenesis, which accelerates esophageal cancer tumorigenesis via binding with miR-27a-3p to upregulate TNPO1. These data suggested circBCAR3 as a potential target in the treatment of esophageal cancer. Hypoxia induces the upregulation of E2F7, which transcriptionally activates QKI in esophageal cancer cells. QKI increases the formation of circBCAR3 by juxtaposing the circularized exons. CircBCAR3 binds with miR-27a-3p to promote TNPO1 expression. CircBCAR3 promoted the proliferation, migration, invasion, and ferroptosis of esophageal cancer cells by miR-27a-3p.
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Affiliation(s)
- Yong Xi
- Department of Thoracic Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, 315040, Zhejiang, China.
| | - Yaxing Shen
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 20032, China
| | - Donglei Wu
- School of Medicine, Jinan University, Guangzhou, 510627, Guangdong, China
| | - Jingtao Zhang
- Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Chengbin Lin
- Department of Thoracic Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, 315040, Zhejiang, China
| | - Lijie Wang
- Department of Thoracic Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, 315040, Zhejiang, China
| | - Chaoqun Yu
- Department of Thoracic Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, 315040, Zhejiang, China
| | - Bentong Yu
- Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.
| | - Weiyu Shen
- Department of Thoracic Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, 315040, Zhejiang, China.
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