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Khosravi M, Behboudi E, Razavi-Nikoo H, Tabarraei A. Hepatitis B Virus X Protein Induces Expression Changes of miR-21, miR-22, miR-122, miR-132, and miR-222 in Huh-7 Cell Line. ARCHIVES OF RAZI INSTITUTE 2024; 79:111-119. [PMID: 39192965 PMCID: PMC11345482 DOI: 10.32592/ari.2024.79.1.111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 07/29/2023] [Indexed: 08/29/2024]
Abstract
Hepatitis B virus (HBV) X protein (HBx) plays a key role in hepatocellular carcinoma (HCC). HBx may alter the expression of multiple microRNAs (miRs), which are important in hepatocarcinogenesis. This study aimed to investigate the importance of HBx protein in the expression of miR-21, miR-22, miR-122, miR-132, and miR-222. A recombinant vector expressing HBx was developed. The Huh-7 cell line was transfected with the HBx-pcDNA3.1+ recombinant plasmid. A Real-Time Polymerase Chain Reaction was used to evaluate the expression of miR-21, miR-22, miR-122, miR-132, and miR-222 in the cell line. It was found that the expression of miR-21 and miR-222 was upregulated at all points of time after HBx transfection. The expression of miR-21 was 4.24-fold 72 h after transfection. The miR-22 had a 7.69-fold downregulation after 24 h, and the miR-122 had a significant downregulation after 48 h (10-fold). The miR-132 expression reached its lowest rate 12 h after HBx transfection (8.33-fold), and the miR-222 expression was upregulated in transfected cells but was not significantly different (1.18- to 2.45-fold). The significant downregulation of miR-22, miR-122, and miR-132 implicates their inhibitory roles in the progression of HBV-associated HCC. The expression of these microRNAs could be used as a prognostic marker for the progression of HBV-associated liver disease.
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Affiliation(s)
- M Khosravi
- Infectious diseases research center, Golestan University of Medical Sciences, Gorgan, Iran
| | - E Behboudi
- Department of Basic Sciences, Khoy University of Medical Sciences, Khoy, Iran
| | - H Razavi-Nikoo
- Infectious diseases research center, Golestan University of Medical Sciences, Gorgan, Iran
| | - A Tabarraei
- Infectious diseases research center, Golestan University of Medical Sciences, Gorgan, Iran
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Ramakrishnan K, Babu S, Shaji V, Soman S, Leelamma A, Rehman N, Raju R. Hepatitis B Virus Modulated Transcriptional Regulatory Map of Hepatic Cellular MicroRNAs. OMICS : A JOURNAL OF INTEGRATIVE BIOLOGY 2023; 27:581-597. [PMID: 38064540 DOI: 10.1089/omi.2023.0171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2023]
Abstract
Hepatitis B virus (HBV) is an enveloped, hepatotropic, noncytopathic virus with a partially double-stranded DNA genome. It infects hepatocytes and is associated with progression to liver fibrosis and cirrhosis, culminating in hepatocellular carcinoma (HCC), accounting for 55% of total HCC cases. MicroRNAs (miRNAs) regulated by HBV play an important role in these pathologies. Mapping the miRNAs responsive to HBV and HBV-specific proteins, including HBV X protein (HBx) that harbor the majority of HBV-human protein interactions, could aid accelerate the diagnostics and therapeutics innovation against the infection and associated diseases. With this in mind, we used a unique annotation strategy whereby we first amassed 362 mature HBV responsive-human Differentially Expressed miRNAs (HBV-hDEmiRs). The core experimentally-validated messenger RNA targets of the HBV-hDEmiRs were mostly associated with viral infections and hepatic inflammation processes. Moreover, our annotation strategy enabled the characterization of HBx-dependent/independent HBV-hDEmiRs as a tool for evaluation of the impact of HBx as a therapeutic target. Bioinformatics analysis of the HBV-human protein-protein interactome revealed new insights into the transcriptional regulatory network of the HBV-hDEmiRs. We performed a comparative analysis of data on miRNAs gathered from HBV infected cell line studies and from tissue studies of fibrosis, cirrhosis, and HCC. Accordingly, we propose hsa-miR-15a-5p that is downregulated by multiple HBV proteins, including HBx, as a potential biomarker of HBV infection, and its progression to HCC. In all, this study underscores (1) the complexity of miRNA regulation in response to HBV infection and its progression into other liver pathologies and (2) provides a regulatory map of HBV-hDEmiRs and the underlying mechanisms modulating their expression through a cross talk between HBV viral proteins and human transcription factors.
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Affiliation(s)
| | - Sreeranjini Babu
- Centre for Integrative Omics Data Science, Yenepoya (Deemed to be University), Mangalore, India
- Centre for Systems Biology and Molecular Medicine (CSBMM), Yenepoya Research Centre, Yenepoya (Deemed to be University), Deralakatte, Mangalore, Karnataka, India
| | - Vineetha Shaji
- Centre for Integrative Omics Data Science, Yenepoya (Deemed to be University), Mangalore, India
- Centre for Systems Biology and Molecular Medicine (CSBMM), Yenepoya Research Centre, Yenepoya (Deemed to be University), Deralakatte, Mangalore, Karnataka, India
| | - Sowmya Soman
- Centre for Integrative Omics Data Science, Yenepoya (Deemed to be University), Mangalore, India
| | - Anila Leelamma
- Department of Biochemistry, NSS College, Nilamel, Kollam, Kerala, India
| | - Niyas Rehman
- Centre for Integrative Omics Data Science, Yenepoya (Deemed to be University), Mangalore, India
| | - Rajesh Raju
- Centre for Integrative Omics Data Science, Yenepoya (Deemed to be University), Mangalore, India
- Centre for Systems Biology and Molecular Medicine (CSBMM), Yenepoya Research Centre, Yenepoya (Deemed to be University), Deralakatte, Mangalore, Karnataka, India
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Zhang MH, Yuan YF, Liu LJ, Wei YX, Yin WY, Zheng LZY, Tang YY, Lv Z, Zhu F. Dysregulated microRNAs as a biomarker for diagnosis and prognosis of hepatitis B virus-associated hepatocellular carcinoma. World J Gastroenterol 2023; 29:4706-4735. [PMID: 37664153 PMCID: PMC10473924 DOI: 10.3748/wjg.v29.i31.4706] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 06/29/2023] [Accepted: 08/01/2023] [Indexed: 08/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a malignancy with a high incidence and fatality rate worldwide. Hepatitis B virus (HBV) infection is one of the most important risk factors for its occurrence and development. Early detection of HBV-associated HCC (HBV-HCC) can improve clinical decision-making and patient outcomes. Biomarkers are extremely helpful, not only for early diagnosis, but also for the development of therapeutics. MicroRNAs (miRNAs), a subset of non-coding RNAs approximately 22 nucleotides in length, have increasingly attracted scientists' attention due to their potential utility as biomarkers for cancer detection and therapy. HBV profoundly impacts the expression of miRNAs potentially involved in the development of hepatocarcinogenesis. In this review, we summarize the current progress on the role of miRNAs in the diagnosis and treatment of HBV-HCC. From a molecular standpoint, we discuss the mechanism by which HBV regulates miRNAs and investigate the exact effect of miRNAs on the promotion of HCC. In the near future, miRNA-based diagnostic, prognostic, and therapeutic applications will make their way into the clinical routine.
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Affiliation(s)
- Ming-He Zhang
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Yu-Feng Yuan
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Li-Juan Liu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Yu-Xin Wei
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Wan-Yue Yin
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Lan-Zhuo-Yin Zheng
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Ying-Ying Tang
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Zhao Lv
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Fan Zhu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Hubei Province Key Laboratory of Allergy & Immunology, Wuhan University, Wuhan 430071, Hubei Province, China
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Du Y, Rokavec M, Hermeking H. Squalene epoxidase/SQLE is a candidate target for treatment of colorectal cancers with p53 mutation and elevated c- MYC expression. Int J Biol Sci 2023; 19:4103-4122. [PMID: 37705742 PMCID: PMC10496509 DOI: 10.7150/ijbs.85724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Accepted: 07/30/2023] [Indexed: 09/15/2023] Open
Abstract
Elevated expression of c-MYC and inactivation of p53 represent two of the most common alterations in colorectal cancer (CRC). However, c-MYC and defective p53 are difficult to target therapeutically. Therefore, effectors downstream of both c-MYC and p53 may represent attractive, alternative targets for cancer treatment. In a bioinformatics screen we identified Squalene epoxidase/SQLE as a candidate therapeutic target that appeared to be especially relevant for cell survival in CRCs, which display elevated c-MYC expression and loss of p53 function. SQLE is a rate-limiting enzyme in the cholesterol synthesis. Here, we show that p53 supresses SQLE expression, cholesterol levels, and cell viability via the induction of miR-205, which directly targets SQLE. Furthermore, c-MYC induced SQLE expression directly and via its target gene AP4. The transcription factor AP4/TFAP4 directly induced SQLE expression and cholesterol levels, whereas inactivation of AP4 resulted in decreased SQLE expression and caused resistance to Terbinafine, an inhibitor of SQLE. Inhibition of SQLE decreased viability of CRC cells. This effect was enhanced in CRCs cells with p53 inactivation and/or enhanced c-MYC/AP4 expression. Altogether, our results demonstrate that SQLE represents a vulnerability for CRCs with p53 inactivation and elevated c-MYC activity.
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Affiliation(s)
- Yuyun Du
- Experimental and Molecular Pathology, Institute of Pathology, Medical Faculty, Ludwig-Maximilians-Universität München, D-80337 Munich, Germany
| | - Matjaz Rokavec
- Experimental and Molecular Pathology, Institute of Pathology, Medical Faculty, Ludwig-Maximilians-Universität München, D-80337 Munich, Germany
| | - Heiko Hermeking
- Experimental and Molecular Pathology, Institute of Pathology, Medical Faculty, Ludwig-Maximilians-Universität München, D-80337 Munich, Germany
- German Cancer Consortium (DKTK), Partner site Munich, D-80336 Munich, Germany
- German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany
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Deng Y, Wang L, Zhang Y, Sun D, Min H, Zhou H, Xu C, Xu N, Qiu F, Zhou J, Zhou J. HBx promotes hepatocellular carcinoma progression by repressing the transcription level of miR-187-5p. Aging (Albany NY) 2023; 15:7533-7550. [PMID: 37531206 PMCID: PMC10457053 DOI: 10.18632/aging.204921] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 06/23/2023] [Indexed: 08/03/2023]
Abstract
HBV-associated hepatitis B virus x protein (HBx) plays multiple roles in the development of hepatocellular carcinoma. In our prior study, we discovered that miR-187-5p expression was inhibited by HBx. To investigate the underlying molecular mechanism of HBx-mediated miR-187-5p downregulation in hepatocellular carcinoma cells, effects of HBx and miR-187-5p on hepatoma carcinoma cell were observed, as well as their interactions. Through in vitro and in vivo experiments, we demonstrated that overexpression of miR-187-5p inhibited proliferation, migration, and invasion. Simultaneously, we observed a dysregulation in the expression of miR-187-5p in liver cancer cell lines, which may be attributed to transcriptional inhibition through the E2F1/FoxP3 axis. Additionally, we noted that HBx protein is capable of enhancing the expression of E2F1, a transcription factor that promotes the expression of FoxP3. In conclusion, our results suggest that the inhibitory effect of HBx on miR-187-5p is mediated through the E2F1/FoxP3 axis. As shown in this work, HBx promotes hepatoma carcinoma cell proliferation, migration, and invasion through the E2F1/FoxP3/miR-187 axis. It provides a theoretical basis for finding therapeutic targets that will help clinic treatment for HCC.
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Affiliation(s)
- Yang Deng
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430081, China
| | - La Wang
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430081, China
| | - Yingjie Zhang
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430081, China
| | - Dandan Sun
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430081, China
| | - Hang Min
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430081, China
| | - Hao Zhou
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430081, China
| | - Chengchen Xu
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430081, China
| | - Na Xu
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430081, China
| | - Fengwu Qiu
- Hubei Institute of Blood Transfusion, Wuhan Blood Center, Wuhan 430033, China
| | - Jingjiao Zhou
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430081, China
| | - Jun Zhou
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430081, China
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6
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Megahed F, Tabll A, Atta S, Ragheb A, Smolic R, Petrovic A, Smolic M. MicroRNAs: Small Molecules with Significant Functions, Particularly in the Context of Viral Hepatitis B and C Infection. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:173. [PMID: 36676797 PMCID: PMC9862007 DOI: 10.3390/medicina59010173] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Revised: 01/10/2023] [Accepted: 01/12/2023] [Indexed: 01/18/2023]
Abstract
A MicroRNA (miRNA) is defined as a small molecule of non-coding RNA (ncRNA). Its molecular size is about 20 nucleotides (nt), and it acts on gene expression's regulation at the post-transcription level through binding to the 3'untranslated regions (UTR), coding sequences, or 5'UTR of the target messenger RNAs (mRNAs), which leads to the suppression or degradation of the mRNA. In recent years, a huge evolution has identified the origin and function of miRNAs, focusing on their important effects in research and clinical applications. For example, microRNAs are key players in HCV infection and have important host cellular factors required for HCV replication and cell growth. Altered expression of miRNAs affects the pathogenicity associated with HCV infection through regulating different signaling pathways that control HCV/immunity interactions, proliferation, and cell death. On the other hand, circulating miRNAs can be used as novel biomarkers and diagnostic tools for HCV pathogenesis and early therapeutic response. Moreover, microRNAs (miRNA) have been involved in hepatitis B virus (HBV) gene expression and advanced antiviral discovery. They regulate HBV/HCV replication and pathogenesis with different pathways involving facilitation, inhibition, activation of the immune system (innate and adaptive), and epigenetic modifications. In this short review, we will discuss how microRNAs can be used as prognostic, diagnostic, and therapeutic tools, especially for chronic hepatitis viruses (HBV and HCV), as well as how they could be used as new biomarkers during infection and advanced treatment.
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Affiliation(s)
- Fayed Megahed
- Nucleic Acid Research Department, Genetic Engineering and Biotechnological Research Institute (GEBRI), City for Scientific Researches and Technological Applications (SRTA-City), Alexandria 21934, Egypt
| | - Ashraf Tabll
- Microbial Biotechnology Department, National Research Centre, Giza 12622, Egypt
- Egypt Center for Research and Regenerative Medicine (ECRRM), Cairo 11517, Egypt
| | - Shimaa Atta
- Department of Immunology, Theodor Bilharz Research Institute, Cairo 12411, Egypt
| | - Ameera Ragheb
- Egypt Center for Research and Regenerative Medicine (ECRRM), Cairo 11517, Egypt
| | - Robert Smolic
- Faculty of Dental Medicine and Health Osijek, University of Osijek, Crkvena 21, 31000 Osijek, Croatia
| | - Ana Petrovic
- Faculty of Dental Medicine and Health Osijek, University of Osijek, Crkvena 21, 31000 Osijek, Croatia
| | - Martina Smolic
- Faculty of Dental Medicine and Health Osijek, University of Osijek, Crkvena 21, 31000 Osijek, Croatia
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7
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miRNA-205: a future therapeutic molecule for liver diseases. FUTURE DRUG DISCOVERY 2023; 4:FDD78. [PMID: 36908931 PMCID: PMC9990095 DOI: 10.4155/fdd-2022-0012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 12/06/2022] [Indexed: 01/28/2023] Open
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8
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Ishaq Y, Ikram A, Alzahrani B, Khurshid S. The Role of miRNAs, circRNAs and Their Interactions in Development and Progression of Hepatocellular Carcinoma: An Insilico Approach. Genes (Basel) 2022; 14:genes14010013. [PMID: 36672755 PMCID: PMC9858589 DOI: 10.3390/genes14010013] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 12/06/2022] [Accepted: 12/14/2022] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a type of malignant tumor. miRNAs are noncoding RNAs and their differential expression patterns are observed in HCC-induced by alcoholism, HBV and HCV infections. By acting as a competing endogenous RNA (ceRNA), circRNA regulates the miRNA function, indirectly controlling the gene expression and leading to HCC progression. In the present study, data mining was performed to screen out all miRNAs and circRNA involved in alcohol, HBV or HCV-induced HCC with statistically significant (≤0.05%) expression levels reported in various studies. Further, the interaction of miRNAs and circRNA was also investigated to explore their role in HCC due to various causative agents. Together, these study data provide a deeper understanding of the circRNA-miRNA regulatory mechanisms in HCC. These screened circRNA, miRNA and their interactions can be used as prognostic biomarkers or therapeutic targets for the treatment of HCC.
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Affiliation(s)
- Yasmeen Ishaq
- Institute of Molecular Biology and Biotechnology (IMBB), University of Lahore (UOL), Lahore 54000, Pakistan
| | - Aqsa Ikram
- Institute of Molecular Biology and Biotechnology (IMBB), University of Lahore (UOL), Lahore 54000, Pakistan
- Correspondence:
| | - Badr Alzahrani
- Department of Clinical Laboratory Sciences, Jouf University, Sakaka 42421, Saudi Arabia
| | - Sana Khurshid
- Department of Molecular Biology, Virtual University of Pakistan, 1-Davis Road, Lahore 54000, Pakistan
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9
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Liu G, Yang ZF, Sun J, Sun BY, Zhou PY, Zhou C, Guan RY, Wang ZT, Yi Y, Qiu SJ. The LINC00152/miR-205-5p/CXCL11 axis in hepatocellular carcinoma cancer-associated fibroblasts affects cancer cell phenotypes and tumor growth. Cell Oncol (Dordr) 2022; 45:1435-1449. [PMID: 36435866 PMCID: PMC9747837 DOI: 10.1007/s13402-022-00730-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/08/2022] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND CXCL11 has been reported to be up-regulated in hepatocellular carcinoma (HCC) tissues and cancer-associated fibroblasts (CAFs), and CAF-secreted CXCL11 has been found to promote HCC cell proliferation and migration. Knowledge on how CAFs promote HCC progression is imperative for the future design of anti-tumor drugs addressing the high rates of disease recurrence. Herein, we propose a mechanism by which LINC00152 positively regulates CXCL11 expression and, subsequently, HCC cell phenotypes and growth characteristics via miR-205-5p in CAFs. METHODS The expression of LINC00152, miR-205-5p in HCC/non-cancerous tissues, CAFs/NFs and HCC cell lines was determined by RT-qPCR. The CXCL11 expression and secretion were determined by westernblot and ELISA. Different expressions of LINC00152, CXCL11 and miR-205-5p in CAFs were achieved by transfection with corresponding overexpression/knockdown vectors or mimics/inhibitor. The interactions among LINC00152, miR-205-5p and CXCL11 were confirmed by FISH, luciferase, AGO2 and RNA-pulldown assays. Transwell, colony formation and MTT assays were performed to assess the role of CAFs conditioned medium (CM) in HCC cell phenotype. BALB/c nude mice xenografts were used to determine the role of CAFs on HCC growth in vivo. RESULTS We found that in vitro, CM from CAFs transfected with sh-LINC00152 dramatically suppressed HCC cell viability, colony formation and migration, and that CM from CAFs transfected with miR-205-5p inhibitor (CAF-CM (miR-205-5p inhibitor)) exerted opposite effects on HCC cell phenotypes. Exogenous overexpression of CXCL11 in CAFs or CAF-CM (miR-205-5p inhibitor) could partially attenuate the effects of LINC00152 knockdown. In contrast, CM from CAFs transfected with LINC00152 dramatically increased HCC cell viability, colony formation and migration, and CM from CAFs transfected with miR-205-5p mimics (CAF-CM (miR-205-5p mimics)) exerted opposite effects on HCC cell phenotypes. Knockdown of CXCL11 in CAFs or CAF-CM (miR-205-5p mimics) could partially attenuate the effects of LINC00152 overexpression. In vivo, LINC00152 knockdown in CAFs inhibited tumor growth in a mouse model, which could be reversed by CXCL11 overexpression in CAFs. Mechanistically, we found that LINC00152 could act as a ceRNA to counteract miR-205-5p-mediated suppression on CXCL11 by directly binding to miR-205-5p and the 3'UTR of CXCL11. CONCLUSION Our data indicate that a LINC00152/miR-205-5p/CXCL11 axis in HCC CAFs can affect the proliferative and migrative abilities of HCC cells in vitro and HCC tumor growth in vivo.
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Affiliation(s)
- Gao Liu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Biomedical Research Center, Zhongshan Hospital, Fudan University, 180 Fenglin Road, 200032 Shanghai, People’s Republic of China
| | - Zhang-Fu Yang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Biomedical Research Center, Zhongshan Hospital, Fudan University, 180 Fenglin Road, 200032 Shanghai, People’s Republic of China
| | - Jian Sun
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Biomedical Research Center, Zhongshan Hospital, Fudan University, 180 Fenglin Road, 200032 Shanghai, People’s Republic of China
| | - Bao-Ye Sun
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Biomedical Research Center, Zhongshan Hospital, Fudan University, 180 Fenglin Road, 200032 Shanghai, People’s Republic of China
| | - Pei-Yun Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Biomedical Research Center, Zhongshan Hospital, Fudan University, 180 Fenglin Road, 200032 Shanghai, People’s Republic of China
| | - Cheng Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Biomedical Research Center, Zhongshan Hospital, Fudan University, 180 Fenglin Road, 200032 Shanghai, People’s Republic of China
| | - Ruo-Yu Guan
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Biomedical Research Center, Zhongshan Hospital, Fudan University, 180 Fenglin Road, 200032 Shanghai, People’s Republic of China
| | - Zhu-Tao Wang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Biomedical Research Center, Zhongshan Hospital, Fudan University, 180 Fenglin Road, 200032 Shanghai, People’s Republic of China
| | - Yong Yi
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Biomedical Research Center, Zhongshan Hospital, Fudan University, 180 Fenglin Road, 200032 Shanghai, People’s Republic of China
| | - Shuang-Jian Qiu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Biomedical Research Center, Zhongshan Hospital, Fudan University, 180 Fenglin Road, 200032 Shanghai, People’s Republic of China
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10
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Hepatitis B Viral Protein HBx and the Molecular Mechanisms Modulating the Hallmarks of Hepatocellular Carcinoma: A Comprehensive Review. Cells 2022; 11:cells11040741. [PMID: 35203390 PMCID: PMC8870387 DOI: 10.3390/cells11040741] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 02/10/2022] [Accepted: 02/16/2022] [Indexed: 02/06/2023] Open
Abstract
With 296 million cases estimated worldwide, chronic hepatitis B virus (HBV) infection is the most common risk factor for hepatocellular carcinoma (HCC). HBV-encoded oncogene X protein (HBx), a key multifunctional regulatory protein, drives viral replication and interferes with several cellular signalling pathways that drive virus-associated hepatocarcinogenesis. This review article provides a comprehensive overview of the role of HBx in modulating the various hallmarks of HCC by supporting tumour initiation, progression, invasion and metastasis. Understanding HBx-mediated dimensions of complexity in driving liver malignancies could provide the key to unlocking novel and repurposed combinatorial therapies to combat HCC.
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11
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Zhang D, Guo S, Schrodi SJ. Mechanisms of DNA Methylation in Virus-Host Interaction in Hepatitis B Infection: Pathogenesis and Oncogenetic Properties. Int J Mol Sci 2021; 22:9858. [PMID: 34576022 PMCID: PMC8466338 DOI: 10.3390/ijms22189858] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Revised: 09/10/2021] [Accepted: 09/10/2021] [Indexed: 12/11/2022] Open
Abstract
Hepatitis B virus (HBV), the well-studied oncovirus that contributes to the majority of hepatocellular carcinomas (HCC) worldwide, can cause a severe inflammatory microenvironment leading to genetic and epigenetic changes in hepatocyte clones. HBV replication contributes to the regulation of DNA methyltransferase gene expression, particularly by X protein (HBx), and subsequent methylation changes may lead to abnormal transcription activation of adjacent genes and genomic instability. Undoubtedly, the altered expression of these genes has been known to cause diverse aspects of infected hepatocytes, including apoptosis, proliferation, reactive oxygen species (ROS) accumulation, and immune responses. Additionally, pollutant-induced DNA methylation changes and aberrant methylation of imprinted genes in hepatocytes also complicate the process of tumorigenesis. Meanwhile, hepatocytes also contribute to epigenetic modification of the viral genome to affect HBV replication or viral protein production. Meanwhile, methylation levels of HBV integrants and surrounding host regions also play crucial roles in their ability to produce viral proteins in affected hepatocytes. Both host and viral changes can provide novel insights into tumorigenesis, individualized responses to therapeutic intervention, disease progress, and early diagnosis. As such, DNA methylation-mediated epigenetic silencing of cancer-related genes and viral replication is a compelling therapeutic goal to reduce morbidity and mortality from liver cancer caused by chronic HBV infection. In this review, we summarize the most recent research on aberrant DNA methylation associated with HBV infection, which is involved in HCC development, and provide an outlook on the future direction of the research.
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Affiliation(s)
- Dake Zhang
- Key Laboratory of Biomechanics and Mechanobiology, Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing 100083, China
| | - Shicheng Guo
- Department of Medical Genetics, University of Wisconsin-Madison, Madison, WI 53706, USA;
| | - Steven J. Schrodi
- Department of Medical Genetics, University of Wisconsin-Madison, Madison, WI 53706, USA;
- Computation and Informatics in Biology and Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA
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12
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Crosstalk between Environmental Inflammatory Stimuli and Non-Coding RNA in Cancer Occurrence and Development. Cancers (Basel) 2021; 13:cancers13174436. [PMID: 34503246 PMCID: PMC8430834 DOI: 10.3390/cancers13174436] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Revised: 08/20/2021] [Accepted: 08/31/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Increasing evidence has indicated that chronic inflammatory processes have an influence on tumor occurrence and all stages of tumor development. A dramatic increase of studies into non-coding RNAs (ncRNAs) biology has shown that ncRNAs act as oncogenic drivers and tumor suppressors in various inflammation-induced cancers. Thus, this complex network of inflammation-associated cancers and ncRNAs offers targets for prevention from the malignant transformation from inflammation and treatment of malignant diseases. Abstract There is a clear relationship between inflammatory response and different stages of tumor development. Common inflammation-related carcinogens include viruses, bacteria, and environmental mutagens, such as air pollutants, toxic metals, and ultraviolet light. The expression pattern of ncRNA changes in a variety of disease conditions, including inflammation and cancer. Non-coding RNAs (ncRNAs) have a causative role in enhancing inflammatory stimulation and evading immune responses, which are particularly important in persistent pathogen infection and inflammation-to-cancer transformation. In this review, we investigated the mechanism of ncRNA expression imbalance in inflammation-related cancers. A better understanding of the function of inflammation-associated ncRNAs may help to reveal the potential of ncRNAs as a new therapeutic strategy.
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13
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Sun Q, Zhang X, Tan Z, Gu H, Ding S, Ji Y. Bone marrow mesenchymal stem cells-secreted exosomal microRNA-205-5p exerts inhibitory effect on the progression of liver cancer through regulating CDKL3. Pathol Res Pract 2021; 225:153549. [PMID: 34329837 DOI: 10.1016/j.prp.2021.153549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 07/08/2021] [Indexed: 10/20/2022]
Abstract
OBJECTIVE Bone marrow mesenchymal stem cells-derived exosomes (BMSCs-exo) carrying microRNA (miR) cargo have been emerged as a promising therapy for human cancers. Therein, we pivoted on the integral function of BMSCs-exo and miR-205-5p in liver cancer through mediation of cyclin-dependent kinase-like 3 (CDKL3). METHODS Patients with liver cancer were enrolled to collect the clinical tissue and determine miR-205-5p and CDKL3 expression. miR-205-5p expression in BMSCs was altered by transfection, and BMSCs-exo were extracted and co-cultured with LM3 cells. Meanwhile, LM3 cells were independently transfected with CDKL3 low or high expression vector. Since then, cell growth in vitro was observed, and the effect of exosomal miR-205-5p on tumor growth in vivo was further investigated. RESULTS miR-205-5p expression was low while CDKL3 was high in liver cancer. BMSCs-exo blocked cellular growth of liver cancer in vitro and in vivo. Overexpressing exosomal miR-205-5p decelerated the biological development of liver cancer cells while suppressing exosomal miR-205-5p had the contrary function in vitro and in vivo. Loss of CDKL3 impaired the malignant activities of liver cancer cells, and could even impair the pro-tumor effects of down-regulated exosomal miR-205-5p. CONCLUSION It is clearly concluded that BMSCs-secreted exosomal miR-205-5p exerts inhibitory effect on the progression of liver cancer through regulating CDKL3.
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Affiliation(s)
- Qin Sun
- Department of Infectious Diseases, Jingjiang People's Hospital, Jingjiang, Jiangsu 214500, PR China
| | - Xuesong Zhang
- Department of Infectious Diseases, Jingjiang People's Hospital, Jingjiang, Jiangsu 214500, PR China
| | - Zhengbing Tan
- Department of Infectious Diseases, Jingjiang People's Hospital, Jingjiang, Jiangsu 214500, PR China
| | - Hong Gu
- Department of Infectious Diseases, Jingjiang People's Hospital, Jingjiang, Jiangsu 214500, PR China
| | - Song Ding
- Department of Infectious Diseases, Jingjiang People's Hospital, Jingjiang, Jiangsu 214500, PR China
| | - Yong Ji
- Department of General Surgery, Jingjiang People's Hospital, Jingjiang, Jiangsu 214500, PR China.
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14
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Lu H, Yi W, Sun F, Zeng Z, Zhang L, Li M, Xie Y. Comprehensive investigation of HBV-related hepatocellular carcinoma and choice of anti-HBV therapy. BIOSAFETY AND HEALTH 2021. [DOI: 10.1016/j.bsheal.2021.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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15
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Jia X, Yin Y, Chen Y, Mao L. The Role of Viral Proteins in the Regulation of Exosomes Biogenesis. Front Cell Infect Microbiol 2021; 11:671625. [PMID: 34055668 PMCID: PMC8155792 DOI: 10.3389/fcimb.2021.671625] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 04/29/2021] [Indexed: 12/16/2022] Open
Abstract
Exosomes are membrane-bound vesicles of endocytic origin, secreted into the extracellular milieu, in which various biological components such as proteins, nucleic acids, and lipids reside. A variety of external stimuli can regulate the formation and secretion of exosomes, including viruses. Viruses have evolved clever strategies to establish effective infections by employing exosomes to cloak their viral genomes and gain entry into uninfected cells. While most recent exosomal studies have focused on clarifying the effect of these bioactive vesicles on viral infection, the mechanisms by which the virus regulates exosomes are still unclear and deserve further attention. This article is devoted to studying how viral components regulate exosomes biogenesis, composition, and secretion.
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Affiliation(s)
- Xiaonan Jia
- Department of Laboratory Medicine, The Affiliated People's Hospital, Jiangsu University, Zhenjiang, China.,Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Yiqian Yin
- Department of Laboratory Medicine, The Affiliated People's Hospital, Jiangsu University, Zhenjiang, China.,Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Yiwen Chen
- Department of Laboratory Medicine, The Affiliated People's Hospital, Jiangsu University, Zhenjiang, China.,Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Lingxiang Mao
- Department of Laboratory Medicine, The Affiliated People's Hospital, Jiangsu University, Zhenjiang, China
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16
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Sartorius K, An P, Winkler C, Chuturgoon A, Li X, Makarova J, Kramvis A. The Epigenetic Modulation of Cancer and Immune Pathways in Hepatitis B Virus-Associated Hepatocellular Carcinoma: The Influence of HBx and miRNA Dysregulation. Front Immunol 2021; 12:661204. [PMID: 33995383 PMCID: PMC8117219 DOI: 10.3389/fimmu.2021.661204] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 04/15/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatitis B virus (HBV)-associated hepatocellular carcinoma (HBV-HCC) pathogenesis is fueled by persistent HBV infection that stealthily maintains a delicate balance between viral replication and evasion of the host immune system. HBV is remarkably adept at using a combination of both its own, as well as host machinery to ensure its own replication and survival. A key tool in its arsenal, is the HBx protein which can manipulate the epigenetic landscape to decrease its own viral load and enhance persistence, as well as manage host genome epigenetic responses to the presence of viral infection. The HBx protein can initiate epigenetic modifications to dysregulate miRNA expression which, in turn, can regulate downstream epigenetic changes in HBV-HCC pathogenesis. We attempt to link the HBx and miRNA induced epigenetic modulations that influence both the HBV and host genome expression in HBV-HCC pathogenesis. In particular, the review investigates the interplay between CHB infection, the silencing role of miRNA, epigenetic change, immune system expression and HBV-HCC pathogenesis. The review demonstrates exactly how HBx-dysregulated miRNA in HBV-HCC pathogenesis influence and are influenced by epigenetic changes to modulate both viral and host genome expression. In particular, the review identifies a specific subset of HBx induced epigenetic miRNA pathways in HBV-HCC pathogenesis demonstrating the complex interplay between HBV infection, epigenetic change, disease and immune response. The wide-ranging influence of epigenetic change and miRNA modulation offers considerable potential as a therapeutic option in HBV-HCC.
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Affiliation(s)
- Kurt Sartorius
- Hepatitis Virus Diversity Research Unit, School of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa.,Department of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban, South Africa.,Department of Surgery, University of KwaZulu-Natal Gastrointestinal Cancer Research Centre, Durban, South Africa
| | - Ping An
- Basic Research Laboratory, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, United States
| | - Cheryl Winkler
- Basic Research Laboratory, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, United States
| | - Anil Chuturgoon
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, College of Health Science, University of KwaZulu-Natal, Durban, South Africa
| | - Xiaodong Li
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Department of Nutrition and Food Hygiene, School of Public Health, Soochow University, Suzhou, China
| | - Julia Makarova
- Faculty of Biology and Biotechnology, National Research University Higher School of Economics, Moscow, Russia.,Higher School of Economics University, Moscow, Russia
| | - Anna Kramvis
- Hepatitis Virus Diversity Research Unit, School of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa
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17
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Zhang J, Ling N, Lei Y, Peng M, Hu P, Chen M. Multifaceted Interaction Between Hepatitis B Virus Infection and Lipid Metabolism in Hepatocytes: A Potential Target of Antiviral Therapy for Chronic Hepatitis B. Front Microbiol 2021; 12:636897. [PMID: 33776969 PMCID: PMC7991784 DOI: 10.3389/fmicb.2021.636897] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 02/18/2021] [Indexed: 12/17/2022] Open
Abstract
Hepatitis B virus (HBV) is considered a “metabolic virus” and affects many hepatic metabolic pathways. However, how HBV affects lipid metabolism in hepatocytes remains uncertain yet. Accumulating clinical studies suggested that compared to non-HBV-infected controls, chronic HBV infection was associated with lower levels of serum total cholesterol and triglycerides and a lower prevalence of hepatic steatosis. In patients with chronic HBV infection, high ALT level, high body mass index, male gender, or old age was found to be positively correlated with hepatic steatosis. Furthermore, mechanisms of how HBV infection affected hepatic lipid metabolism had also been explored in a number of studies based on cell lines and mouse models. These results demonstrated that HBV replication or expression induced extensive and diverse changes in hepatic lipid metabolism, by not only activating expression of some critical lipogenesis and cholesterolgenesis-related proteins but also upregulating fatty acid oxidation and bile acid synthesis. Moreover, increasing studies found some potential targets to inhibit HBV replication or expression by decreasing or enhancing certain lipid metabolism-related proteins or metabolites. Therefore, in this article, we comprehensively reviewed these publications and revealed the connections between clinical observations and experimental findings to better understand the interaction between hepatic lipid metabolism and HBV infection. However, the available data are far from conclusive, and there is still a long way to go before clarifying the complex interaction between HBV infection and hepatic lipid metabolism.
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Affiliation(s)
- Jiaxuan Zhang
- Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ning Ling
- Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yu Lei
- Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Mingli Peng
- Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Peng Hu
- Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Min Chen
- Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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18
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Han N, Yan L, Wang X, Sun X, Huang F, Tang H. An updated literature review: how HBV X protein regulates the propagation of the HBV. Future Virol 2020. [DOI: 10.2217/fvl-2020-0251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Chronic HBV infection constitutes a burden on human beings and is closely associated with hepatocellular carcinoma. The propagation of the HBV is determined by many factors, and the HBV X protein (HBx) could have a significant influence on this. HBx is a regulatory protein that can directly or indirectly interact with many cellular proteins to affect both the propagation of the HBV and the activity of the host cells. In this review, we summarized the possible mechanisms by which HBx regulates HBV replication at transcriptional and post-transcriptional levels in various experimental systems.
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Affiliation(s)
- Ning Han
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, PR China
| | - Libo Yan
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, PR China
| | - Xueer Wang
- Department of Forensic Pathology, West China School of Basic Science & Forensic Medicine, Sichuan University, Chengdu, Sichuan, PR China
| | - Xuehong Sun
- Department of Forensic Pathology, West China School of Basic Science & Forensic Medicine, Sichuan University, Chengdu, Sichuan, PR China
| | - Feijun Huang
- Department of Forensic Pathology, West China School of Basic Science & Forensic Medicine, Sichuan University, Chengdu, Sichuan, PR China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, PR China
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19
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Chauhan N, Dhasmana A, Jaggi M, Chauhan SC, Yallapu MM. miR-205: A Potential Biomedicine for Cancer Therapy. Cells 2020; 9:cells9091957. [PMID: 32854238 PMCID: PMC7564275 DOI: 10.3390/cells9091957] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 08/18/2020] [Accepted: 08/21/2020] [Indexed: 12/14/2022] Open
Abstract
microRNAs (miRNAs) are a class of small non-coding RNAs that regulate the expression of their target mRNAs post transcriptionally. miRNAs are known to regulate not just a gene but the whole gene network (signaling pathways). Accumulating evidence(s) suggests that miRNAs can work either as oncogenes or tumor suppressors, but some miRNAs have a dual nature since they can act as both. miRNA 205 (miR-205) is one such highly conserved miRNA that can act as both, oncomiRNA and tumor suppressor. However, most reports confirm its emerging role as a tumor suppressor in many cancers. This review focuses on the downregulated expression of miR-205 and discusses its dysregulation in breast, prostate, skin, liver, gliomas, pancreatic, colorectal and renal cancers. This review also confers its role in tumor initiation, progression, cell proliferation, epithelial to mesenchymal transition, and tumor metastasis. Restoration of miR-205 makes cells more sensitive to drug treatments and mitigates drug resistance. Additionally, the importance of miR-205 in chemosensitization and its utilization as potential biomedicine and nanotherapy is described. Together, this review research article sheds a light on its application as a diagnostic and therapeutic marker, and as a biomedicine in cancer.
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Affiliation(s)
- Neeraj Chauhan
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA; (N.C.); (A.D.); (M.J.); (S.C.C.)
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA
| | - Anupam Dhasmana
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA; (N.C.); (A.D.); (M.J.); (S.C.C.)
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA
| | - Meena Jaggi
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA; (N.C.); (A.D.); (M.J.); (S.C.C.)
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA
| | - Subhash C. Chauhan
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA; (N.C.); (A.D.); (M.J.); (S.C.C.)
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA
| | - Murali M. Yallapu
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA; (N.C.); (A.D.); (M.J.); (S.C.C.)
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA
- Correspondence: ; Tel.: +1-(956)-296-1734
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20
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Sartorius K, Swadling L, An P, Makarova J, Winkler C, Chuturgoon A, Kramvis A. The Multiple Roles of Hepatitis B Virus X Protein (HBx) Dysregulated MicroRNA in Hepatitis B Virus-Associated Hepatocellular Carcinoma (HBV-HCC) and Immune Pathways. Viruses 2020; 12:v12070746. [PMID: 32664401 PMCID: PMC7412373 DOI: 10.3390/v12070746] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 07/08/2020] [Accepted: 07/09/2020] [Indexed: 12/11/2022] Open
Abstract
Currently, the treatment of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) [HBV-HCC] relies on blunt tools that are unable to offer effective therapy for later stage pathogenesis. The potential of miRNA to treat HBV-HCC offer a more targeted approach to managing this lethal carcinoma; however, the complexity of miRNA as an ancillary regulator of the immune system remains poorly understood. This review examines the overlapping roles of HBx-dysregulated miRNA in HBV-HCC and immune pathways and seeks to demonstrate that specific miRNA response in immune cells is not independent of their expression in hepatocytes. This interplay between the two pathways may provide us with the possibility of using candidate miRNA to manipulate this interaction as a potential therapeutic option.
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Affiliation(s)
- Kurt Sartorius
- Faculty of Commerce, Law and Management, University of the Witwatersrand, Johannesburg 2050, South Africa
- Department of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban 4041, South Africa;
- UKZN Gastrointestinal Cancer Research Centre, Durban 4041, South Africa
- Correspondence:
| | - Leo Swadling
- Division of Infection and Immunity, University College London, London WC1E6BT, UK;
| | - Ping An
- Basic Research Laboratory, Centre for Cancer Research, National Cancer Institute, Leidos Biomedical Research, Inc. Frederick Nat. Lab. for Cancer Research, Frederick, MD 20878, USA; (P.A.); (C.W.)
| | - Julia Makarova
- National Research University Higher School of Economics, Faculty of Biology and Biotechnology, 10100 Moscow, Russia;
| | - Cheryl Winkler
- Basic Research Laboratory, Centre for Cancer Research, National Cancer Institute, Leidos Biomedical Research, Inc. Frederick Nat. Lab. for Cancer Research, Frederick, MD 20878, USA; (P.A.); (C.W.)
| | - Anil Chuturgoon
- Department of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban 4041, South Africa;
| | - Anna Kramvis
- Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2050, South Africa;
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21
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Ochi M, Otsuka M, Maruyama R, Koike K. HBx increases EGFR expression by inhibiting miR129-5p function. Biochem Biophys Res Commun 2020; 529:198-203. [PMID: 32703411 DOI: 10.1016/j.bbrc.2020.06.018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 06/04/2020] [Indexed: 12/29/2022]
Abstract
Despite the efficient suppression of hepatitis B virus (HBV) replication by nucelos(t)ide analogs, HBV RNA expression usually continues even during nucleots(t)ide analog therapy because episomal covalently closed circular DNA (ccDNA), which is the template for HBV RNA transcription, cannot be eliminated. Here, we found that the common sequences of all HBV RNAs and that encoding the X protein (HBx) have similarities with the sequences of a host cellular microRNA (miRNA), miR129-5p. HBx inhibits miR129-5p function, resulting in increased expression of ZBTB20, a target gene of miR129-5p. ZBTB20 activates transcription and increases cell-surface epidermal growth factor receptor (EGFR) levels, promoting the cell growth rate, and this effect was reversed through ZBTB20 knockdown. mir129-5p levels in Ago2-containing complexes were reduced by expression of HBx, suggesting that the viral RNA sequestered miR129-5p from Ago2-containing complexes. These results indicate the possibility that HBV RNA may maintain pathogenicity even through nucleos(t)ide analog therapy.
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Affiliation(s)
- Masanori Ochi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.
| | - Motoyuki Otsuka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.
| | - Reo Maruyama
- Project for Cancer Epigenomics, The Cancer Institute of the Japanese Foundation for Cancer Research, Tokyo, 135-8550, Japan.
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.
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22
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Bandopadhyay M, Bharadwaj M. Exosomal miRNAs in hepatitis B virus related liver disease: a new hope for biomarker. Gut Pathog 2020; 12:23. [PMID: 32346400 PMCID: PMC7183117 DOI: 10.1186/s13099-020-00353-w] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 03/31/2020] [Indexed: 02/06/2023] Open
Abstract
The World Health Organisation, in its 2019 progress report on HIV, viral hepatitis and STDs indicates that 257 million people are afflicted with chronic HBV infections, of which, 1 million patients lose their lives every year due to HBV related chronic liver diseases including serious complications such as liver cirrhosis and hepatocellular carcinoma. The course of HBV infection and associated liver injury depend on several host factors, genetic variability of the virus, and the host viral interplay. The challenge of medical science is the early diagnosis/identification of the potential for development of fatal complications like liver cirrhosis and HCC so that timely medical intervention can improve the chances of survival. Currently, neither the vaccination regime nor the diagnostic methods are completely effective as reflected in the high number of annual deaths. It is evident from numerous publications that microRNAs (miRNAs) are the critical regulators of gene expression and various cellular processes like proliferation, development, differentiation, apoptosis and tumorigenesis. Expressions of these diminutive RNAs are significantly affected in cancerous tissues as a result of numerous genomic and epigenetic modifications. Exosomes are membrane-derived vesicles (30–100 nm) secreted by normal as well as malignant cells, and are present in all body fluids. They are recognized as critical molecules in intercellular communication between cells through horizontal transfer of information via their cargo, which includes selective proteins, mRNAs and miRNAs. Exosomal miRNAs are transferred to recipient cells where they can regulate target gene expression. This provides an insight into the elementary biology of cancer progression and therefore the development of therapeutic approaches. This concise review outlines various on-going research on miRNA mediated regulation of HBV pathogenesis with special emphasis on association of exosomal miRNA in advanced stage liver disease like hepatocellular carcinoma. This review also discusses the possible use of exosomal miRNAs as biomarkers in the early detection of HCC and liver cirrhosis.
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Affiliation(s)
- Manikankana Bandopadhyay
- Molecular Genetics and Biochemistry, National Institute of Cancer Prevention and Research (NICPR), Indian Council of Medical Research (ICMR), Noida, Uttar Pradesh 201301 India
| | - Mausumi Bharadwaj
- Molecular Genetics and Biochemistry, National Institute of Cancer Prevention and Research (NICPR), Indian Council of Medical Research (ICMR), Noida, Uttar Pradesh 201301 India
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23
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A miR-205-LPCAT1 axis contributes to proliferation and progression in multiple cancers. Biochem Biophys Res Commun 2020; 527:474-480. [PMID: 32334831 DOI: 10.1016/j.bbrc.2020.04.071] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 04/16/2020] [Indexed: 01/25/2023]
Abstract
In the past two decades, miRNAs have been demonstrated to play critical roles in development and progression of malignant diseases. To identify the role and mechanism of miRNA are urgent for the application of miRNA-based therapeutics in cancers. MiR-205 is a conserved miRNA from the invertebrate to mammalian species. Previous studies showed a large body of evidence to demonstrate the oncogenic or tumor suppressive role of it in different types of cancers. Our aim here is to clarify the role and novel mechanism of miR-205 in solid tumors. In the present study, we found that a high level of miR-205 is an independent biomarker for favorable prognosis in LIHC, HNSCC and LUSC. In the functional experiment, we stably expressed miR-205 in tumor cell lines derived from above mentioned cancers. The result showed that overexpression of miR-205 significantly inhibits cancer cell proliferation. Mechanistically, we identified that the lysophosphatidylcholine acyltransferase-1 (LPCAT1) is a novel target of miR-205 in multiple cancer cells. Furthermore, we found that LPCAT1 is required for sustained proliferation of cancer cells and a high level of it is closely associated with poor prognosis in clinical patients. Collectively, we revealed the important prognostic value of a miR-205-LPCAT1 axis in multiple cancers and highlighted an essential role of LPCAT1 in miR-205-regulated cancer cell proliferation. All these discoveries make a miR-205-LPCAT1 axis to shed light upon a potential therapeutic target in cancer treatment.
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24
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The Regulatory Role of MicroRNA in Hepatitis-B Virus-Associated Hepatocellular Carcinoma (HBV-HCC) Pathogenesis. Cells 2019; 8:cells8121504. [PMID: 31771261 PMCID: PMC6953055 DOI: 10.3390/cells8121504] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 11/11/2019] [Accepted: 11/12/2019] [Indexed: 02/06/2023] Open
Abstract
The incidence and mortality of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HBV-HCC) is an intractable public health problem in developing countries that is compounded by limited early detection and therapeutic options. Despite the early promise of utilizing the regulatory role of miRNA in liver cancer, this field remains largely in the work-in-progress phase. This exploratory review paper adopts a broad focus in order to collate evidence of the regulatory role of miRNA in each stage of the HBV-HCC continuum. This includes the regulatory role of miRNA in early HBV infection, chronic inflammation, fibrosis/cirrhosis, and the onset of HCC. The paper specifically investigates HBV dysregulated miRNA that influence the expression of the host/HBV genome in HBV-HCC pathogenesis and fully acknowledges that this does not cover the full spectrum of dysregulated miRNA. The sheer number of dysregulated miRNA in each phase support a hypothesis that future therapeutic interventions will need to consider incorporating multiple miRNA panels.
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25
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Tu W, Yang Y, Song Y, Zhu W. Hepatitis B virus x protein accelerated the proliferation of hepatocellular carcinoma cell through lncRNA SNHG20/PTEN pathway. J Biochem 2019; 165:423-431. [PMID: 30690477 DOI: 10.1093/jb/mvy120] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 01/21/2019] [Indexed: 12/15/2022] Open
Abstract
This study investigated the underlying mechanism of long noncoding RNA (lncRNA) small nucleolar RNA host gene 20 (SNHG20) in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). LncRNA SNHG20 and PTEN expression levels were detected by quantitative real-time polymerase chain reaction and western blot. The proliferation of HCC cells was measured by MTT assay, and the apoptosis of HCC cells was measured by flow cytometry analysis. SNHG20 expression level and HBx protein level were upregulated in HBV(+) group than that of HBV(-) group, whereas PTEN protein level was downregulated in HBV(+) group. Besides, SNHG20 was highly expressed in HBV(+) HCC cells than in HBV(-) HCC cells. SNHG20 expression level was positively associated with HBV x protein (HBx) in HCC cells, and HBx-SNHG20 involved in regulating the proliferation and apoptosis of HCC cells. Moreover, SNHG20 was confirmed to interact with PTEN, which negatively regulated PTEN protein level. Finally, we proved HBx-SNHG20-PTEN signalling pathway involved in the regulation of HCC cell proliferation and apoptosis. In vivo experiments showed SNHG20 knockdown inhibited tumour growth of HBV(+) HCC. HBx promoted the proliferation of HCC cell and reduced the apoptosis of HCC cells through the SNHG20/PTEN signalling pathway.
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Affiliation(s)
- Wenhui Tu
- Department of Infectious Disease, Taizhou Municipal Hospital, 381-1 Zhongshandong Rd, Jiaojiang District, Taizhou, Zhejiang Province, China
| | - Yonghong Yang
- Department of Infectious Disease, Taizhou Municipal Hospital, 381-1 Zhongshandong Rd, Jiaojiang District, Taizhou, Zhejiang Province, China
| | - Yulong Song
- Department of Infectious Disease, Taizhou Municipal Hospital, 381-1 Zhongshandong Rd, Jiaojiang District, Taizhou, Zhejiang Province, China
| | - Weijun Zhu
- Department of Pathology, Taizhou Municipal Hospital, 381-1 Zhongshandong Rd, Jiaojiang District, Taizhou, Zhejiang Province, China
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26
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Wei Z, Shen X, Ni B, Luo G, Tian Y, Sun Y. Contribution of hepatitis B virus X protein-induced aberrant microRNA expression to hepatocellular carcinoma pathogenesis. ACTA ACUST UNITED AC 2019; 43:113-123. [PMID: 31320813 PMCID: PMC6620039 DOI: 10.3906/biy-1807-196] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The hepatitis B virus-encoded X (HBX) protein plays important roles in Hepatocellular carcinoma (HCC). Previous studies have demonstrated that HBX can induce alterations in the expression of numerous microRNAs (miRNAs) involved in the carcinogenesis of various tumors. However, the global profile of liver miRNA changes induced by HBX has not been characterized. In this study, we conducted a miRNA microarray analysis to investigate the influence of HBX on the expression of total miRNAs in liver in relation to HCC. Comparative analysis of the data from human normal liver cells (L02) and human HCC cells (HepG2), with or without HBX, identified 19 differentially expressed miRNAs, including 5 with known association to HBX. Target gene prediction for the aberrantly expressed miRNAs identified a total of 304 potential target genes, involved in sundry pathways. Finally, pathway analysis of the HBXinduced miRNAs pathway showed that 5 of the total miRNAs formed an internetwork, suggesting that HBX might exert its pathological effects on hepatic cells through functional synergy with miRNAs that regulated common pathways in liver cells. Therefore, this work provides new insights into the mechanisms of HCC as well as potential diagnostic markers or therapeutic targets for use in clinical management of HCC.
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Affiliation(s)
- Zhiyuan Wei
- Institute of Immunology, PLA, Army Medical University (Third Military Medical University) , Chongqing , P.R. China.,Southwest Hospital, Army Medical University (Third Military Medical University) , Chongqing , P. R. China
| | - Xiaohe Shen
- Department of Microbiology and Immunology, Shanxi Medical University , Taiyuan, Shanxi , P.R. China
| | - Bing Ni
- Department of Pathophysiology and High Altitude Pathology, Army Medical University (Third Military Medical University) , Chongqing , P.R. China.,Institute of Immunology, PLA, Army Medical University (Third Military Medical University) , Chongqing , P.R. China
| | - Gaoxing Luo
- Southwest Hospital, Army Medical University (Third Military Medical University) , Chongqing , P. R. China
| | - Yi Tian
- Institute of Immunology, PLA, Army Medical University (Third Military Medical University) , Chongqing , P.R. China
| | - Yi Sun
- Southwest Hospital, Army Medical University (Third Military Medical University) , Chongqing , P. R. China
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27
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Tian JH, Liu WD, Zhang ZY, Tang LH, Li D, Tian ZJ, Lin SW, Li YJ. Influence of miR-520e-mediated MAPK signalling pathway on HBV replication and regulation of hepatocellular carcinoma cells via targeting EphA2. J Viral Hepat 2019; 26:496-505. [PMID: 30521133 DOI: 10.1111/jvh.13048] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Revised: 10/09/2018] [Accepted: 11/01/2018] [Indexed: 12/12/2022]
Abstract
We determined the role of miR-520e in the replication of hepatitis B virus (HBV) and the growth of hepatocellular carcinoma (HCC) cells. MiR-520e and EPH receptor A2 (EphA2) in HBV-positive HCC tissues and cells were detected, and we studied the impact of miR-520e and the EphA2 receptor in cellular and murine HBV replication models. We find that MiR-520e was upregulated and EphA2 was downregulated in HBV-positive HCC tissues and cells. MiR-520e was decreased in Huh7-X and HepG2-X cells in which HBx was stably expressed, but was dose-dependently elevated after interfering with HBx. Additionally, miR-520e mimic and si-EphA2 groups were reduced in association with increases in HBV DNA content, HBsAg and HBeAg levels, cell proliferation and were enhanced in the expressions of EphA2, p-p38MAPK/p38MAPK, phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2)/ERK1/2 and cell apoptosis. Furthermore, si-EphA2 reversed the promotion effect of miR-520e inhibitor on HBV replication and tumour cell growth. Upregulating miR-520e in rAAV8-1.3HBV-infected mouse resulted in reduced EphA2 in liver tissues and HBV DNA content in serum. We find that MiR-520e was decreased in HBV-positive HCC, while overexpression of miR-520e blocked p38MAPK and ERK1/2 signalling pathways by an inhibitory effect on EphA2 and ultimately reduced HBV replication and inhibited tumour cell growth. These data indicate a role for miR-520e in the regulation of HBV replication.
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Affiliation(s)
- Jing-Hui Tian
- Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong University, Ji'nan, China.,School of Public Health, Taishan Medical University, Taian, China
| | - Wen-Dong Liu
- Department of Blood Transfusion, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Zhi-Yong Zhang
- Clinical Laboratory, Dezhou People's Hospital, Dezhou, China
| | - Li-Hua Tang
- Department of Blood Transfusion, Tai'an City Central Hospital, Tai'an, China
| | - Dong Li
- School of Public Health, Taishan Medical University, Taian, China
| | - Zhao-Ju Tian
- School of Public Health, Taishan Medical University, Taian, China
| | - Shao-Wei Lin
- School of Public Health, Taishan Medical University, Taian, China
| | - Ying-Jie Li
- Department of Health Examination, Qilu Hospital, Shandong University, Jinan, China
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28
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Xu Q, Gu S, Liang J, Lin Z, Zheng S, Yan J. The Biological Function of Hepatitis B Virus X Protein in Hepatocellular Carcinoma. Oncol Res 2019; 27:509-514. [PMID: 29891022 PMCID: PMC7848407 DOI: 10.3727/096504018x15278771272963] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the major malignant tumors that lead to death. Chronic hepatitis B virus infection is an important risk factor for HCC initiation. HBx protein, encoded by the HBV X gene, is a significant factor that promotes HBV-related HCC, although the exact molecular mechanism remains unclear. This article summarizes the pathological roles and related mechanisms of HBx in HCC. HBx plays a carcinogenic role by promoting cell proliferation, metastasis, and angiogenesis and inhibiting apoptosis in HCC. A detailed study of the biological functions of HBx will help to elucidate the mechanism of hepatocarcinogenesis and lead to the development of novel therapeutic targets for the treatment of HBV-related HCC.
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Affiliation(s)
- Qiaodong Xu
- Department of Biliary-Pancreatic Minimally Invasive Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, P.R. China
| | - Songgang Gu
- Department of Biliary-Pancreatic Minimally Invasive Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, P.R. China
| | - Jiahong Liang
- Department of Biliary-Pancreatic Minimally Invasive Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, P.R. China
| | - Zhihua Lin
- Department of Biliary-Pancreatic Minimally Invasive Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, P.R. China
| | - Shaodong Zheng
- Department of Biliary-Pancreatic Minimally Invasive Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, P.R. China
| | - Jiang Yan
- Department of Biliary-Pancreatic Minimally Invasive Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, P.R. China
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29
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Molecular Mechanisms Driving Progression of Liver Cirrhosis towards Hepatocellular Carcinoma in Chronic Hepatitis B and C Infections: A Review. Int J Mol Sci 2019. [PMID: 30889843 DOI: 10.3390/ijms] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Almost all patients with hepatocellular carcinoma (HCC), a major type of primary liver cancer, also have liver cirrhosis, the severity of which hampers effective treatment for HCC despite recent progress in the efficacy of anticancer drugs for advanced stages of HCC. Here, we review recent knowledge concerning the molecular mechanisms of liver cirrhosis and its progression to HCC from genetic and epigenomic points of view. Because ~70% of patients with HCC have hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection, we focused on HBV- and HCV-associated HCC. The literature suggests that genetic and epigenetic factors, such as microRNAs, play a role in liver cirrhosis and its progression to HCC, and that HBV- and HCV-encoded proteins appear to be involved in hepatocarcinogenesis. Further studies are needed to elucidate the mechanisms, including immune checkpoints and molecular targets of kinase inhibitors, associated with liver cirrhosis and its progression to HCC.
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30
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Molecular Mechanisms Driving Progression of Liver Cirrhosis towards Hepatocellular Carcinoma in Chronic Hepatitis B and C Infections: A Review. Int J Mol Sci 2019; 20:ijms20061358. [PMID: 30889843 PMCID: PMC6470669 DOI: 10.3390/ijms20061358] [Citation(s) in RCA: 183] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2019] [Revised: 02/23/2019] [Accepted: 03/14/2019] [Indexed: 02/07/2023] Open
Abstract
Almost all patients with hepatocellular carcinoma (HCC), a major type of primary liver cancer, also have liver cirrhosis, the severity of which hampers effective treatment for HCC despite recent progress in the efficacy of anticancer drugs for advanced stages of HCC. Here, we review recent knowledge concerning the molecular mechanisms of liver cirrhosis and its progression to HCC from genetic and epigenomic points of view. Because ~70% of patients with HCC have hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection, we focused on HBV- and HCV-associated HCC. The literature suggests that genetic and epigenetic factors, such as microRNAs, play a role in liver cirrhosis and its progression to HCC, and that HBV- and HCV-encoded proteins appear to be involved in hepatocarcinogenesis. Further studies are needed to elucidate the mechanisms, including immune checkpoints and molecular targets of kinase inhibitors, associated with liver cirrhosis and its progression to HCC.
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31
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Nakamura M, Chiba T, Kanayama K, Kanzaki H, Saito T, Kusakabe Y, Kato N. Epigenetic dysregulation in hepatocellular carcinoma: an up-to-date review. Hepatol Res 2019; 49:3-13. [PMID: 30238570 DOI: 10.1111/hepr.13250] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2018] [Revised: 08/30/2018] [Accepted: 09/12/2018] [Indexed: 12/14/2022]
Abstract
Due to the advances made in research based on next generation sequencers, it is now possible to detect and analyze epigenetic abnormalities associated with cancer. DNA methylation, various histone modifications, chromatin remodeling, and non-coding RNA-associated gene silencing are considered to be transcriptional regulatory mechanisms associated with gene expression changes. The breakdown of this precise regulatory system is involved in the transition to cancer. The important role of epigenetic regulation can be observed from the high rate of genetic mutations and abnormal gene expression leading to a breakdown in epigenetic gene expression regulation seen in hepatocellular carcinoma (HCC). Based on an understanding of epigenomic abnormalities associated with pathological conditions, these findings will lead the way to diagnosis and treatment. In particular, in addition to the fact that there are few choices in terms of extant drug therapies aimed at HCC, there are limits to their antitumor effects. The clinical application of epigenetic therapeutic agents for HCC has only just begun, and future developments are expected.
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Affiliation(s)
- Masato Nakamura
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tetsuhiro Chiba
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Kengo Kanayama
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Hiroaki Kanzaki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tomoko Saito
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Yuko Kusakabe
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Naoya Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
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32
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Yang Z, Li J, Feng G, Wang Y, Yang G, Liu Y, Zhang S, Feng J, Zhang X. Hepatitis B virus X protein enhances hepatocarcinogenesis by depressing the targeting of NUSAP1 mRNA by miR- 18b. Cancer Biol Med 2019; 16:276-287. [PMID: 31516748 PMCID: PMC6713641 DOI: 10.20892/j.issn.2095-3941.2018.0283] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Objective The aim of this study was to investigate the underlying mechanism whereby HBx modulates the targeting of NUSAP1 by miR-18b to enhance hepatocarcinogenesis. Methods We employed an integrated approach of bioinformatics analysis and molecular experiments in hepatoma cells, HBV transgenic mice, and clinical liver cancer tissues to investigate the role of HBx-regulated miR-18b in the development of liver cancer. Results In this study, we report that the HBx-mediated tumor suppressor miR-18b modulates hepatocarcinogenesis during the host-HBV interaction. The expression levels of miR-18b were lower in clinical HBV-positive liver cancer tissues and liver tissues of HBV-transgenic mice. Interestingly, HBx inhibited miR-18b expression by inducing the methylation of CpG islands in its promoter. Accordingly, we tested the hypothesis that HBx enhanced hepatocarcinogenesis by increasing the expression of target genes of miR-18b. Moreover, we identified nucleolar spindle-associated protein 1 (NUSAP1) as one of the target genes of miR-18b. NUSAP1 was expressed at high levels in liver cancer tissues. Interestingly, HBx up-regulated NUSAP1 by suppressing miR-18b. Functionally, miR-18b significantly inhibited the proliferation of hepatoma cells by depressing NUSAP1 levels in vivo and in vitro. Conclusions Thus, we conclude that the targeting of NUSAP1 mRNA by the tumor suppressor miR-18b is controlled by HBx-modulated promoter methylation during the host-virus interaction, leading to hepatocarcinogenesis. Our findings provide new insights into the mechanism by which HBx-mediated miRNAs modulate hepatocarcinogenesis.
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Affiliation(s)
- Zhe Yang
- Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Jiong Li
- Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Guoxing Feng
- Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Yuan Wang
- Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Guang Yang
- Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Yunxia Liu
- Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Shuqin Zhang
- Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Jinyan Feng
- Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Xiaodong Zhang
- Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin 300071, China
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33
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Kim ES, Choi JY, Hwang SJ, Bae IH. Hypermethylation of miR-205-5p by IR Governs Aggressiveness and Metastasis via Regulating Bcl-w and Src. MOLECULAR THERAPY. NUCLEIC ACIDS 2018; 14:450-464. [PMID: 30743214 PMCID: PMC6369268 DOI: 10.1016/j.omtn.2018.12.013] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Revised: 12/25/2018] [Accepted: 12/26/2018] [Indexed: 02/07/2023]
Abstract
Although radiotherapy has been successfully applied to treat many cancer types, surviving cancer cells often acquire therapeutic resistance, leading to increased risk of local recurrence and distant metastases via modification of the tumor microenvironment. Previously, we reported that high expression of Bcl-w in cancer patients is significantly correlated with poor survival as well as malignant activity. However, the relationship between ionizing radiation (IR)-induced resistance and Bcl-w expression in cancer cells is currently unclear. We showed that IR-induced Bcl-w contributes to EMT (epithelial-mesenchymal transition), migration, angiogenesis, stemness maintenance, and metastasis by promoting the expression of factors related to these phenotypes, both in vitro and in vivo. Meanwhile, IR enhanced hypermethylation of miR-205-5p CpG islands through Src activation, leading to decreased miR-205-5p expression and, in turn, potentially stimulating Bcl-w-mediated malignant activity and metastasis. The clinical applicability of Bcl-w and miR-205-5p from cells or animal models was confirmed using tissues and plasma of breast carcinoma patients. Based on the collective findings, we propose that miR-205-5ps as important negative mediators of resistance in radiotherapy could serve as useful potential targets of concurrently applied genetic therapy aimed to inhibit tumor aggressiveness and enhance the efficiency of radiotherapy in cancer patients.
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Affiliation(s)
- Eun Sook Kim
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Republic of Korea
| | - Jae Yeon Choi
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Republic of Korea
| | - Su Jin Hwang
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Republic of Korea
| | - In Hwa Bae
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Republic of Korea.
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34
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Sadri Nahand J, Bokharaei-Salim F, Salmaninejad A, Nesaei A, Mohajeri F, Moshtzan A, Tabibzadeh A, Karimzadeh M, Moghoofei M, Marjani A, Yaghoubi S, Keyvani H. microRNAs: Key players in virus-associated hepatocellular carcinoma. J Cell Physiol 2018; 234:12188-12225. [PMID: 30536673 DOI: 10.1002/jcp.27956] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Accepted: 11/19/2018] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is known as one of the major health problems worldwide. Pathological analysis indicated that a variety of risk factors including genetical (i.e., alteration of tumor suppressors and oncogenes) and environmental factors (i.e., viruses) are involved in beginning and development of HCC. The understanding of these risk factors could guide scientists and clinicians to design effective therapeutic options in HCC treatment. Various viruses such as hepatitis B virus (HBV) and hepatitis C virus (HCV) via targeting several cellular and molecular pathways involved in HCC pathogenesis. Among various cellular and molecular targets, microRNAs (miRNAs) have appeared as key players in HCC progression. miRNAs are short noncoding RNAs which could play important roles as oncogenes or tumor suppressors in several malignancies such as HCC. Deregulation of many miRNAs (i.e., miR-222, miR-25, miR-92a, miR-1, let-7f, and miR-21) could be associated with different stages of HCC. Besides miRNAs, exosomes are other particles which are involved in HCC pathogenesis via targeting different cargos, such as DNAs, RNAs, miRNAs, and proteins. In this review, we summarize the current knowledge of the role of miRNAs and exosomes as important players in HCC pathogenesis. Moreover, we highlighted HCV- and HBV-related miRNAs which led to HCC progression.
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Affiliation(s)
- Javid Sadri Nahand
- Department of Virology, Iran University of Medical Sciences, Tehran, Iran
| | | | - Arash Salmaninejad
- Drug Applied Research Center, Student Research Committee, Tabriz University of Medical Science, Tabriz, Iran.,Department of Medical Genetics, Medical Genetics Research Center, Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Abolfazl Nesaei
- Department of Basic Sciences, Faculty of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Fatemeh Mohajeri
- Department of Infectious Disease, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Azadeh Moshtzan
- Department of Infectious Disease, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Alireza Tabibzadeh
- Department of Virology, Iran University of Medical Sciences, Tehran, Iran
| | | | - Mohsen Moghoofei
- Department of Microbiology, Faculty of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Arezo Marjani
- Department of Virology, Iran University of Medical Sciences, Tehran, Iran
| | - Shoeleh Yaghoubi
- Department of Infectious Disease, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Hossein Keyvani
- Department of Virology, Iran University of Medical Sciences, Tehran, Iran
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35
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Sagnelli E, Potenza N, Onorato L, Sagnelli C, Coppola N, Russo A. Micro-RNAs in hepatitis B virus-related chronic liver diseases and hepatocellular carcinoma. World J Hepatol 2018; 10:558-570. [PMID: 30310534 PMCID: PMC6177563 DOI: 10.4254/wjh.v10.i9.558] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2018] [Revised: 04/24/2018] [Accepted: 05/30/2018] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that modulate gene expression at the post-transcriptional level by affecting both the stability and translation of complementary mRNAs. Several studies have shown that miRNAs are important regulators in the conflicting efforts between the virus (to manipulate the host for its successful propagation) and the host (to inhibit the virus), culminating in either the elimination of the virus or its persistence. An increasing number of studies report a role of miRNAs in hepatitis B virus (HBV) replication and pathogenesis. In fact, HBV is able to modulate different host miRNAs, particularly through the transcriptional transactivator HBx protein and, conversely, different cellular miRNAs can regulate HBV gene expression and replication by a direct binding to HBV transcripts or indirectly targeting host factors. The present review will discuss the role of miRNAs in the pathogenesis of HBV-related diseases and their role as a biomarker in the management of patients with HBV-related disease and as therapeutic targets.
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Affiliation(s)
- Evangelista Sagnelli
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania Luigi Vanvitelli, Naples 80135, Italy.
| | - Nicoletta Potenza
- DISTABIF, University of Campania "Luigi Vanvitelli", Naples 80100, Italy
| | - Lorenzo Onorato
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania Luigi Vanvitelli, Naples 80135, Italy
| | - Caterina Sagnelli
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania Luigi Vanvitelli, Naples 80135, Italy
| | - Nicola Coppola
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania Luigi Vanvitelli, Naples 80135, Italy
| | - Aniello Russo
- DISTABIF, University of Campania "Luigi Vanvitelli", Naples 80100, Italy
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36
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Sun W, Zhang J, Chen J. MicroRNA-520a suppresses HBV replication in HepG2.2.15 cells by inactivating AKT. J Int Med Res 2018; 46:4693-4704. [PMID: 30191752 PMCID: PMC6259377 DOI: 10.1177/0300060518792780] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Objective To investigate whether the mechanism by which a microRNA, miR-520a, suppresses the replication of hepatitis B virus (HBV) involves the regulation of the serine/threonine kinase (AKT) gene. Methods The effects of miR-520a on the proliferation, mitotic index and apoptosis of the HBV-replicating human hepatocellular carcinoma cell line HepG2.2.15 were measured using standard laboratory methods including flow cytometry. The effects of miR-520a on HBV transcription and replication were assessed using methods including immunoassays and reverse transcription–polymerase chain reaction. The effect of small interfering RNA (siRNA) to AKT on the levels of AKT mRNA and protein were also evaluated. Results In HepG2.2.15 cells, miRNA-520a reduced HBV transcription and replication by reducing AKT levels. MiRNA-520a decreased cell proliferation and mitosis entry of cells and increased apoptosis in HepG2.2.15 cells. AKT levels were reduced significantly by its siRNA, which resulted in suppression of HBV replication in HepG2.2.15 cells. Conclusions MiRNA-520a inhibited AKT gene expression and suppressed HBV transcription and replication. These findings suggest that miRNA-520a may be a novel target for the treatment of HBV infection because miRNA-520a reduced HepG2.2.15 cell survival and inhibited HBV replication associated with the AKT signalling pathway.
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Affiliation(s)
- Wei Sun
- 1 Department of Oncology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Jinqian Zhang
- 2 Department of Laboratory Medicine, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong Province, China
| | - Jinglong Chen
- 1 Department of Oncology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
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37
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Li D, Wang Q, Li N, Zhang S. miR‑205 targets YAP1 and inhibits proliferation and invasion in thyroid cancer cells. Mol Med Rep 2018; 18:1674-1681. [PMID: 29845281 DOI: 10.3892/mmr.2018.9074] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Accepted: 03/26/2018] [Indexed: 11/06/2022] Open
Abstract
MicroRNA‑205 (miR‑205) has been reported to be downregulated, and serves critical roles in the pathogenesis and progression of several types of cancer, including breast, prostate and lung cancer. However, the underlying mechanism of miR‑205 in thyroid cancer remains unclear. In the present study, it was demonstrated that the expression of miR‑205 was reduced in thyroid cancer tissues compared with non‑cancer tissues. In addition, miR‑205‑knockdown models in the BHT‑101 cell line and ectopic expression models in the 8505‑C cell line were used to measure the biological functions of miR‑205. The results indicated that miR‑205 inhibited certain aspects of thyroid cancer, including cell proliferation, migration and invasion. Furthermore, Yes‑associated protein 1 (YAP1) was identified as a target gene of miR‑205 and its expression was negatively correlated with that of miR‑205 in thyroid cancer tissues. Depletion of YAP1 partially reduced the anti‑miR‑205‑induced cell growth and invasion. The results of the present study suggested that the tumor suppressive functions of miR‑205 via targeting YAP1 could be a novel target for the treatment of thyroid cancer.
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Affiliation(s)
- Dewei Li
- Department of Thyroid Surgery, Shanxi Provincial People's Hospital, Taiyuan, Shanxi 030012, P.R. China
| | - Qiang Wang
- Department of Thyroid Surgery, Shanxi Provincial People's Hospital, Taiyuan, Shanxi 030012, P.R. China
| | - Ning Li
- Department of General Surgery, Shanxi Provincial People's Hospital, Taiyuan, Shanxi 030012, P.R. China
| | - Shuilong Zhang
- Department of Thyroid Surgery, Shanxi Provincial People's Hospital, Taiyuan, Shanxi 030012, P.R. China
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Dysregulation of cellular microRNAs by human oncogenic viruses - Implications for tumorigenesis. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2018; 1861:95-105. [PMID: 29378330 DOI: 10.1016/j.bbagrm.2018.01.017] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Revised: 01/15/2018] [Accepted: 01/21/2018] [Indexed: 12/11/2022]
Abstract
Infection with certain animal and human viruses, often referred to as tumor viruses, induces oncogenic processes in their host. These viruses can induce tumorigenesis through direct and/or indirect mechanisms, and the regulation of microRNAs expression has been shown to play a key role in this process. Some human oncogenic viruses can express their own microRNAs; however, they all can dysregulate the expression of cellular microRNAs, facilitating their respective life cycles. The modulation of cellular microRNAs expression brings consequences to the host cells that may lead to malignant transformation, since microRNAs regulate the expression of genes involved in oncogenic pathways. This review focus on the mechanisms used by each human oncogenic virus to dysregulate the expression of cellular microRNAs, and their impact on tumorigenesis.
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Shao P, Qu WK, Wang CY, Tian Y, Ye ML, Sun DG, Sui JD, Wang LM, Fan R, Gao ZM. MicroRNA-205-5p regulates the chemotherapeutic resistance of hepatocellular carcinoma cells by targeting PTEN/JNK/ANXA3 pathway. Am J Transl Res 2017; 9:4300-4307. [PMID: 28979703 PMCID: PMC5622272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Accepted: 08/25/2017] [Indexed: 06/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is a common malignant tumor of the digestive system, and patients with advanced HCC have a poor outlook, partly due to resistance to chemotherapeutic drugs. Previous studies have implicated microRNAs in the regulation of chemoresistance, and we have previously shown that microRNA (miR)-205-5p is down-regulated in multiple hepatoma cell lines. Here, we investigate whether miR-205-5p is involved in chemotherapeutic resistance in HCC. Expression of miR-205-5p was measured by real-time quantitative reverse transcription PCR and cell viability was determined using a CCK-8 cell viability assay. Expression of proteins in the PTEN/JNK/ANXA3 pathway were assessed via Western blotting. We found that miR-205-5p expression was down-regulated in all HCC cell lines investigated. In addition, miR-205-5p expression was upregulated by 5-fluorouracil (5-Fu) treatment in Bel-7402 (Bel) cells. Interestingly, miR-205-5p expression was increased in multidrug-resistant Bel-7402/5-Fu (Bel/Fu) cells, compared with Bel cells. We next demonstrated that sensitivity to 5-Fu was increased in Bel/Fu cells after treatment with a miR-205-5p inhibitor. Similarly, increased resistance to 5-Fu was observed in Bel cells after transfection with a miR-205-5p mimic. We injected nude mice with Bel/5-Fu cells to promote tumor growth, and found that co-treatment with a miR-205-5p antagomir and 5-Fu slowed tumor growth more than either treatment alone. Finally, we found that these effects were all associated with changes in the PTEN/JNK/ANXA3 pathway. In conclusion, inhibition of miR-205-5p may reverse chemotherapeutic resistance to 5-Fu, and this may occur via the PTEN/JNK/ANXA3 pathway.
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Affiliation(s)
- Ping Shao
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Second Affiliated Hospital of Dalian Medical UniversityDalian, China
| | - Wei-Kun Qu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Second Affiliated Hospital of Dalian Medical UniversityDalian, China
| | - Cheng-Ye Wang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Second Affiliated Hospital of Dalian Medical UniversityDalian, China
| | - Yu Tian
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Second Affiliated Hospital of Dalian Medical UniversityDalian, China
| | - Ming-Liang Ye
- Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of SciencesDalian, China
| | - De-Guang Sun
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Second Affiliated Hospital of Dalian Medical UniversityDalian, China
| | - Ji-Dong Sui
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Second Affiliated Hospital of Dalian Medical UniversityDalian, China
| | - Li-Ming Wang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Second Affiliated Hospital of Dalian Medical UniversityDalian, China
| | - Rong Fan
- VIP Ward No. 2, The Second Affiliated Hospital of Dalian Medical UniversityDalian, China
| | - Zhen-Ming Gao
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Second Affiliated Hospital of Dalian Medical UniversityDalian, China
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40
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Feng GX, Li J, Yang Z, Zhang SQ, Liu YX, Zhang WY, Ye LH, Zhang XD. Hepatitis B virus X protein promotes the development of liver fibrosis and hepatoma through downregulation of miR-30e targeting P4HA2 mRNA. Oncogene 2017; 36:6895-6905. [PMID: 28846110 DOI: 10.1038/onc.2017.291] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Revised: 06/26/2017] [Accepted: 06/27/2017] [Indexed: 02/06/2023]
Abstract
Hepatitis B virus (HBV)-induced liver necrosis takes great part in liver cirrhosis progression. However, less is known about whether hepatitis B virus X protein (HBx) has effect on liver fibrosis. Here, we report that HBV leads to liver fibrosis and hepatocarcinogenesis through miR-30e targeting P4HA2. HBV transgenic mouse was treated by CCl4 to generate a model of liver fibrosis. A crucial enzyme catalyzing collagen formation, prolyl 4-hydroxylase subunit α2 (P4HA2) was evaluated by immunohistochemistry, western blotting or quantitative reverse transcription-PCR analysis. The function of HBV-modulated P4HA2 in hepatoma cell growth in vitro and in vivo was analyzed by EdU, MTT, colony-forming assay and animal transplantation assay. HBV transgenic mice exhibited more collagen deposition in liver after intraperitoneal injection of CCl4. P4HA2 was dramatically augmented in liver samples of HBV transgenic mice, clinical liver cirrhosis and liver cancer patients. Mechanistically, HBx was capable of inducing P4HA2 through suppressing miR-30e, in which miR-30e could target P4HA2 mRNA 3' untranslated region in liver cancer cells. HBx inhibited the miR-30e expression through increasing methylation of CpG islands in its promoter mediated by EZH2-formed complexes. Functionally, HBx-elevated P4HA2 enhanced the collagen deposition in the liver in vivo and in vitro, leading to liver fibrosis and liver cancer progression. In conclusion, HBx promotes the development of liver fibrosis and hepatocellular carcinoma through miR-30e targeting P4HA2 mRNA. We provide novel perspective on how HBx induces liver fibrosis.
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Affiliation(s)
- G X Feng
- State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, China
| | - J Li
- State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, China
| | - Z Yang
- State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, China
| | - S Q Zhang
- State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, China
| | - Y X Liu
- State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, China
| | - W Y Zhang
- State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, China
| | - L H Ye
- State Key Laboratory of Medicinal Chemical Biology, Department of Biochemistry, College of Life Sciences, Nankai University, Tianjin, China
| | - X D Zhang
- State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, China
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Zhang SQ, Yang Z, Cai XL, Zhao M, Sun MM, Li J, Feng GX, Feng JY, Ye LH, Niu JQ, Zhang XD. miR-511 promotes the proliferation of human hepatoma cells by targeting the 3'UTR of B cell translocation gene 1 (BTG1) mRNA. Acta Pharmacol Sin 2017; 38:1161-1170. [PMID: 28603285 DOI: 10.1038/aps.2017.62] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Accepted: 02/27/2017] [Indexed: 12/17/2022]
Abstract
Aberrant expression of miR-511 is involved in the development of cancer, but the role of miR-511 in hepatocellular carcinoma (HCC) is not well documented. In this study, we explored the molecular mechanisms of miR-511 in hepatocarcinogenesis. Our results of bioinformatics analysis suggested that B cell translocation gene 1 (BTG1), a member of anti-proliferative gene family, was one of the putative targets of miR-511. The expression levels of miR-511 were significantly higher in 30 clinical HCC tissues than in corresponding peritumor tissues, and were negatively correlated with those of BTG1 in the HCC tissues (r=-0.6105, P<0.01). In human hepatoma cell lines HepG2 and H7402, overexpression of miR-511 dose-dependently inhibited the expression of BTG1, whereas knockdown of miR-511 dose-dependently increased the expression of BTG1. Luciferase reporter gene assays verified that miR-511 targeted the 3'UTR of BTG1 mRNA. In the hepatoma cells, overexpression of miR-511 significantly decreased BTG1-induced G1 phase arrest, which was rescued by overexpression of BTG1. Furthermore, overexpression of miR-511 promoted the proliferation of the hepatoma cells, which was rescued by overexpression of BTG1. Conversely, knockdown of miR-511 inhibited cell proliferation, which was reversed by knockdown of BTG1. In conclusion, miR-511 promotes the proliferation of human hepatoma cells in vitro by targeting the 3'UTR of BTG1 mRNA.
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42
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Hasegawa T, Adachi R, Iwakata H, Takeno T, Sato K, Sakamaki T. ErbB2 signaling epigenetically suppresses microRNA-205 transcription via Ras/Raf/MEK/ERK pathway in breast cancer. FEBS Open Bio 2017; 7:1154-1165. [PMID: 28781955 PMCID: PMC5537069 DOI: 10.1002/2211-5463.12256] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Revised: 05/05/2017] [Accepted: 05/25/2017] [Indexed: 01/28/2023] Open
Abstract
We previously reported that microRNA-205 (miR-205) is downregulated by overexpression of the receptor tyrosine kinase ErbB2 and that ectopic transfection of miR-205 precursor decreases ErbB2 tumorigenicity in soft agar. In this study, we further analyzed the regulatory mechanisms linking ErbB2 overexpression and miR-205 downregulation. In ErbB2-overexpressing breast epithelial cells, miR-205 expression was significantly increased by treatment with MEK inhibitor U0126 or PD98059, Raf-1 inhibitor ZM-336372, and ERK inhibitor SCH772984, but PI3K inhibitor LY294002 and p38 MAPK inhibitor SB203580 had no effect. We established breast epithelial cells overexpressing RafCAAX, a constitutively active form of Raf-1, and showed that overexpression of RafCAAX dramatically reduced miR-205 expression. In RafCAAX-overexpressing cells, miR-205 expression was also significantly increased by SCH772984. Moreover, miR-205 expression was significantly increased by treatment with DNA methyltransferase (DNMT) inhibitor 5-aza-2'-deoxycytidine and expression of several DNMT family members was increased in both ErbB2- and RafCAAX-overexpressing cells. DNA methylation analysis by bisulfite sequencing revealed that the putative miR-205 promoters were predominantly hypermethylated in both ErbB2- and RafCAAX-overexpressing cells. Reporter activity of the putative miR-205 promoters was reduced in both ErbB2-overexpressing and RafCAAX-overexpressing cells. Together, these findings indicate that ErbB2 signaling epigenetically suppresses miR-205 transcription via the Ras/Raf/MEK/ERK pathway.
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Affiliation(s)
- Takuya Hasegawa
- Department of Public Health Faculty of Pharmaceutical Sciences Niigata University of Pharmacy and Applied Life Sciences Japan
| | - Ryohei Adachi
- Department of Public Health Faculty of Pharmaceutical Sciences Niigata University of Pharmacy and Applied Life Sciences Japan
| | - Hitoshi Iwakata
- Department of Public Health Faculty of Pharmaceutical Sciences Niigata University of Pharmacy and Applied Life Sciences Japan
| | - Takayoshi Takeno
- Department of Public Health Faculty of Pharmaceutical Sciences Niigata University of Pharmacy and Applied Life Sciences Japan
| | - Koji Sato
- Department of Public Health Faculty of Pharmaceutical Sciences Niigata University of Pharmacy and Applied Life Sciences Japan
| | - Toshiyuki Sakamaki
- Department of Public Health Faculty of Pharmaceutical Sciences Niigata University of Pharmacy and Applied Life Sciences Japan
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43
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Wang Z, Wu Z, Huang P. The function of miRNAs in hepatocarcinogenesis induced by hepatitis B virus X protein. Oncol Rep 2017. [DOI: 10.3892/or.2017.5716] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
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44
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Deng W, Zhang X, Ma Z, Lin Y, Lu M. MicroRNA-125b-5p mediates post-transcriptional regulation of hepatitis B virus replication via the LIN28B/let-7 axis. RNA Biol 2017; 14:1389-1398. [PMID: 28267418 DOI: 10.1080/15476286.2017.1293770] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023] Open
Abstract
MicroRNAs (miRNAs) are able to modulate hepatitis B virus (HBV) replication and play an important role in the pathogenesis of HBV infection. Recently, we have identified that serum miR-125b-5p levels correlated with HBV DNA levels and liver necroinflammation. In the present study, we addressed how miR-125b-5p regulated HBV replication at the different steps, inclduing viral transcription, assembly, and virion production and investigated the underlying mechanisms. We found that miR-125b-5p overexpression increased HBV replication without altering HBV transcription. This is the first demonstration of post-transcriptional miRNA regulation of HBV replication. In contrast, transfection of miR-125b-5p inhibitor resulted in downregulation of HBV replication in hepatoma cells. Further, miR-125b-5p inhibited the phosphorylation of retinoblastoma protein and blocked cell cycle progression at the G1/S phase in hepatoma cell lines. Our results indicate that certain miRNAs are able to arrest the cell cycle at G1 phase and may increase HBV replication. RNA sequencing revealed several liver-specific metabolic pathways regulated by miR-125b-5p, which was also found to suppress LIN28B and induce let-7 family members. Additional data demonstrated that miR-125b-5p targeted the LIN28B/let-7 axis to stimulate HBV replication at a post-transcriptional step.
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Affiliation(s)
- Wanyu Deng
- a Institute of Virology, University Hospital Essen, University of Duisburg-Essen , Essen , Germany.,b College of Life Science, Shangrao Normal University , Shangrao , China
| | - Xiaoyong Zhang
- a Institute of Virology, University Hospital Essen, University of Duisburg-Essen , Essen , Germany
| | - Zhiyong Ma
- a Institute of Virology, University Hospital Essen, University of Duisburg-Essen , Essen , Germany
| | - Yong Lin
- a Institute of Virology, University Hospital Essen, University of Duisburg-Essen , Essen , Germany
| | - Mengji Lu
- a Institute of Virology, University Hospital Essen, University of Duisburg-Essen , Essen , Germany
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45
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Zhang B, Han S, Feng B, Chu X, Chen L, Wang R. Hepatitis B virus X protein-mediated non-coding RNA aberrations in the development of human hepatocellular carcinoma. Exp Mol Med 2017; 49:e293. [PMID: 28186085 PMCID: PMC5336563 DOI: 10.1038/emm.2016.177] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2016] [Revised: 11/03/2016] [Accepted: 11/14/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) has an important role in the development of human hepatocellular carcinoma (HCC). Accumulated evidence has shown that HBV-encoded X protein (HBx) can induce both genetic alterations in tumor suppressor genes and oncogenes, as well as epigenetic aberrations in HCC pathogens. Non-coding RNAs (ncRNAs) mainly include microRNAs and long non-coding RNAs (lncRNAs). Although ncRNAs cannot code proteins, growing evidence has shown that they have various important biological functions in cell proliferation, cell cycle control, anti-apoptosis, epithelial–mesenchymal transition, tumor invasion and metastasis. This review summarizes the current knowledge regarding the mechanisms and emerging roles of ncRNAs in the pathogenesis of HBV-related HCC. Accumulated data have shown that ncRNAs regulated by HBx have a crucial role in HBV-associated hepatocarcinogenesis. The findings of these studies will contribute to more clinical applications of HBV-related ncRNAs as potential diagnostic markers or as molecular therapeutic targets to prevent and treat HBV-related HCC.
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Affiliation(s)
- Bei Zhang
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Siqi Han
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Bing Feng
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xiaoyuan Chu
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Longbang Chen
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Rui Wang
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
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46
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Zhang S, Gao S, Zhao M, Liu Y, Bu Y, Jiang Q, Zhao Q, Ye L, Zhang X. Anti-HBV drugs suppress the growth of HBV-related hepatoma cells via down-regulation of hepatitis B virus X protein. Cancer Lett 2017; 392:94-104. [PMID: 28192212 DOI: 10.1016/j.canlet.2017.02.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Revised: 01/13/2017] [Accepted: 02/02/2017] [Indexed: 02/07/2023]
Abstract
Chronic infection of hepatitis B virus (HBV) is closely associated with the development of hepatocellular carcinoma (HCC). Meta-analyses show that adjuvant anti-HBV therapy is effective for HBV-related HCC patients in clinical. However, the significance that anti-HBV drugs depress HCC is poorly understood. Here, we investigated the effects of telbivudine (LdT), entecavir (ETV) and interferon-α2b (IFN-α2b) on HBV-related HCC. Our data showed that the treatment with the drugs significantly suppressed the growth of HBV-expressing hepatoma cells in vitro and in vivo, but failed to work in HBV-free liver cells. We present the hypothesis that HBx may be involved in the event. As expected, we observed that the expression of HBx was down-regulated by the agents. Meanwhile, the expression of HBx downstream factors was significantly down-regulated. Interestingly, LdT, ETV and IFN-α2b lost the anti-proliferation effects on HBV-related hepatoma cells when the cells were treated with HBx siRNA. Moreover, combination of those drugs enhanced the anti-proliferation effects. In conclusion, LdT, ETV and IFN-α2b suppress the growth of HBV-related HCC through down-regulation of HBx. Our finding provides new insights into the mechanisms of anti-HBV drugs in HCC therapy.
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Affiliation(s)
- Shuqin Zhang
- State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Shan Gao
- State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Man Zhao
- State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Yunxia Liu
- State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Yanan Bu
- State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Qiulei Jiang
- State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Qiang Zhao
- State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Lihong Ye
- State Key Laboratory of Medicinal Chemical Biology, Department of Biochemistry, College of Life Sciences, Nankai University, Tianjin, 300071, China.
| | - Xiaodong Zhang
- State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, 300071, China.
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Abstract
MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression mainly at the posttranscriptional level. Similar to protein-coding genes, their expression is also controlled by genetic and epigenetic mechanisms. Disruption of these control processes leads to abnormal expression of miRNAs in cancer. In this chapter, we discuss the supportive links between miRNAs and epigenetics in the context of carcinogenesis. miRNAs can be epigenetically regulated by DNA methylation and/or specific histone modifications. However, they can themselves (epi-miRNAs) repress key enzymes that drive epigenetic remodeling and also bind to complementary sequences in gene promoters, recruiting specific protein complexes that modulate chromatin structure and gene expression. All these issues affect the transcriptional landscape of cells. Most important, in the cancer clinical scenario, knowledge about miRNAs epigenetic dysregulation can not only be beneficial as a prognostic biomarker, but can also help in the design of new therapeutic approaches.
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Affiliation(s)
- Catia Moutinho
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain
| | - Manel Esteller
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain; School of Medicine and Health Sciences, University of Barcelona (UB), Catalonia, Spain.
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48
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Wu A, Chen H, Xu C, Zhou J, Chen S, Shi Y, Xu J, Gan J, Zhang J. miR-203a is involved in HBx-induced inflammation by targeting Rap1a. Exp Cell Res 2016; 349:191-197. [PMID: 27780730 DOI: 10.1016/j.yexcr.2016.10.016] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2016] [Revised: 10/18/2016] [Accepted: 10/20/2016] [Indexed: 12/14/2022]
Abstract
Hepatitis B virus (HBV) causes acute and chronic hepatitis, and is one of the major causes of cirrhosis and hepatocellular carcinoma. Accumulating evidence suggests that inflammation is the key factor for liver cirrhosis and hepatocellular carcinoma. MicroRNAs play important roles in many biological processes. Here, we aim to explore the function of microRNAs in the HBX-induced inflammation. First, microarray experiment showed that HBV+ liver samples expressed higher level of miR-203a compared to HBV- liver samples. To verify these alterations, HBx-coding plasmid was transfected into HepG2 cells to overexpress HBx protein. The real-time PCR results suggested that over-expression of HBx could induce up-regulation of miR-203a. To define how up-regulation of miR-203a can induce liver cells inflammation, we over-expressed miR-203a in HepG2 cells. Annexin V staining and BrdU staining suggested that overexpression of miR-203a significantly increased the cell apoptosis and proliferation, meanwhile, over-expression of miR-203a could lead to a decrease in G0/G1 phase cells and an increase in G2/M phase cells. Some cytokines production including IL-6 and IL-8 were significantly increased, but TGFβ and IFNγ were decreased in miR-203a over-expressed HepG2 cells. Luciferase reporter assay experiments, protein mass-spectrum assay and real-time PCR all together demonstrated that Rap1a was the target gene of miR-203a. Further experiments showed that these alterations were modulated through PI3K/ERK/p38/NFκB pathways. These data suggested that HBV-infection could up-regulate the expression of miR-203a, thus down regulated the expression of Rap1a and affected the PI3K/ERK/p38/NFκB pathways, finally induced the hepatitis inflammation.
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Affiliation(s)
- AiRong Wu
- Department of gastroenterology, The First affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Huo Chen
- Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China
| | - ChunFang Xu
- Department of gastroenterology, The First affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Ji Zhou
- Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China
| | - Si Chen
- Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China
| | - YuQi Shi
- Department of gastroenterology, The First affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Jie Xu
- Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China
| | - JianHe Gan
- Department of gastroenterology, The First affiliated Hospital of Soochow University, Suzhou 215006, China.
| | - JinPing Zhang
- Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China.
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49
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Zhu M, Lu Y, Li W, Guo J, Dong X, Lin B, Chen Y, Xie X, Li M. Hepatitis B Virus X Protein Driven Alpha Fetoprotein Expression to Promote Malignant Behaviors of Normal Liver Cells and Hepatoma Cells. J Cancer 2016; 7:935-946. [PMID: 27313784 PMCID: PMC4910586 DOI: 10.7150/jca.13628] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Accepted: 03/15/2016] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND The infection of Hepatitis B virus (HBV) is closely associated with the development of hepatocellular carcinoma(HCC), HBV-X protein(HBx) is able to induce expression of alpha-fetoprotein(AFP) in normal liver cells, and AFP harbors a function to promote malignant transformation of normal liver cells, but the role AFP playing in malignant behaviors of HCC cells is still unclear. METHODS Fifty-six liver tissue samples were collected from the clinical patients through hepatectomy(include normal liver tissues, HBV-related hepatitis liver tissues and HBV-related HCC tissues), and diagnosis of these tissues by pathology section, expression of AFP, Ras and CXCR4 were evidenced by immunohisochemical staining and Western blotting; The proliferation of human normal liver cells line L-02 cells and human hepatoma cells line, HLE cells(non AFP-producing) were performed by MTT method; Repaired capacity of L-02 and HLE cells were compared by wound healing assay; Migration and invasion of these cells were analyzed by Transwell chamber assay; HBx expressed vectors(pcDNA3.1-HBx) were constructed and transfected into L-02 and HLE cells, effects of pcDNA3.1-HBx on the malignant behaviors were also detected by MTT, Transwell chamber assay and the expression of AFP, Ras and CXCR4 were evidenced by Western blotting. RESULTS we found that expression of AFP, Ras and CXCR4 in HBV-related HCC and lymph nodes metastasis tissues were significantly elevated compared with HBV-related HCC, non metastasis tissues and HBV-related hepatitis tissues; Expression of AFP, Ras and CXCR4 in HBV-related hepatitis tissues were significantly enhanced compared with normal liver tissues; The growth ratio, migratory and invasive ability, expression of AFP, Ras and CXCR4 of the cells were outstanding promoted while L-02 and HLE cells were transfected with pcDNA3.1-HBx vectors. The proliferation ratio, migration and invasion ability, and expression of Ras and CXCR4 were significantly inhibited while L-02-X and HLE-X cells(stably transfected with pcDNA3.1-HBx) were silenced AFP expression by AFP-siRNA. CONCLUSIONS HBx through stimulating expression of AFP to promote malignant behaviors of human normal liver cells and HCC cells; AFP maybe used as a novel biotarget for therapeutics of HCC patients.
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Affiliation(s)
- Mingyue Zhu
- 1. Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, Hainan Province, PR. China
- 2. Key Laboratory of Molecular Biology, Hainan Medical College, Haikou 571199, PR. China
| | - Yan Lu
- 1. Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, Hainan Province, PR. China
- 2. Key Laboratory of Molecular Biology, Hainan Medical College, Haikou 571199, PR. China
| | - Wei Li
- 1. Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, Hainan Province, PR. China
- 2. Key Laboratory of Molecular Biology, Hainan Medical College, Haikou 571199, PR. China
| | - Junli Guo
- 1. Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, Hainan Province, PR. China
- 2. Key Laboratory of Molecular Biology, Hainan Medical College, Haikou 571199, PR. China
| | - Xu Dong
- 1. Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, Hainan Province, PR. China
- 2. Key Laboratory of Molecular Biology, Hainan Medical College, Haikou 571199, PR. China
| | - Bo Lin
- 1. Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, Hainan Province, PR. China
- 2. Key Laboratory of Molecular Biology, Hainan Medical College, Haikou 571199, PR. China
| | - Yi Chen
- 1. Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, Hainan Province, PR. China
- 2. Key Laboratory of Molecular Biology, Hainan Medical College, Haikou 571199, PR. China
| | - Xieju Xie
- 1. Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, Hainan Province, PR. China
- 3. Department of Pathophysiology, Hainan Medical College, Haikou 571199, Hainan Province, PR. China
| | - Mengsen Li
- 1. Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, Hainan Province, PR. China
- 2. Key Laboratory of Molecular Biology, Hainan Medical College, Haikou 571199, PR. China
- 4. Institution of Tumor, Hainan Medical College, Haikou 570102, Hainan Province, PR. China
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Louten J, Beach M, Palermino K, Weeks M, Holenstein G. MicroRNAs Expressed during Viral Infection: Biomarker Potential and Therapeutic Considerations. Biomark Insights 2016; 10:25-52. [PMID: 26819546 PMCID: PMC4718089 DOI: 10.4137/bmi.s29512] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2015] [Revised: 10/22/2015] [Accepted: 10/24/2015] [Indexed: 12/13/2022] Open
Abstract
MicroRNAs (miRNAs) are short sequences of noncoding single-stranded RNAs that exhibit inhibitory effects on complementary target mRNAs. Recently, it has been discovered that certain viruses express their own miRNAs, while other viruses activate the transcription of cellular miRNAs for their own benefit. This review summarizes the viral and/or cellular miRNAs that are transcribed during infection, with a focus on the biomarker and therapeutic potential of miRNAs (or their antagomirs). Several human viruses of clinical importance are discussed, namely, herpesviruses, polyomaviruses, hepatitis B virus, hepatitis C virus, human papillomavirus, and human immunodeficiency virus.
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Affiliation(s)
- Jennifer Louten
- Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, GA, USA
| | - Michael Beach
- Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, GA, USA
| | - Kristina Palermino
- Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, GA, USA
| | - Maria Weeks
- Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, GA, USA
| | - Gabrielle Holenstein
- Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, GA, USA
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