title: MiR-942 mediates hepatitis C virus-induced apoptosis via regulation of ISG12a.
abstract: The interaction between hepatitis C virus (HCV) and human hepatic innate antiviral responses is unclear. The aim of this study was to examine how human hepatocytes respond to HCV infection. An infectious HCV isolate, JFH1, was used to infect a newly established human hepatoma cell line HLCZ01. Viral RNA or NS5A protein was examined by real-time PCR or immunofluorescence respectively. The mechanisms of HCV-induced IFN-β and apoptosis were explored. Our data showed that HLCZ01 cells supported the entire HCV lifecycle and IFN-β and interferon-stimulated genes (ISGs) were induced in HCV-infected cells. Viral infection caused apoptosis of HLCZ01 cells. Silencing of RIG-I, IRF3 or TRAIL inhibited ISG12a expression and blocked apoptosis of viral-infected HLCZ01 cells. Knockdown ISG12a blocked apoptosis of viral-infected cells. MiR-942 is a candidate negative regulator of ISG12a predicted by bioinformatics search. Moreover, HCV infection decreased miR-942 expression in HLCZ01 cells and miR-942 was inversely correlated with ISG12a expression in both HCV-infected cells and liver biopsies. MiR-942 forced expression in HLCZ01 cells decreased ISG12a expression and subsequently suppressed apoptosis triggered by HCV infection. Conversely, silencing of miR-942 expression by anti-miR-942 increased ISG12a expression and enhanced apoptosis in HCV-infected cells. Induction of Noxa by HCV infection contributed to ISG12a-mediated apoptosis. All the data indicated that innate host response is intact in HCV-infected hepatocytes. MiR-942 regulates HCV-induced apoptosis of human hepatocytes by targeting ISG12a. Our study provides a novel mechanism by which human hepatocytes respond to HCV infection.
authors.affiliation: Department of Molecular Medicine, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha, China.
authors.forename: Darong
authors.initials: D
authors.lastname: Yang
authors.affiliation: Department of Molecular Medicine, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha, China.
authors.forename: Xianghe
authors.initials: X
authors.lastname: Meng
authors.affiliation: Department of Molecular Medicine, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha, China.
authors.forename: Binbin
authors.initials: B
authors.lastname: Xue
authors.affiliation: Department of Molecular Medicine, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha, China.
authors.forename: Nianli
authors.initials: N
authors.lastname: Liu
authors.affiliation: Department of Molecular Medicine, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha, China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Molecular Medicine, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha, China; Research Center of Cancer Prevention & Treatment, Translational Medicine Research Center of Liver Cancer, Hunan Provincial Tumor Hospital (Affiliated Tumor Hospital of Xiangya Medical School of Central South University), Changsha, China.
authors.forename: Haizhen
authors.initials: H
authors.lastname: Zhu
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016174:Hepacivirus / Q000302:isolation & purification / Q000502:physiology*; D006526:Hepatitis C / Q000235:genetics / Q000473:pathology / Q000821:virology; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology / Q000821:virology; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D016899:Interferon-beta / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011971:Receptors, Immunologic; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology
chemical_list: C406887:IFI27 protein, human; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; C000594372:MIRN942 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D011971:Receptors, Immunologic; D053221:TNF-Related Apoptosis-Inducing Ligand; D016899:Interferon-beta; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases
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