title: Hepatitis B virus core protein inhibits Fas-mediated apoptosis of hepatoma cells via regulation of mFas/FasL and sFas expression.
abstract: Hepatitis B virus core protein (HBc) has been implicated in hepatocarcinogenesis through several mechanisms. Resistance of hepatitis B virus (HBV)-infected hepatocytes to apoptosis is considered one of the major contributors to the progression of chronic hepatitis to cirrhosis and ultimately to hepatocellular carcinoma. The Fas receptor/ligand (Fas/FasL) system plays a prominent role in hepatocyte death during HBV infection. Here we report that HBc mediates resistance of hepatoma cells to agonistic anti-Fas antibody (CH11)-induced apoptosis. When HBc was introduced into human hepatoma cells, the cells became resistant to CH11 cytotoxicity in a p53-dependent manner. HBc significantly down-regulated the expression of p53, total Fas, and membrane-bound Fas at the mRNA and protein levels and reduced FasL mRNA expression. In contrast, HBc up-regulated the expression of soluble forms of Fas by increasing Fas alternative mRNA splicing. Mechanistically, HBc-mediated Fas alternative mRNA splicing was associated with up-regulation of polypyrimidine tract-binding protein 1 and down-regulation of Fas-activated serine/threonine kinase. These results indicated that HBc may prevent hepatocytes from Fas-induced apoptosis by the dual effects of reducing the expression of the proapoptotic form of Fas and enhancing the expression of the antiapoptotic form of the receptor, which may contribute to the survival and persistence of infected hepatocytes during chronic infection.
authors.affiliation: *Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Minhou, China; and Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Minhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: *Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Minhou, China; and Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Minhou, China.
authors.forename: Yan-Ting
authors.initials: YT
authors.lastname: Lin
authors.affiliation: *Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Minhou, China; and Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Minhou, China.
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Yan
authors.affiliation: *Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Minhou, China; and Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Minhou, China.
authors.forename: Ya-Lan
authors.initials: YL
authors.lastname: Ding
authors.affiliation: *Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Minhou, China; and Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Minhou, China.
authors.forename: Yun-Li
authors.initials: YL
authors.lastname: Wu
authors.affiliation: *Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Minhou, China; and Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Minhou, China.
authors.forename: Wan-Nan
authors.initials: WN
authors.lastname: Chen
authors.affiliation: *Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Minhou, China; and Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Minhou, China linxu@mail.fjmu.edu.cn.
authors.forename: Xu
authors.initials: X
authors.lastname: Lin
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D006509:Hepatitis B / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D006512:Hepatitis B Core Antigens / Q000235:genetics / Q000378:metabolism*; D006515:Hepatitis B virus / Q000502:physiology; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*
chemical_list: C491901:FAS protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D006512:Hepatitis B Core Antigens; D012333:RNA, Messenger; D019014:fas Receptor
keywords: FASTK; PTBP1; chronic HBV infection; p53