title: Epigenetically regulated miR-449a enhances hepatitis B virus replication by targeting cAMP-responsive element binding protein 5 and modulating hepatocytes phenotype.
abstract: Cellular microRNAs (miRNAs) are able to influence hepatitis B virus (HBV) replication directly by binding to HBV transcripts or indirectly by targeting cellular factors. Here, we investigate the effect of epigenetically regulated miR-449a on HBV replication and the underlying mechanisms. miR-449a expression was lower in human hepatocellular carcinoma (HCC) cells than in primary hepatocytes and could be induced by trichostatin A. Ectopic miR-449a expression in HCC cells strongly enhanced HBV replication, transcription, progeny virions secretion, and antigen expression in a dose-dependent manner. miR-449a directly targeted cAMP-responsive element binding protein 5 (CREB5), which in turn induced the expression of farnesoid X receptor α (FXRα), a transcription factor that facilitates HBV replication. CREB5 knockdown and overexpression demonstrated that it is a negative regulator of HBV replication. Additionally, miR-449a overexpression inhibited proliferation, caused cell cycle arrest, and promoted HCC cell differentiation. The results indicated that epigenetically regulated miR-449a targets CREB5 to increase FXRα expression, thereby promoting HBV replication and gene expression. Our findings provide a new understanding of the role of miRNAs in HBV replication.
authors.affiliation: Institute of Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.|State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Zhanglian
authors.initials: Z
authors.lastname: Xie
authors.affiliation: Institute of Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Wangyu
authors.initials: W
authors.lastname: Deng
authors.affiliation: Institute of Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Chunchen
authors.initials: C
authors.lastname: Wu
authors.affiliation: Institute of Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Bo
authors.initials: B
authors.lastname: Qin
authors.affiliation: State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Jinlin
authors.initials: J
authors.lastname: Hou
authors.affiliation: Institute of Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Mengji
authors.initials: M
authors.lastname: Lu
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology / Q000821:virology; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D051699:Cyclic AMP Response Element-Binding Protein A / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006509:Hepatitis B / Q000235:genetics / Q000821:virology; D006515:Hepatitis B virus / Q000235:genetics* / Q000472:pathogenicity; D022781:Hepatocytes / Q000378:metabolism / Q000821:virology; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology / Q000821:virology; D035683:MicroRNAs / Q000235:genetics*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D014779:Virus Replication / Q000235:genetics*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D051699:Cyclic AMP Response Element-Binding Protein A; D035683:MicroRNAs; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C497102:CREB5 protein, human; C544530:MIRN449 microRNA, human