title: Hepatitis C virus infection stimulates transforming growth factor-β1 expression through up-regulating miR-192.
abstract: The objective of this study was to determine the molecular mechanisms underlying chronic liver injury and fibrosis caused by hepatitis C virus (HCV). This study revealed that miR-192 expreßsion was induced by HCV infection without affecting viral replication. However, viral-induced miR-192 up-regulated transforming growth factor-ß1 (TGF-ß1) expreßsion in liver cells at transcriptional level. TGF-ß1 stimulation by HCV-induced miR-192 was caused through ZEB1 down-regulation and TGF-ß1 increased miR-192 level via positive feedback pathway. Increase in miR-192 expreßsion by HCV infection was due to HCV core protein released and/or expressed by viral infection. TGF-ß1 promoter activity was also increased by HCV core protein in liver cells. Taken together, HCV infection resulted in increased TGF-ß1 transcription in hepatocytes through ZEB1 down-regulation by HCV core-mediated miR-192 stimulation. Importantly, miR-192 inhibition with anti-miR-192 rescued ZEB1 expression down-regulated by HCV infection, thus reducing the level of TGF-ß1 expression increased by HCV infection in hepatocytes. These results suggest a novel mechanism of HCV-mediated liver fibrogenesis with miR-192 being a potential molecular target to ameliorate viral pathogenesis.
authors.affiliation: Department of Molecular Biology, Research Institute of Advanced Omics, Dankook University, Yongin, 16890, Republic of Korea.
authors.forename: Ji Hyun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Molecular Biology, Research Institute of Advanced Omics, Dankook University, Yongin, 16890, Republic of Korea.
authors.forename: Chang Ho
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Department of Molecular Biology, Research Institute of Advanced Omics, Dankook University, Yongin, 16890, Republic of Korea. SWL0208@dankook.ac.kr.
authors.forename: Seong-Wook
authors.initials: SW
authors.lastname: Lee
mesh_terms: D016174:Hepacivirus / Q000235:genetics / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000821:virology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation; D014758:Viral Core Proteins / Q000235:genetics / Q000378:metabolism; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000235:genetics / Q000378:metabolism
chemical_list: C546783:MIRN192 microRNA, human; D035683:MicroRNAs; D053773:Transforming Growth Factor beta1; D014758:Viral Core Proteins; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; C069130:nucleocapsid protein, Hepatitis C virus
keywords: TGF-β1; ZEB1; hepatitis C Virus; liver fibrosis; miR-192