Hepatitis C virus infection stimulates transforming growth factor-β1 expression through up-regulating miR-192

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 expression was induced by HCV infection without affecting viral replication. However, viral-induced miR-192 up-regulated transforming growth factor-beta 1 (TGF-beta 1) expression in liver cells at transcriptional level. TGF-beta 1 stimulation by HCV-induced miR-192 was caused through ZEB1 down-regulation and TGF-beta 1 increased miR-192 level via positive feedback pathway. Increase in miR-192 expression by HCV infection was due to HCV core protein released and/or expressed by viral infection. TGF-beta 1 promoter activity was also increased by HCV core protein in liver cells. Taken together, HCV infection resulted in increased TGF-beta 1 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-beta 1 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.