Modification of Cell Growth Regulation by Hepatitis C virus

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Hepatitis C virus (HCV) infects persistently and causes chronic hepatitis, liver cirrhosis and hepatocellular carcinoma (HCC). To address the effect of persistent infection, the conditional expression system of full-genome HCV in human liver cells was established. Following HCV expression, DNA synthesis of cells was suppressed, cell growth was mainly retarded at G0/G1 phase through apoptosis independent pathway. However, after 48 days passage, cell growth has been recovered to be initial level. In order to clarify the target of HCV, we examined the expression level of growth regulators. The cell growth modification by HCV correlated to the extent of p21WAF1/CIP1 expression and hyperphosphorylation of Rb was induced after 48 days passage. This modification of p21WAF1/CIP1 by HCV was caused at transcriptional level in the p53 independent manner. Thus, HCV could modify the cell cycle checkpoint to accelerate the tomurigenicity of hepatocyte through p21WA1/CIP1.The effect of HCV in vivo was also characterized with HCV-transgenic mice model. Expression of HCV made hepatocytes more resistant to Fas-mediated apoptosis. By using in vitro and in vivo HCV expression model, we further characterized the molecular mechanism of pathogenesis of HCV.