Mechanisms of hepatocarcinogenesis in chronic hepatitis C

Infection with hepatitis C virus (HCV) is a major risk factor for hepatocellular carcinoma. The genetic changes that drive cancer development are heterogeneous and how chronic hepatitis C promotes the initiation of hepatocellular carcinoma is incompletely understood. Cancer typically arises in the setting of advanced fibrosis and/or cirrhosis where chronic immune-mediated inflammation over decades promotes hepatocyte turnover providing selective pressure that favors the malignant phenotype. As well as contributions of unresolved inflammation to carcinogenesis, evidence from transgenic mice with liver-specific expression of viral sequences suggests that some HCV-encoded proteins may directly promote cancer. Numerous in vitro studies suggest roles for HCV proteins in subversion of cellular pathways that normally act to suppress tumorigenesis. Here, we review the mechanisms by which persistent HCV infection might promote cancer in addition to the procarcinogenic effects of inflammatory liver disease.