Viral hepatitis and liver cancer: the case of hepatitis C.
Chronic infection with the hepatitis C virus (HCV) is a major risk factor for the development of hepatocellular carcinoma (HCC) worldwide. The pathogenesis of HCC in HCV infection has extensively been analysed. Hepatitis C virus-induced chronic inflammation and the effects of cytokines in the development of fibrosis and liver cell proliferation are considered as one of the major pathogenic mechanisms. Increasing experimental evidence suggests that HCV contributes to HCC by directly modulating pathways that promote the malignant transformation of hepatocytes. Hepatitis C virus is an RNA virus that does not integrate into the host genome but HCV proteins interact with many host-cell factors well beyond their roles in the viral life cycle and are involved in a wide range of activities, including cell signaling, transcription, cell proliferation, apoptosis, membrane rearrangements, vesicular trafficking and translational regulation. At least four of the HCV gene products, namely HCV core, NS3, NS4B and NS5A, have been shown to exhibit transformation potential in tissue culture and several potentially oncogenic pathways have been shown to be altered by the expression of HCV proteins. Both HCV core and NS5A induce the accumulation of wild-type beta-catenin and the Wnt-beta-catenin pathway emerges as a common target for HCV (and HBV) in human HCCs, also independently from axin/beta-catenin gene mutations. Induction of both endoplasmic reticulum stress and oxidative stress by HCV proteins might also contribute to HCV transformation. Most of the putative transforming functions of the HCV proteins have been defined in artificial cellular systems, which may not be applicable to HCV infection in vivo, and still need to be established in relevant infection and disease models.
Levrero
M
M
Department of Internal Medicine, University of Rome La Sapienza, Rome, Italy. Massimo.levrero@uniroma1.it
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000821:virology*; D004195:Disease Models, Animal; D016174:Hepacivirus / Q000235:genetics / Q000472:pathogenicity*; D019698:Hepatitis C, Chronic / Q000175:diagnosis / Q000473:pathology / Q000821:virology*; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology / Q000821:virology*