Molecular basis of hepatitis C virus-associated hepatocarcinogenesis: lessons from animal model studies.
Despite numerous lines of epidemiologic evidence connecting HCV infection and the development of hepatocellular carcinoma (HCC), it remains controversial whether HCV itself plays a direct role or an indirect role in the pathogenesis of HCC. Through the use of transgenic mice, it has become evident that the core protein of HCV has oncogenic potential. HCV is directly involved in hepatocarcinogenesis, albeit other factors such as inflammation and environmental factors might also play a role. The direct involvement of HCV in hepatocarcinogenesis would be achieved via 2 pathways. In one pathway, the core protein acts on the function of mitochondria, leading to the overproduction of oxidative stress, which yields genetic aberrations in cell growth-related genes. The other pathway involves the modulation of cellular gene expressions and intracellular signal transductions, such as mitogen-activated protein kinase pathway, which results in the activation of transcription factors and cell cycle machineries. The combination of these alterations would be hypothesized to provoke the development of HCC in HCV infection. This would be a mechanism for HCC development in HCV infection that is distinct from those for other cancers. The presence of the HCV core protein, to which an oncogenic potential is ascribed, might allow some of the multiple steps to be bypassed in hepatocarcinogenesis. Therefore, unlike in other cancers, HCV infection can elicit HCC in the absence of a complete set of genetic aberrations. Such a scenario, "non-Vogelstein type" carcinogenesis, may explain the unusually high incidence and multicentric nature of HCC development in HCV infection.
Koike
Kazuhiko
K
Department of Infectious Diseases, Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. kkoike-tky@umin.ac.jp
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000473:pathology; D002471:Cell Transformation, Neoplastic; D002472:Cell Transformation, Viral; D004195:Disease Models, Animal; D016174:Hepacivirus / Q000235:genetics / Q000472:pathogenicity; D006526:Hepatitis C / Q000150:complications* / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology* / Q000473:pathology; D018384:Oxidative Stress; D012367:RNA, Viral / Q000235:genetics
D012367:RNA, Viral