Functional abnormality in the mitochondria and pathogenesis of chronic hepatitis C: relation to hepatocellular carcinoma

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Overwhelming lines of epidemiological evidence have indicated that chronic infection with hepatitis C virus (HCV) poses a major risk toward development of HCC. In the pathogenesis of HCC associated with HCV, it remains controversial whether the virus plays a direct role or merely serves for an indirect role. The studies using transgenic mouse models by us and others, in which the core protein of HCV has an oncogenic potential, indicate that HCV is directly involved in hepatocarcinogenesis, albeit other factors such as continued cell death and regeneration associated with inflammation may play a role, as well.The downstream events of the core protein are segregated into two components. One is the augmented production of reactive oxygen species (ROS) along with the activation of scavenging system including catalase and GSH in the putative preneoplastic stage with steatosis in the liver. Thus, ROS production in the absence of inflammation by the core protein may partly contribute to the d … More evelopment of HCC. The generation of ROS is estimated to originate from mitochondrial dysfunction in hepatocytes by HCV infection. The other is the alteration of intracellular signaling cascade of MAPK (JNK), AP-1, cyclin D1 and CDK4. These events, combined with alterations in lipid and glucose metabolism, would lead to the development of hepatocellular carcinoma (HCC) in persistent HCV infection.Our results suggest that there would be a mechanism for hepatocarcinogenesis in persistent HCV infection that is distinct from those for the other cancers. Similar to the pathogenesis of other malignancies represented by colorectal cancer, the accumulation of a set of genetic aberrations may also be necessary for a multi-stage development of HCC. However, HCV core protein, to which an oncogenic potential is ascribed, may allow some of the multiple stages skipped in hepatocarcinogenesis. Unlike for the other cancers, therefore, infection with HCV may be capable of inducing HCC in the absence of a complete set of genetic aberrations. Such a scenario would explain an unusually high incidence and multicentric nature of HCC developing in chronic hepatitis C. Less