Molecular basis for the synergy between alcohol and hepatitis C virus in hepatocarcinogenesis

Overwhelming lines of epidemiological evidence have indicated that persistent infection with hepatitis C virus (HCV) is a major risk for the development of hepatocellular carcinoma (HCC). In addition, heavy alcohol use has been linked with earlier progression to HCC in chronic hepatitis C patients. However, in the pathogenesis of HCV-associated HCC, it still remains controversial as to whether the virus plays a direct or an indirect role, and as to how alcohol operates in the acceleration of HCC development. Several studies using transgenic mouse models, in which the core protein of HCV has an oncogenic potential, indicate that HCV is directly involved in hepatocarcinogenesis, although other factors such as continuous inflammation or environmental factors seem also to play a role. The downstream events of the HCV core protein expression in the transgenic mouse HCC model are segregated into two pathways. One is the augmented production of oxidative stress in the absence of inflammation along with the attenuation of some scavenging systems in the putative preneoplastic stage with steatosis in the liver. The other pathway is the alteration in cellular gene expression and intracellular signaling, including the mitogen-activated protein kinase cascade. The combination of these pathways would explain the unusually high incidence and multicentric nature of HCC development in HCV infection. In addition, alcohol feeding in this animal model further activated the two pathways synergistically with HCV, leading to an earlier development of HCC. Such a synergy would reveal the molecular basis for the acceleration of HCC development by alcohol in HCV infection.