Clarification of molecular mechanisims of hepatocellular carcinoma caused by hepatitis virus infection.

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(l) HBV X protein has versatile functions. One of such the functions is to modulate cellular transcriptional machinary. It was shown that X protein associates with one of RNA polymerase binding protein and that X protein also competes with other cellular protein to interact with transcriptional machinary.(2) HBV X protein associates with mitochondrial membrane and disrupt the function of it. This disruption induces apoptosis. (3) HCV encode several proteins, some of which are shown to modulate cell proliferation. Among them we found that HCV core protein has anti-apoptotic function to cells induced by anti-Fas antibody or TNFa.(4) HCV protein also functions to activate Raf/Ras signaling by yet unclarified mechanism.(5) Trangenic mice expressing the entire HCV proteins was analyzed for their activation of CTL to clarify the mechanism of persistence of survival of HCV protein expressing hepatocytes. It was shown from this analysis that the level of MHC class II molecule on cell surface of dendritic cells was reduced although the production of the protein was not altered. Thus, it is suggested that activation of CTL by the antigen presenting cells is down regulated in this mouse and this may be one mechanism that the CTL activity in patients with chronic hepatitis is low.(6) Cancerous tissues of hepatocyte often have anti-apoptotic activity. To clarify the mechanism underling this phenomenon, phosphorylation of BAD, a regulator of apoptosis, was examined. Phosphorylation of BAD was enhanced in the cancerous portion, suggesting that BAD play a role in anti-apoptotic function of hepatoma cells.