The long term objective of this program is to elucidate the pathogenesis of hepatocellular carcinoma (HCC) due to chronic hepatitis B virus (HBV) infection. To approach this objective we have developed two transgenic mouse models of HCC. In the """"""""immune"""""""" model, HCC occurs after several months of chronic hepatitis due to a persistent HBV-specific cytotoxic T lymphocyte response in mice that produce nontoxic amounts of the large (L-HBs), middle (M-HBs) and small (S-HBs) HBV envelope proteins. In the """"""""storage"""""""" model, HCC occurs after several months of chronic hepatitis caused by the overproduction of nonsecretable subviral L-HBs filaments that accumulate in the endoplasmic reticulum and lyse the hepatocyte, triggering a necroinflammatory liver disease that stimulates hepatocellular proliferation, macrophage activation and inflammation, oxidative DNA damage, aneuploidy, preneoplastic foci and the development of HCC. Recently we have discovered that, in addition to causing hepatitis, progressive L-HBs retention inhibits hepatocellular apoptosis in theses animals. These provocative observations suggest that L-HBs retention may contribute to the development of HCC not only by causing the necroinflammatory regenerative liver disease that creates the genotoxic milieu in which transforming mutations can occur, but also by inhibiting apoptosis and preventing the elimination of transformed hepatocytes. The major thrust of this application is to determine whether L-HBs regulates apoptosis directly or indirectly in the """"""""storage"""""""" model of HCC and, if so, how. In the course of these studies, we will identify the apoptosis related cellular pathways and proteins that L-HBs intersects in this model and to determine whether L-HBs retention and decreased apoptosis are required for cancer to occur in the """"""""immune"""""""" models of HCC. Additionally, since S-HBs coexpression inhibits L-HBs-induced HCC in the """"""""storage"""""""" model we will determine if S-HBs prevents HCC by unloading L-HBs from the cell or if it is a tumor suppressor protein that can prevent the development of HCC in other models as well. These studies will provide insight into the pathogenesis of HBV-induced hepatocellular carcinoma, a disease that kills more than 1 million people worldwide each year.
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