Hepatitis B virus HBx gene and hepatocarcinogenesis.

The association between hepatitis B virus (HBV) and hepatocellular carcinoma (HCC) has been known over the past 20 years. We have shown that the HBx gene of HBV induces HCC in transgenic mice and that HBx protein may be involved in hepatocarcinogenesis in human chronic HBV infection. To further characterize the role of the HBx gene in carcinogenesis, we analyzed the preneoplastic liver in HBx transgenic mice. From the age of 2 months, there appeared preneoplastic liver foci, which consisted of hepatocytes with cytoplasmic vacuolations, but they did not increase in size until the age of 12 months. Hepatocytes in these foci which showed higher levels of HBx protein in the cytoplasm than those in the surrounding tissues demonstrated increased DNA synthesis in their nuclei. We then established mouse fibroblast cell lines in which the expression of the HBx gene is under the control of a hormone-regulated promoter. Upon induction of the HBx gene, resting cells began to enter the S-phase of the cell cycle. These results indicate that the HBx gene has mitogenic activity both in vivo and in vitro and suggest that the HBx gene may contribute to hepatocarcinogenesis by driving cells into deregulated cell cycle control. We propose a mechanism for hepatocarcinogenesis in which continuous stimulation for cell cycle progression in vivo may lead to the development of HCC by placing hepatocytes in a subthreshold state for transformation.