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The long-term goal of our laboratory is to define the role of the HBV in the development of hepatocellular carcinoma (HCC). HBV encodes a single regulatory protein called HBx, and although HBx is required for virus replication, it's critical function is not known. We have developed and characterized HBx transgenic mice (ATX mice) and have demonstrated that HBx functions as a tumor promoter to enhance chemical carcinogenesis and further increase the risk of HCC. The finding that HBx can deregulate the cell cycle in vivo led us to hypothesize that during virus replication, one normal function of HBx is to prepare the G0 hepatocyte to become competent for virus replication. Our present objectives are to explore the effects of HBx on G0 hepatocytes and their transition into the G1 phase of the cell cycle. Other studies with the ATX mice are designed to investigate cooperation with mutant p53 and with hepatitis C virus, both known risk factors that are present in some chronic HBV patients. Results obtained from studies in the mice and from cell culture experiments will be extended to humans using our collection of 47 sets of matched normal and liver tumor tissue (stored at - 80°C).

Recent Publications (PubMed)

Keasler, V. V., Lerat, H., Madden, C .R., Finegold, McGarvey, M.J., Mohammed, E. M. A., Forbes, S. J., Lemon, S. M., Hadsell, D. L., Grona, S. J., Hollinger, F.B., and Slagle, B.L. Increased liver pathology in Hepatitis C Virus Transgenic Mice Expressing the Hepatitis B Virus X Protein. Virology 347:466-475, 2006.

Keasler, V.V., Hodgson, A.J., Madden, C.R., Slagle, B. L. Enhancement of hepatitis B virus replication by the regulatory X protein in vitro and in vivo. J. Virol. 81:2656-2662, 2007.

Becker, S., Lee, T.-H., Butel, J.S., and Slagle, B.L. Hepatitis B virus X protein interferes with cellular DNA repair. J. Virol. 72:266-272, 1998.

Madden, C.R., Finegold, M.J., and Slagle, B.L. Expression of hepatitis B virus X protein does not alter the accumulation of spontaneous mutations in transgenic mice. J. Virol. 74: 5266-5272, 2000.

Wentz, M.J., Becker, S.A., and Slagle, B.L. Dissociation of DDB1-binding activity from transactivation by hepatitis B virus X protein. Virus Res. 68: 87-92, 2000.

Madden, C.R., Finegold, M.J., and Slagle, B.L. Hepatitis B virus X protein acts as a tumor promoter in the development of diethylnitrosamine-induced preneoplastic lesions J. Virol. 75:3851-3858, 2001.

Madden, C.R. , Finegold, M.F. and Slagle, B.L. Altered DNA mutation spectrum in aflatoxin B1-treated transgenic mice that express the hepatitis B virus X protein. J. Virol. 76:11770-11774, 2002.