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Journal of Virology, April 2001, p. 3851-3858, Vol. 75, No. 8
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.8.3851-3858.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Hepatitis B Virus X Protein Acts as a Tumor Promoter in Development of Diethylnitrosamine-Induced Preneoplastic Lesions

Charles R. Madden,1 Milton J. Finegold,2 and Betty L. Slagle1,*

Department of Molecular Virology and Microbiology1 and Department of Pathology,2 Baylor College of Medicine, Houston, Texas 77030

Received 16 November 2000/Accepted 19 January 2001

Chronic infection with hepatitis B virus (HBV) is one of the major etiological factors in the development of human hepatocellular carcinoma. Transgenic mice that express the HBV X protein (HBx) have previously been shown to be more sensitive to the effects of hepatocarcinogens. Although the mechanism for this cofactor role remains unknown, the ability of HBx to inhibit DNA repair and to influence cell cycle progression suggests two possible pathways. To investigate these possibilities in vivo, we treated double-transgenic mice that both express HBx (ATX mice) and possess a bacteriophage lambda transgene with the hepatocarcinogen diethylnitrosamine (DEN). Histological examination of liver tissue confirmed that DEN-treated ATX mice developed approximately twice as many focal lesions of basophilic hepatocytes as treated wild-type littermates. Treatment of mice with DEN resulted in a six- to eightfold increase in the mutation frequency (MF), as measured by a functional analysis of the lambda transgene. HBx expression was confirmed by immunoprecipitation and Western blotting and was associated with a modest 23% increase in the MF. Importantly, the extent of hepatocellular proliferation in 14-day-old mice, as measured by the detection of proliferating cell nuclear antigen and by the incorporation of 5-bromo-2'-deoxyuridine, was determined to be approximately twofold higher in ATX livers than in wild-type livers. These results are consistent with a model in which HBx expression contributes to the development of DEN-mediated carcinogenesis by promoting the proliferation of altered hepatocytes rather than by directly interfering with the repair of DNA lesions.

* Corresponding author. Mailing address: Department of Molecular Virology and Microbiology, Mailstop BCM-385, One Baylor Plaza, Baylor College of Medicine, Houston, TX 77030-3411. Phone: (713) 798-3006. Fax: (713) 798-5075. E-mail: bslagle{at}bcm.tmc.edu.

Journal of Virology, April 2001, p. 3851-3858, Vol. 75, No. 8
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.8.3851-3858.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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