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Multiple Oncogenes and Tumor Suppressor Genes Are Structurally and Functionally Intact during Hepatocarcinogenesis in Hepatitis B Virus Transgenic Mice¹

Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037

In the current study we sought to elucidate the molecular mechanisms which might contribute to hepatocarcinogenesis in a hepatitis B virus (HBV) envelope transgenic mouse model in which chronic hepatocellular injury and inflammation lead to regenerative hyperplasia and eventually to the development of chromosomal abnormalities and hepatocellular carcinoma (HCC), thereby reiterating many of the pathophysiological events that occur prior to the development of HCC in chronic HBV infection in humans. We have previously demonstrated that HBV envelope gene expression is decreased in regenerating hepatocytes and preneoplastic nodules early in the disease process and that expression of -fetoprotein and the multidrug transporter gene mdr-III is activated in the tumors that develop in this model, but not prior to tumor development. In the current study, we examined the structure and expression of a large panel of dominant acting oncogenes and tumor suppressor genes in the liver at all stages of the disease process in order to determine the extent to which they contribute to hepatocarcinogenesis in these transgenic mice. To our surprise, no changes were observed in the structure or function of any of these genes, many of which are commonly activated in other rodent models of hepatocarcinogenesis but rarely activated in human HCC. These findings suggest that the HBV transgenic mouse model is different from most other rodent models of hepatocarcinogenesis and that it may relate more closely to the events involved in HBV-induced human hepatocarcinogenesis, where generalized chromosomal abnormalities are common, while structural and functional changes in most of the commonly studied positive-acting oncogenes examined herein are not. Since p53 and RB mutations have recently been reported to be late events in human hepatocarcinogenesis, the structural integrity of the RB locus and the absence of p53 mutations in the HBV transgenic mouse model suggest that they may represent a relatively early stage of hepatocellular tumorigenesis and that further manipulation of this model is warranted in order to more fully reproduce the molecular-genetic events that characterize HBV-induced HCC in humans.

¹ Paper 7073-MEM from The Scripps Research Institute. Supported by NIH Grants 5 R37 CA40489 and 1 RO1 CA54560. C. P. was the recipient of NIH-Fogarty Fellowship 1 F05 TWO4287.

² To whom requests for reprints should be addressed, at Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10666 N. Torrey Pines Road, La Jolla, CA 92037.

Received 10/ 8/91. Accepted 3/10/92.

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