Studies on the roles of N-myc2 and insulin-like growth factor II (IGF-II) in woodchuck hepatitis virus induced hepatocarcinogenesis
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The chronic woodchuck hepatitis virus (WHV) infection almost invariably induces hepatocellular carcinoma (HCC) in woodchucks, therefore, providing a useful model for the study of hepadnavirus-induced carcinogenesis. We have used multiple approaches to identify the cellular and molecular mechanism associated with WHV-induced hepatocarcinogenesis. Our studies encompassed three areas of investigation: (1) Analysis of gene expression in normal and precancerous livers and hepatocellular carcinomas; (2) Analysis of the effects of Insulin-like growth factor II (IGF-II) in mice using a transgenic mouse model; (3) Cell culture studies on the roles of N-myc2 and IGF-II in hepatocarcinogenesis. The major findings are as follows: (1) N-myc2 and IGF-II are coordinately overexpressed in precancerous altered hepatic foci (AHFs) and also in HCCs, suggesting a selective advantage of coordinate expression of N-myc2 and IGF-II during hepatocarcinogenesis, (2) Transgenic mice overexpressing IGF-II developed a variety of malignancies at a much higher frequency than the control mice. The malignancies did not arise until late in life, suggesting that IGF-II may serve as a tumor promoter "in vivo". Dramatic metabolic effects of IGF-II overexpression were observed in the IGF-II mice, such as hypoglycemia, altered body composition and lower body weight. (3) Overexpression of N-myc2 in woodchuck liver epithelial cells (WC-3 cells) induced cell death when the cells were deprived of serum. This effect could be blocked by addition of 100 nM recombinant human IGF-II to the cell culture medium. Furthermore, all the N-myc2 expressing lines showed a partially transformed phenotype, as judged by (1) the increased growth rate, (2) the increased saturation density, (3) the loss of contact inhibition, and (4) the increased nuclear/cytoplasmic ratio.;In summary, this study demonstrates that coordinate expression of N-myc2 and IGF-II in the woodchuck AHFs is an early event in WHV-induced hepatocarcinogenesis. The IGF-II transgenic mouse studies suggest a role for IGF-II in tumor growth promotion. Our cell culture studies (done with woodchuck liver cells) suggest that concurrent overexpression of IGF-II can block the cell death induced by N-myc2 activation.