LIVER-SPECIFIC EXPRESSION AND HIGH ONCOGENIC EFFICIENCY OF A C-MYC TRANSGENE ACTIVATED BY WOODCHUCK HEPATITIS-VIRUS INSERTION

The high oncogenic efficiency of woodchuck hepatitis virus (WHV) has b een correlated with the ability of this virus to provoke insertional a ctivation of mye family genes. To assess the impact of viral integrati on on liver cell transformation, we have generated transgenic mice car rying the mutated c-mye gene and adjacent viral DNA from a woodchuck t umor, in original configuration. Virtually all mice from two different strains developed hepatocellular carcinoma with a mean latency period of 8-12 months. The c-mye transgene was expressed transiently in neon atal livers, and re-expressed at preneoplastic and neoplastic stages i n adult livers. Woodchuck c-mye mRNA driven by the normal P1 and P2 pr omoters and WHV-specific transcripts encoding viral surface antigens w ere produced in a strictly co-regulated fashion during development and tumorigenesis, indicating a predominant regulatory influence of the v iral enhancer. Furthermore, the activity of the viral enhancer in resp onse to various biological stimuli was apparently modulated by glucose uptake and glucogon/insulin balance in differentiated hepatocytes. In this model, a viral integration event selected from a naturally occur ring tumor proved to be determinant for induction of hepatocarcinogene sis, although enforced, liver-specific expression of c-mye was limited to a particular developmental stage.