Integrated Viral Sequences may Contribute in cis and in trans to Hepatocarcinogenesis in Woodchuck Hepatitis Virus-infected Woodchucks

Our recent studies of woodchuck liver tumors have shown that induction of the oncogenic process can be achieved by insertional mutagenesis of the myc protooncogenes by woodchuck hepatitis virus (WHV) DNA. The N-myc2 intronless gene represents a major target for viral insertion. Activation of N-myc2 expression resulting from a cis-acting effect of the viral enhancers on the N-myc2 promoter is strongly associated with the development of liver tumors in woodchuck. Further studies of the expression of integrated WHV sequences in liver tumors, by Northern blotting and cDNA cloning, have revealed abnormal WHV transcripts and viral-host co-transcripts carrying truncated X gene sequences. In one case, the 3′ truncated X gene fused to cellular sequences retained the ability to transactivate a heterologous promoter. These data suggest that, like in hepatitis B virus-related hepatocellular carcinoma, integrated viral sequences in woodchuck tumors may contribute to alteration of normal cell growth control through deregulated expression of the WHV X trans-activator.