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Hepatitis C virus (HCV) infection causes hepatitis, hepatocellular carcinoma (HCC) in a significant number of patients. Previously we have shown that HCV infection causes double-strand DNA breaks and enhances the mutation frequency of cellular genes, including proto-oncogenes and immunoglobulin genes. It has been shown that the transcription factor c-Jun prevents apoptosis by antagonizing p53 activity, contributing to the early stages of HCC development. We have established an HCV core transgenic mouse line, which developed HCC and ulcerative skin lesions, reminiscent of STAT3-transgenic mice. In this study, we examined whether c-jun promotes HCV-induced tumor formation. Conditional inactivation of c-Jun was used to study its role in chemically induced HCCs in HCV core transgenic mice. Conditional knockout of c-jun reduced tumor incidence, but did not have effects on the skin diseases of core transgenic mice, indicating that c-jun is necessary for core-induced liver tumor formation. Diethylnitrosamine (DEN)-treated core transgenic mice developed significantly higher degree of dysplasia in the livers than similarly treated non-transgenic littermates. The disruption of c-jun reduces the degree of dysplasia. STAT3 expression was enhanced in DEN-treated core transgenic livers and skins. HCV core transgenic mice have frequent polyploidy and translocations of chromosomes as determined by spectral karyotying. In addition, cytokine profile was altered in HCV core transgenic mice. These results indicated that HCV core protein expression contributes to the development of chemically induced HCC through c-jun pathway by altering cell proliferating pathway and triggering chromosomal instability. This sequence of events provides the molecular mechanism of HCV oncogenesis.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA