Hepatocarcinogenic Mechanisms in Hepadnavirus-infected Hosts

Abstract

Chronic hepadnavirus infection is associated with hepatocellular carcinoma (HCC) in natural hosts including humans, woodchucks, and Beechey ground squirrels. Several possible oncogenic mechanisms have been identified. These include a potential role of the hepatitis B virus (HBV) X (hbx) gene which has been shown to transactivate transcription regulated by certain cis-acting sequences including regulatory sequences of HBV and heterologous regulatory sequences of other viruses and cellular genes. The diversity of regulatory sequences that appear to be activated by hbx suggests that the hbx protein acts by a general mechanism that is not DNA sequence-specific. The oncogenic potential of hbx is suggested by the observation of HCC in hbx transgenic mice, oncogenic transformation of cells expressing hbx in culture, and transactivation of oncogenes c-myc and c-jun by hbx. Cis-activation of cellular oncogenes N-myc and c-myc by viral promoter insertion has been observed in woodchuck hepatitis virus (WHV)-associated HCC in woodchucks by Buendia, Tiollais, et al. No such cis-activation of any cellular gene has been shown in virus-associated HCC of ground squirrels or humans. Amplification and overexpression of the c-myc gene has been found in some HCC of ground squirrels but not in woodchuck or human HCC. Point mutations in the p53 gene and allelic deletion of p53 have been found in some human HCC but not in HCC of woodchucks or ground squirrels.