Activation of the N-myc2 oncogene by woodchuck hepatitis virus integration in the linked downstream b3n locus in woodchuck hepatocellular carcinoma.
In the woodchuck hepatitis virus (WHV)/woodchuck model for hepatitis B virus-induced hepatocellular carcinoma, frequent activation of N-myc oncogenes by WHV integration has been firmly established. N-myc2, the most frequently affected gene, was reported to be activated by WHV insertion either in the proximity of the gene or in a distant uncoding locus, win. We previously reported that a WHV integration cloned from a liver tumor was located in a chromosomal locus already described by others as the site of WHV integration in another hepatocellular carcinoma. On this basis, the locus, named b3n, was defined as a recurrent site of WHV integration. A scaffold or matrix attachment region (S/MAR) element was subsequently shown to be located in this locus approximately 1 kb from the WHV insertion sites. S/MARs are genetic elements involved both in structural and functional organization of chromosomal DNA and in stimulation of gene expression. In the present work, we investigated the possibility that an N-myc gene might be affected by integration in b3n. Analysis of a liver tumor harboring WHV integration in this locus showed N-myc2 overexpression. By restriction analysis, the b3n locus was shown to be located downstream of N-myc2, so the known sites of viral insertion in b3n were approximately 11 kb downstream of the N-myc2 promoter. Although these data support that WHV insertion in b3n activates N-myc2, the mechanisms previously described to be involved in N-myc2 activation do not appear to properly account for activation in this subset of WHV integrations. Available data suggest that activation of N-myc2 by WHV integration in b3n might be mediated by the S/MAR located near the WHV insertion.
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000662:veterinary*; D015972:Gene Expression Regulation, Neoplastic; D017919:Hepatitis B Virus, Woodchuck / Q000235:genetics*; D008113:Liver Neoplasms / Q000235:genetics / Q000662:veterinary*; D008392:Marmota; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D011519:Proto-Oncogenes; D016662:Virus Integration