Bruni R, D'Ugo E, Giuseppetti R, Argentini C, Rapicetta M
Laboratory of Virology, Istituto Superiore di Sanità, Rome, 00161, Italy.
Virology. 1999 May 10;257(2):483-90. doi: 10.1006/viro.1999.9678.
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.
在土拨鼠肝炎病毒（WHV）/土拨鼠乙型肝炎病毒诱导的肝细胞癌模型中，WHV整合导致N-myc癌基因频繁激活已得到确凿证实。N-myc2是受影响最频繁的基因，据报道，WHV插入该基因附近或远处的非编码位点win可激活该基因。我们之前报道过，从肝肿瘤中克隆的一个WHV整合位点位于其他人已描述为另一种肝细胞癌中WHV整合位点的染色体区域。在此基础上，该位点被命名为b3n，被定义为WHV整合的一个复发位点。随后发现一个支架或基质附着区域（S/MAR）元件位于该位点，距离WHV插入位点约1 kb。S/MAR是参与染色体DNA结构和功能组织以及基因表达刺激的遗传元件。在本研究中，我们调查了N-myc基因可能受b3n整合影响的可能性。对该位点存在WHV整合的肝肿瘤进行分析显示N-myc2过表达。通过限制性分析，b3n位点显示位于N-myc2下游，因此b3n中已知的病毒插入位点在N-myc2启动子下游约11 kb处。尽管这些数据支持b3n中的WHV插入激活了N-myc2，但先前描述的参与N-myc2激活的机制似乎无法很好地解释该子集WHV整合中的激活情况。现有数据表明，b3n中WHV整合导致的N-myc2激活可能由位于WHV插入附近的S/MAR介导。
