Kaplanski C, Chisari F V, Wild C P
Unit of Environmental Carcinogenesis, International Agency for Research on Cancer, Lyon, France.
Carcinogenesis. 1997 Apr;18(4):633-9. doi: 10.1093/carcin/18.4.633.
Transgenic mice carrying an integrated subgenomic human hepatitis B virus (HBV) DNA fragment coding for the viral envelope polypeptides, represent a model for the study of the mechanisms involved in hepatocarcinogenesis. The mice develop a progressive liver injury characterized by inflammation, regenerative hyperplasia and dysplasia terminating in hepatocellular carcinoma (HCC) at around 18-21 months of age. No alterations in specific oncogenes and tumour suppressor genes in the HCC arising in this transgenic model have been observed. However, onset of liver tumours is significantly earlier in mice treated with aflatoxin B1 (AFB1). In order to examine more generally for genetic rearrangements during the natural history of the disease, DNA multilocus fingerprinting was performed using probes recognizing mouse minisatellites. Liver tumour samples from HBV transgenic mice either untreated or treated with AFB1 transplacentally were included in the study. In a total of 28 tumour samples from HBV transgenic mice receiving no carcinogen treatment, using three minisatellite probes, no alterations were detected. The frequency of rearrangements using any one of the three probes is calculated to be below 0.2%. This result demonstrates that genetic instability in minisatellite sequences is not a common event associated with HBV gene expression and liver injury in this model. In 11 liver tumours from mice exposed to AFB1 transplacentally six had minisatellite alterations (band gains and losses) revealed by at least one of the three probes used. The frequency of rearrangements was between 1.1% and 2% depending on the minisatellite probe. These data show that genetic alterations can be induced by transplacental exposure to AFB1 and suggest that genetic instability could be important in hepatocarcinogenesis with combined exposures to AFB1 and HBV.
携带整合的亚基因组人乙型肝炎病毒（HBV）DNA片段（编码病毒包膜多肽）的转基因小鼠，是研究肝癌发生机制的一种模型。这些小鼠会出现进行性肝损伤，其特征为炎症、再生性增生和发育异常，最终在18 - 21个月龄左右发展为肝细胞癌（HCC）。在这个转基因模型中发生的HCC中，未观察到特定癌基因和肿瘤抑制基因的改变。然而，用黄曲霉毒素B1（AFB1）处理的小鼠肝脏肿瘤发病明显更早。为了更全面地检查疾病自然史期间的基因重排情况，使用识别小鼠微卫星的探针进行了DNA多位点指纹分析。研究纳入了未处理或经胎盘暴露于AFB1的HBV转基因小鼠的肝脏肿瘤样本。在总共28个未接受致癌物处理的HBV转基因小鼠的肿瘤样本中，使用三种微卫星探针未检测到改变。使用这三种探针中的任何一种计算出的重排频率均低于0.2%。这一结果表明，在该模型中，微卫星序列中的基因不稳定并非与HBV基因表达和肝损伤相关的常见事件。在11个经胎盘暴露于AFB1的小鼠的肝脏肿瘤中，有6个出现了微卫星改变（条带增加和减少），这是通过所使用的三种探针中的至少一种检测到的。根据微卫星探针的不同，重排频率在1.1%至2%之间。这些数据表明，经胎盘暴露于AFB1可诱导基因改变，并提示在AFB1和HBV联合暴露的肝癌发生过程中，基因不稳定可能起重要作用。
