Molecular investigation on the hepatic caicinogenesis-resistant model animals

Rb基因是视网膜母细胞瘤的致病基因。Rb蛋白具有抗增殖作用，已知在许多肿瘤中丢失。为了研究Rb蛋白在体内的作用，我们在肝脏中建立了Rb蛋白过表达的转基因小鼠。A系有11个拷贝/单倍体，B系有4个拷贝/单倍体。在A系转基因小鼠肝脏中检测到大量Rb蛋白，在B系转基因小鼠肝脏中检测到少量Rb蛋白。这两个品系的小鼠发育正常，肝脏大小和组织学正常。我们调查了Rb转基因小鼠是否对化学致癌具有抵抗力。我们在4周龄和6周龄时向腹腔内注射二乙基亚硝胺，并在饮用水中用苯巴比妥治疗35周。实验结束后，处死小鼠，制作组织切片，计数肝细胞癌和肝结节数目。对照组小鼠出现大量结节和多个肝细胞癌，两系Rb转基因小鼠的结节数明显减少，未检测到肝细胞癌。通过对4周龄和6周龄小鼠的实验，证实了Rb基因的抗癌作用。这些结果表明，HNF1-Rb基因单元可能在不久的将来用于预防医学。

The Rb gene was isolated as the causative gen of retinoblastoma. The Rb protein has an anti-proliferative action and has been known to be lost in many tumors. We made the transgenic mice in the liver of which the Rb protein was overexpressed in order to investigate the in vivo roles of Rb protein. Line A has 11 copies/haploid of the transgenes and line B has 4 copies/haploid. Consistently, a large amount of Rb protein was detected in the liver of line A transgenic mice and a small amount of it was detected in that of line B transgenic mice. The two lines of mice developed normally and the livers were normal in size and histology.We investigated whether the Rb transgenic mice showed resistance to chemical carcinogenesis. We inject diethylnitrosamine into the peritoneal cavity at the ages of 4 and 6 weeks and treated phenobarbital in drinking water for 35 weeks. After the experiment, the mice were sacrificed to make histological sections for counting the numbers of hepatocellular carcinoma and hepatic nodule. In control mice, a large number of nodules and several hepatocellular carcinoma were developed In contrast, the number of nodules was greatly reduced and no hepatocellular carcinomas were detected in both lines of Rb transgenic mice. The anti-carcinogenic effect of Rb gene was demonstrated in the experiments using the 4 week old mice and the 6 week old mice. These results indicate that the HNF1-Rb gene unit might be useful for the preventive medicine in the near future.