Molecular investigation on the hepatic caicinogenesis-resistant model animals

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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.