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Molecular investigation on the hepatic caicinogenesis-resistant model animals

肝脏抗癌模型动物的分子研究

基本信息

批准号：
11557090
负责人：
MIURA Naoyuki
金额：
$ 4.03万
依托单位：
Hamamatsu University School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

项目摘要

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.

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，并且已知在许多肿瘤中丢失。为了研究Rb蛋白在体内的作用，我们在肝脏中制备了Rb蛋白过表达的转基因小鼠。系A具有11个拷贝/单倍体的转基因，系B具有4个拷贝/单倍体。A系转基因小鼠肝脏中检测到大量Rb蛋白，B系转基因小鼠肝脏中检测到少量Rb蛋白。两品系小鼠发育正常，肝脏大小和组织学正常，我们研究了Rb转基因小鼠是否对化学致癌具有抵抗力。我们在4和6周龄时将二乙基亚硝胺注入腹腔，并在饮用水中处理苯巴比妥35周。实验结束后处死小鼠，制作组织切片，计数肝癌和肝结节的数目。在对照组小鼠中，大量的结节和几个肝细胞癌的发展，相比之下，结节的数量大大减少，没有检测到肝细胞癌在两个系的Rb转基因小鼠。在4周龄和6周龄小鼠实验中证实了Rb基因的抗癌作用。这些结果表明，HNF 1-Rb基因单元可能在预防医学上有应用价值。