GENERATION AND APPLICATION OF THE MODEL MICE WHICH SHOW RESISTANCE TO RENAL CARCINOGENESIS

抗肾癌小鼠模型的产生及应用

• 批准号: 08557089
• 负责人: MIURA Naoyuki
• 金额: $ 7.36万
• 依托单位: AKITA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08557089/
• 关键词: TORANSGENIC MICE; CHEMICAL CARCINOGENESIS; RB PROTEN; KIDNEY CANCER; LIVER CANCER; TRANSGENE; HNF1; トランスジェニックス; 腎臓; 肝臓; 肝切除; 癌抑制性遺伝子; Rb遺伝子; 腎臓癌

We have generated the HNF1 -Rb transgenic mice in which the human Rb CDNA is regulated under the 9kbp of HNF1 (hepatocyte nudear factor 1) promoter. They showed no apparent differences compared to the wild mice and they can transmit the transgene to their offspring. The numbers of the Rb transgene were 11.0 copies per haploid for line A and 4.2 copies per haploid for line B.The weights of kidney and liver in the Rb transgenic mice were not different from the control mice.Next we treated the mice with Iron Nitrotriacetate intraperitoneally for 3 months for kidney carcinogenesis and with diethylnitrosamine intraperitoneally and phenobarbital orally for 8 months for liver carcinogenesis. Control mice developed kidney carcinomas and liver carcinomas. The Rb transgenic mice, line A and line B, did not develop liver carcinoma and also showed smaller number of nodules than control mice, However, the Rb transgenic mice develop kidney carcinomas as frequently as control mice. In order to explain the differences between the effects of Rb transgene, we investigated the expression pattern of the Rb trausgene using the coinjected FNF1 -LacZ gene. The results showed that the Rb transgene was expressed in all hepatocytes, but in a small number of renal tubular cells. The expression profile is in good consistency with the resistance to chemical carcinogenesis.

我们已经建立了HNF1-Rb转基因小鼠，其中人Rb CDNA受HNF1(肝细胞核因子1)启动子9kbp的调控。与野生小鼠相比，它们没有表现出明显的差异，它们可以将转基因传播给后代。Rb转基因小鼠的肾脏和肝脏重量与对照小鼠无明显差异。用硝酸三乙酸铁腹腔注射诱发肾癌3个月，用二乙基亚硝胺和苯巴比妥灌胃8个月造成小鼠肝细胞癌。对照组小鼠患上了肾癌和肝癌。Rb转基因小鼠(A系和B系)没有发生肝癌，结节数目也比对照小鼠少，但Rb转基因小鼠患肾癌的频率与对照小鼠一样高。为了解释Rb转基因效果的差异，我们利用共注入的FNF1-LacZ基因研究了Rb trausgene基因的表达模式。结果表明，Rb转基因在所有肝细胞中均有表达，但在少数肾小管细胞中有表达。表达谱与对化学致癌的抗性有很好的一致性。

项目成果

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Schilsky,M.L.: "Copper resistant human hepatoma mutant cell lines without metallothioneion induction overexpress ATP7B." Hepatology. 28. 1347-1356 (1998)

Schilsky, M.L.：“没有金属硫离子诱导的铜抗性人肝癌突变细胞系过度表达 ATP7B。”