THE STUDY OF SEX DIFFERENCE IN HEPATOCARCINOGENESIS-ANALYSIS USING TGF alpha TRANSGENIC MICE-

肝癌发生过程中性别差异的研究-使用TGFα转基因小鼠进行分析-

• 批准号: 07670562
• 负责人: TAKAGI Hitoshi
• 金额: $ 1.47万
• 依托单位: GUNMA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07670562/
• 关键词: TGF alpha; hepatoma; gender; transgenic mice; androgen; LH-RH-agonist; p450

We tested the mechanism of male predominant hepatocarcino-genesis using transforming growth factor alpha transgenic mice which also developed liver tumor preferentially in male. Serum level of testosteron was 1.38ng/dl in control male mice and 29.7ng/dl in transgenic mice. We observed transgenic male mice for 15 months after the treatment as follows ; sham operated (no treatment) (S), castrated (C) and castrated and 5 alpha-dihydrotestosteron complement (C+D). Serum level of testosteron was increased C-C+D-S in this order. On the other hand, body weight and liver weight were lower in (C) than in (C+D) and (S). Seven liver tumors were developed in 6 (S), 2 in (C) and 9 of 6 (C+D) transgenic mice. Two liver tumors in (C) were smaller than those in (S) and (C+D). PCNA staining showed higher labelling index in (S) and (C+D) than (C) in both liver tumors and surrounding liver tissues. Anti-androgenic effect of LH-RH agonist, leuprorelin acetate, was administered to the transgenic mice and suppressed the liver tumor formation. These results suggest the androgen has promotor like effect in hepatic tumorigenesis in TGF alpha transgenic mice and TGF alpha may enhance the androgen production. this evidence was supported by the results of the study using the cell lines (AML12) established from TGF alpha transgenic liver. AML12 produced TGF alpha in culture supernatant higher in the presense of androgen but not changed in that of estrogen. p450 2A family, which is a catabolic enzyme of the liver and highly expressed in female, was significantly expressed in MT42 male liver especially in liver tumors of transgenic mice. The result demonstrated the relationship of TGF alpha-androgen-p450 2A in liver tumor formation.

我们使用转化生长因子α转基因小鼠测试了男性主要肝癌发生的机制，该小鼠也优先在男性中发生肝肿瘤。对照雄性小鼠的血清睾酮水平为1.38ng/dl，转基因小鼠的血清睾酮水平为29.7ng/dl。我们对转基因雄性小鼠进行如下治疗后15个月的观察；假手术（不治疗）（S）、去势（C）和去势和5α-二氢睾酮补体（C+D）。血清睾酮水平按C-C+D-S的顺序升高。另一方面，(C)的体重和肝脏重量比(C+D)和(S)低。 6 只 (S)、2 只 (C) 和 9 只 (C+D) 转基因小鼠中出现了 7 个肝脏肿瘤。 (C)中的两个肝脏肿瘤比(S)和(C+D)中的较小。在肝肿瘤和周围肝组织中，PCNA 染色显示 (S) 和 (C+D) 中的标记指数高于 (C)。 LH-RH 激动剂醋酸亮丙瑞林的抗雄激素作用被给予转基因小鼠并抑制肝脏肿瘤的形成。这些结果表明，雄激素在TGFα转基因小鼠的肝脏肿瘤发生中具有促进剂样作用，并且TGFα可以增强雄激素的产生。这一证据得到了使用从 TGF α 转基因肝脏建立的细胞系 (AML12) 进行的研究结果的支持。 AML12 在培养物上清液中产生的 TGF α 在雄激素存在下更高，但在雌激素存在下没有变化。 p450 2A家族是肝脏的一种分解代谢酶，在雌性中高表达，在MT42雄性肝脏中显着表达，尤其是在转基因小鼠的肝脏肿瘤中。结果证明了TGF α-雄激素-p450 2A与肝肿瘤形成的关系。

项目成果

Takagi H,Takayama H,Shimoda R,Nagamine R.: "TGFalpha transgenic mice and hepatocarcinogenesis. (in Japanese)" Frontiers in Gastroenterology. 1. 69-78 (1996)

Takagi H、Takayama H、Shimoda R、Nagamine R.：“TGFalpha 转基因小鼠和肝癌发生。（日语）”胃肠病学前沿。

Matsumoto T,Takagi H,et al: "Androgen supplement for castrated TGFα transgenic malenice restored Hapatic tumorigenesis." Int Hepatol Communic. 3. S141- (1995)

Matsumoto T、Takagi H 等人：“用于去势 TGFα 转基因雄性的雄激素补充剂可恢复 Hapatic 肿瘤发生。”Int Hepatol Communic 3. S141- (1995)。

Takagi H,Fukusato T,Kawaharada U,Merlino G and Tsutsumi Y.: "Hist o chemical analysis of the hyperplastic stomach of TGFalpha transgenic mice." Dig Dis Sciences. 42. 91-98 (1997)

Takagi H、Fukusato T、Kawaharada U、Merlino G 和 Tsutsumi Y.：“TGFα 转基因小鼠增生性胃的组织化学分析。”

Ichikawa T,Takehara K,Takagi H,Arai H,Shimoda R,Matsumoto T,Saito S,Yuasa T,Arai T,Nagamine T,Yamada S,Mori M.: "Effect of the EGF-receptor-inhibit or on primary cultured hepatocytes isolated from transgenic mice of transforming growth factor alpha." Int

Ichikawa T、Takehara K、Takagi H、Arai H、Shimoda R、Matsumoto T、Saito S、Yuasa T、Arai T、Nagamine T、Yamada S、Mori M.：“EGF 受体抑制或对原代培养物的影响

Takagi H,Matsumoto T,Saitoh S,Sohara N,Shimoda R,Takehara K,Nagamine R,Mori M.: "Contribution of p450-2a in hepatocarcinogenesis of TGFalpha transgenic mice. (in Japanese)" Acta Hepatol Japon. 37 : suppl. 173 (1996)

Takagi H、Matsumoto T、Saitoh S、Sohara N、Shimoda R、Takehara K、Nagamine R、Mori M.：“p450-2a 在 TGFα 转基因小鼠肝癌发生中的贡献。（日语）”Acta Hepatol Japon。