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

我们利用转化生长因子α转基因小鼠检测了男性主导肝癌的发生机制，该转基因小鼠也优先发展为男性肝癌。对照组雄性小鼠血清睾酮水平为1.38 ng/dl，转基因小鼠为29.7 ng/dl。处理后观察转基因雄性小鼠15个月：假手术(不处理)(S)、去势(C)和去势及5α-双氢睾酮补体(C+D)组。血清睾酮水平依次为C-C+D-S。另一方面，体重和肝脏重量(C)低于(C+D)和(S)。在6只转基因小鼠(S)、2只转基因小鼠(C)和9只转基因小鼠(C+D)中，有7只小鼠发生了肝肿瘤。(C)两个肝肿瘤均小于(S)和(C+D)组。增殖细胞核抗原染色显示(S)和(C+D)在肝肿瘤及癌旁肝组织中的标记指数均高于(C)。应用促黄体生成素释放激素激动剂醋酸亮丙瑞林对转基因小鼠进行抗雄激素作用，并抑制肝肿瘤的形成。提示雄激素在转化生长因子α转基因小鼠肝肿瘤形成过程中具有促进剂样作用，转化生长因子α可能促进雄激素的产生。这一证据得到了使用从转化生长因子α转基因肝脏建立的细胞系(AML12)的研究结果的支持。在雄激素存在下，AML12在培养上清液中产生的转化生长因子α水平较高，而在雌激素存在下不发生变化。P4502A族是一种肝脏分解代谢酶，在雌性中高表达，在MT42雄性肝脏中显著表达，尤其在转基因小鼠的肝脏肿瘤中表达。结果证实了转化生长因子α-雄激素-P450-2A在肝肿瘤形成中的作用。

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.