Development of cystic glandular hyperplasia of the endometrium in Mullerian inhibitory substance type II receptor-pituitary tumor transforming gene transgenic mice
Development of cystic glandular hyperplasia of the endometrium in Mullerian inhibitory substance type II receptor-pituitary tumor transforming gene transgenic mice
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DOI：
10.1677/joe-06-0036
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发表时间：
2007-07-01
影响因子：
4
通讯作者：
Kakar, Sham S.
中科院分区：
文献类型：
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作者：
El-Naggar, Shahenda M.;Malik, Mohammad T.;Kakar, Sham S.
垂体肿瘤转化基因(PTTG/securin)是一种参与细胞周期调控和姐妹染色单体分离的癌基因。PTTG在包括卵巢肿瘤在内的多种肿瘤中均有高表达，提示PTTG可能在卵巢肿瘤的发生发展中起一定作用。PTTG过表达可诱导体外细胞转化和裸鼠成瘤。为了探讨PTTG在卵巢肿瘤发生中的作用，我们通过克隆苗勒氏抑制物质11型受体基因启动子下游的PTTG基因构建了PTTG转基因小鼠模型，以靶向卵巢表面上皮细胞。通过对转基因动物的筛选，我们确定了5名创始人(4名男性和1名女性)。利用这四位男性创始人，我们培育了四个转基因株系。PTTG在卵巢表面上皮细胞、卵巢颗粒细胞以及脑下垂体中的表达均增强。转基因雌性在8-10月龄时没有发生任何明显的卵巢肿瘤；然而，转基因卵巢的黄体质量总体上增加了，这表明黄体化程度增加。这些变化与血清黄体生成素和睾酮水平的升高有关。此外，MISIIR-PTTG转基因子宫肌层普遍肥大，伴有囊性腺体和子宫内膜增生。根据这些结果，我们得出结论，PTTG的过度表达可能是启动癌前状态所必需的，但不足以诱导卵巢肿瘤的发生，可能需要另一个伴侣启动细胞转化。
The pituitary tumor transforming gene (PTTG)/securin is an oncogene that is involved in cell cycle regulation and sister chromatid separation. PTTG is highly expressed in various tumors including ovarian tumors, suggesting that PTTG may play a role in ovarian tumorigenesis. Overexpression of PTTG resulted in induction of cellular transformation in vitro and tumor formation in nude mice. To ascertain PTTG function in ovarian tumorigenesis, we generated a transgenic mouse model of PTTG by cloning PTTG cDNA downstream of Mullerian inhibitory substance type 11 receptor gene promoter (MISIIR) in order to target the ovarian surface epithelium. By screening of transgenic animals, we identified five founders (four males and one female). Using the four male founders, we developed four transgenic lines. PTTG expression was increased in ovarian surface epithelium, ovarian granulosa cells, as well as in the pituitary gland. Transgenic females did not develop any visible ovarian tumors at 8-10 months of age; however, there was an overall increase in the corpus luteum mass in transgenic ovary, suggesting increased luteinization. These changes were associated with an increase in serum LH and testosterone levels. In addition, there was a generalized hypertrophy of the myometrium of MISIIR-PTTG transgenic uteri with cystic glandular and hyperplasia of the endometrium. Based on these results, we conclude that the overexpression of PTTG may be required to initiate precancerous conditions but is not sufficient to induce ovarian tumorigenesis and may require another partner to initiate cellular transformation.