Critical tumor suppressor function mediated by epithelial Mig-6 in endometrial cancer.
Critical tumor suppressor function mediated by epithelial Mig-6 in endometrial cancer.
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DOI：
10.1158/0008-5472.can-13-0241
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发表时间：
2013-08-15
期刊：
影响因子：
11.2
通讯作者：
Jeong JW
中科院分区：
文献类型：
--
作者：
Kim TH;Lee DK;Cho SN;Orvis GD;Behringer RR;Lydon JP;Ku BJ;McCampbell AS;Broaddus RR;Jeong JW
子宫内膜癌发生前有子宫内膜增生、无对抗性雌激素暴露和基因改变，但子宫内膜癌的确切病因尚不清楚。Mig-6主要被称为EGF受体的负调节因子，是子宫内孕激素信号传导的重要介质，通过调节子宫内膜间质-上皮的通讯介导肿瘤抑制。在这项研究中，我们使用组织特异性基因敲除策略研究了米格-6在子宫上皮中的功能，其中将floxed米格-6（米格-6f/f）小鼠与Wnt7a-Cre小鼠（Wnt7acre+米格-6f/f）杂交。Wnt7acre+ Mig-6f/f小鼠出现子宫内膜增生和雌激素依赖性子宫内膜癌，上皮细胞增殖增加，亚上皮间质细胞凋亡。我们记录了Wnt7acre+ Mig-6f/f小鼠上皮细胞中NOTCH1和BIRC3的表达增加，基质细胞中孕激素受体（PR）的表达降低。黄体酮治疗可以控制子宫内膜生长并预防子宫内膜癌，但黄体酮治疗子宫内膜癌的有效性尚不清楚。我们注意到，孕激素治疗可以预防Wnt7acre+米格-6f/f小鼠的增生性表型，而孕激素治疗对PRcre/+米格-6f/f小鼠没有影响，因为子宫上皮和间质室中都缺失了米格-6。相反，间质中黄体酮信号的激活通过抑制ERα信号调节上皮细胞的增殖和凋亡。综上所述，我们的研究结果证实上皮细胞的米格-6作为一种关键的肿瘤抑制因子，介导孕酮预防子宫内膜癌的发生。
Endometrial cancer is preceded by endometrial hyperplasia, unopposed estrogen exposure and genetic alterations, but the precise causes of endometrial cancer remain uncertain. Mig-6, mainly known as a negative regulator of the EGF receptor, is an important mediator of progesterone signaling in the uterus, where it mediates tumor suppression by modulating endometrial stromal-epithelial communications. In this study, we investigated the function of Mig-6 in the uterine epithelium using a tissue-specific gene knockout strategy, in which floxed Mig-6 (Mig-6f/f) mice were crossed to Wnt7a-Cre mice (Wnt7acre+ Mig-6f/f). Wnt7acre+ Mig-6f/f mice developed endometrial hyperplasia and estrogen-dependent endometrial cancer, exhibiting increased proliferation in epithelial cells as well as apoptosis in sub-epithelial stromal cells. We documented increased expression of NOTCH1 and BIRC3 in epithelial cells of Wnt7acre+ Mig-6f/f mice and decreased expression of the progesterone receptor (PR) in stromal cells. Progesterone therapy controls endometrial growth and prevents endometrial cancer, but the effectiveness of progesterone as a treatment for women with endometrial cancer is less clear. We noted that the hyperplasic phenotype of Wnt7acre+ Mig-6f/f mice was prevented by progesterone treatment, whereas this treatment had no effect in PRcre/+ Mig-6f/f mice where Mig-6 was deleted in both the epithelial and stromal compartments of the uterus. In contrast, activation of progesterone signaling in the stroma regulated proliferation and apoptosis in the epithelium via suppression of ERα signaling there. In summary, our results establish that epithelial Mig-6 functions as a critical tumor suppressor that mediates the ability of progesterone to prevent the development of endometrial cancer.