近期研究提示，雌激素核受体（ER）缺失的Ⅱ型子宫内膜癌（内膜癌）也具有雌激素依赖性，经典的Ⅱ型内膜癌非雌激素致癌理论遭到质疑。课题组前期研究分别证明了：雌激素与G蛋白偶联雌激素受体1（GPER1）结合产生的非基因组快速效应是调控Ⅱ型内膜癌细胞增殖和侵袭的重要途径；Ⅱ型内膜癌细胞产生的自分泌移动因子（AMF）能激活下游MAPK信号通路，诱导肿瘤细胞的EMT。我们推测并得到预实验结果的初步验证：在雌激素影响下，Ⅱ型内膜癌细胞存在的GPER1-AMF相互间正向反馈调控能加速肿瘤增殖。课题将构建移植瘤中AMF被敲除（CRISPR／Cas9技术）的雌性裸鼠模型，观察AMF被敲除后GPER1表达；分析AMF拯救条件下GPER1的表达反弹趋势；比较在雌激素刺激下体内AMF和GPER1表达。研究将会加深我们对Ⅱ型内膜癌预后更为凶险的内在机制理解，为寻找能阻断雌激素作用靶点关键因子的分子靶向治疗提供新思路。

Recent studies have revealed that type Ⅱ endometrial cancer which is lack of estrogen nuclear receptor (ER) expression may also associate with estrogen stimulation, the etiology of type Ⅱ endometrial cancer may, therefore, not be completely estrogen independent, as previously believed. Our previous studies showed that the rapid non-genomic effects induced by conjugation of estrogen and G protein-coupled estrogen receptor 1 (GPER1) promoted type Ⅱ endometrial cancer cell proliferation and invasion. Autocrine motility factor (AMF) secreted by type Ⅱ endometrial cancer cells mediated tumor cells migration and epithelial-mesenchymal transition (EMT) through the MAPK signaling pathway. We presume and obtain preliminary validation of the preliminary experimental results: under the condition of estrogen stimulation, the positive feedback regulation loop between GPER1 and AMF probably accelerate the proliferation of type Ⅱ endometrial cancer cells. On the basis of the preliminary experiments, the present study aims to perform adenovirus-mediated somatic genome editing of AMF by CRISPR/Cas9 in female nude mouse transplanted tumor, and explore the expression of GPER1 after AMF knockout; to analysis GPER1 expression trend under AMF rescue condition; to compare the expression of AMF and GPER1 under estrogen stimulation in vivo. The research will deepen the understanding of the underlying mechanism of poorer prognosis of type Ⅱ endometrial cancer, and provide a new approach of molecular targeted therapy for estrogen.