雌激素介导Wnt/β-catenin信号通路调控子宫内膜异位症上皮-间质转化的分子机制研究

Endometriosis is estrogen-depentment disease.The pathogenesis of endometriosis is the focal of clinical and scientific studies in gynecology. Epithelial-mesenchymal transition (EMT) might be a key mechanism underlying the induction of invasion and metastasis of tumors..Due to the invasive behaviour and cytoskeletal rearrangement of endometrial epithelial cells during ectopic implantation, some studies have demonstrated that EMT might be involved in the development of endometriosis, However the mechanism of this uterine disorder is poorly understood. In our previous study,we have demonstrated that estrogen may triggers Wnt-?-catenin signaling that may be responsible for activation of ESC and involved in the pathogenesis and the progression of endometriosis. EMT can be induced by a number ofsignals, including Wnt-?-catenin signaling. On the basis of these data, we hypothesized that estrogen may induction of EMT through triggers Wnt-?-catenin signaling pathway within endometrial epithelial cells, which thenstimulates the migration of endometrial epithelial cells to ectopic sites and increases the risk of endometriosis.We may finally demonstrate that EMT play an important role on development endometriosis,and explore the origin of pathogenesis of endometriosis, which provide the theoretical evidence to therapeutic targets.

子宫内膜异位症（内异症）是一种雌激素依赖性疾病,其发病机制一直是妇科基础与临床研究的热点。上皮-间质转化（EMT）在许多生命过程和肿瘤侵袭转移起关键作用。近年研究发现雌激素通过调控异位子宫内膜EMT参与了内异症的发生和发展，但机制不明。课题组在前期研究中证实雌激素可通过介导Wnt/β-catenin信号通路促进异位子宫内膜粘附、侵袭和转移，而Wnt/β-catenin是调控EMT发生的关键信号通路。为此，本研究拟在采用生物化学、免疫学及分子生物学等研究方法，研究雌激素在内异症中是否通过激活Wnt/β-catenin信号通路，启动下游靶基因如Slug、Snail、Twist等表达，降低E- Cadherin并形成EMT，参与内异症的形成和发展。证明EMT在内异症发生、发展中起关键作用，并阐明EMT在内异症发生中的分子机制，为寻找内异症发生的源头分子机制及治疗靶点提供理论依据。

本课题组在四年的研究工作中按照既定的研究计划执行，较好的达到了预期目标，完成了以下工作：1）成功分离和培养原代子宫内膜上皮细胞（EEC）并进行鉴定；2）细胞水平实验证实雌激素（E2）能够促进Wnt/β-catenin信号通路激活和启动上皮间质转化（EMT）程序，并促进细胞侵袭转移；3）CHIP及双荧光报告实验明确ERα 通过结合β-cateninTCF/LEF基因启动子附近直接调控其表达、β-catenin/ TCF/LEF 通过结合Snail、Slug 及Twist基因启动子附近直接调控其表达；4）通过子宫内膜异位症动物实验模型的建立，进一步在整体水平证明雌激素介导Wnt/β-catenin 信号通路参与内异症EMT 的发生；5）已发表论文10篇，其中SCI论文10篇，发表于生殖医学权威期刊Hum Reprod、Fertil Steril、 Mol Hum Reprod、Biol Reprod、Reproduction；6）已培养博士研究生3人及硕士研究生2人毕业。