17β-雌二醇通过Notch1/Numb/Snail信号通路调控子宫内膜异位症上皮-间质转化的机制探索

Endometriosis is a common gynecological medical condition in women of reproductive age and significantly reduces patients' quality of life and work. In recent studies, epithelial-to-mesenchymal transition (EMT) is found to participate in the development of endometriosis. However, the mechanism that maybe involved is still unknown. Notch signaling is a key mechanism in regulating EMT. In addition, Notch signaling is proved to be upstream regulator of PI3K/AKT signaling. In previous studies, we found that 17β-estradiol increased cell growth in endometriotic epithelial cells via PI3K/AKT signaling, while 17β-estradiol has been proved to be involved in EMT of series of estrogen-dependent diseases. Thus, we assume that Notch signaling and estrogen participate in the EMT of endometriotic epithelial cells. In the present project, we will investigate the roles of 17β-estradiol and Notch1/Numb/Snail signaling pathway in the EMT of endometriosis through histological experiments, cell cultures and animal experiments. We aim to explore the expression and activity of Notch1/Numb/Snail signaling pathway and the expression of downstream EMT-associated proteins in endometriosis, to prove the role of Notch1/Numb/Snail signaling pathway in the EMT of endometriosis, to investigate the effect of 17β-estradiol on the activity of Notch1/Numb/Snail signaling pathway and the EMT in endometriosis. Through the study, we will provide new idea for the mechanism study of endometriosis development, provide new marker for the diagnosis and prognosis of endometriosis, provide new target for the therapy of endometriosis.

子宫内膜异位症是妇科常见疾病。近期研究表明，上皮-间质转化参与了子宫内膜异位症的发生发展过程，但其机制尚不明确。Notch信号通路是调控上皮-间质转化的关键通路，亦是PI3K信号通路的上游调控机制；在前期工作中，我们证明雌激素可以通过PI3K信号通路促进异位腺上皮细胞的生长，而雌激素已被证明可调控多种雌激素依赖性疾病中的上皮-间质转化，因此，我们提出假设：雌激素及Notch信号通路亦参与了异位腺上皮细胞的上皮-间质转化。本项目拟通过组织、细胞以及动物实验三个层次研究：阐述并证明Notch1/Numb/Snail信号通路及其下游EMT相关蛋白在子宫内膜异位症中的表达、活性及其在异位腺上皮细胞上皮-间质转化中的作用；阐明雌激素通过作用于Notch1/Numb/Snail信号通路调控异位腺上皮细胞上皮-间质转化的可能机制。本项目研究将为探索疾病新的发生发展机制及治疗领域提供理论实验基础。

子宫内膜异位症是妇科常见疾病。研究表明，上皮-间质转化（Epithelial - mesenchymal transition，EMT）参与了子宫内膜异位症的发生发展过程，但其机制尚不明确。Notch信号通路是调控EMT的关键通路，亦是PI3K信号通路的上游调控机制；在前期工作中，我们证明雌激素可以通过PI3K信号通路促进异位腺上皮细胞的生长，而雌激素已被证明可调控多种雌激素依赖性疾病中的EMT。在本项目研究中，我们进一步发现，EMT相关信号通路Notch1/numb/snail信号通路表达异常存在于人类子宫腺肌病及子宫内膜异位症；17β雌二醇可通过Notch1/numb信号通路调控子宫内膜异位症在位内膜腺上皮细胞的EMT；褪黑素（melatonin）可通过上调numb表达抑制子宫内膜异位症在位内膜腺上皮细胞的EMT；正常子宫内膜间质细胞可通过调控Notch1信号通路抑制17β雌二醇诱导的-子宫内膜异位症腺上皮细胞的EMT；EMT抑制性调控分子βKlotho表达缺失存在于子宫腺肌病；同时，我们还发现，褪黑素可通过上调numb表达抑制子宫内膜腺癌细胞的生长及EMT；二甲双胍可通过β-klotho相关ERK1/2信号通路及AMPKα信号通路抑制17β雌二醇诱导的子宫内膜腺癌细胞的EMT；正常子宫内膜间质细胞在体外通过Slug和E-cadherin调节17β-雌二醇诱导的子宫内膜癌EMT。通过本项目研究，我们深入研究了雌激素、褪黑素及二甲双胍等对子宫内膜上皮细胞EMT的调控及其可能机制，研究结果将为探索疾病新的发生发展机制及治疗领域提供理论实验基础。