17β雌二醇调控lncRNAH19在子宫内膜异位症上皮-间质转化及干细胞转分化中的作用

Endometriosis is an infertility-associated estrogen-dependent and stem cell related disease. Epithelial –to- mesenchymal transition (EMT) is responsible for its invasion phenomenon. Studies have shown that long non-coding RNA H19 plays an important part in EMT and stem cell property maintaining, but there are rare related reports in endometriosis. We have demonstrated that both estrogen and TGFβ could regulate the expression of H19 in tumor cells, also H19 expression was higher in both endometriotic eutopic stromal cells and glandular epithelial cell than in normal endometrium. We proposed our hypotheses as follows: estrogen could regulate H19 level in endometriotic endometrial cells through different mechanisms including the H19/TGFβ positive feedback loop, also could promote EMT process in glandular epithelial cell and invasion ability in stroma cells. H19 which may be regulated by estrogen could also participate in endometrial mesenchymal stem cell trans-differentiation. We would study the regulation mechanism of estrogen towards H19 and the promotion of H19/TGFβ to endometrial EMT and stem cell trans-differentiation through gene expression regulation, drug intervention, cell morphological function and novel endometriosis animal model, both in vitro and in vivo. This study would help to demonstrate the differences between endometriotic and normal endometrium and could shed lights on exploring the possible intervention to endometriosis targeting at estrogen pathway and endometrial stem cell.

子宫内膜异位症是不孕相关雌激素依赖性和干细胞疾病，上皮-间质转化(EMT)与其侵袭行为有关。研究表明长链非编码RNAH19在肿瘤细胞侵袭、EMT和干细胞性维持中起重要作用，但在内异症缺乏研究。申请者研究表明，雌激素、TGFβ可调控肿瘤细胞H19表达，内异症在位间质细胞和上皮细胞H19表达较正常内膜增高。故提出假设：雌激素可通过包含H19/TGFβ正反馈环在内的多种机制调控内异症细胞H19表达，促使腺上皮细胞发生EMT，同时增强间质细胞侵袭能力，而抑制间质干细胞向上皮细胞转分化。在本项目中，申请者拟通过人体标本、细胞实验和动物实验三个层次，从基因表达调控、干预、细胞功能、新型动物模型等几方面，研究雌激素调控H19的机制、H19在内异症腺上皮细胞EMT及干细胞转分化中的作用。本研究有助于发现上述机制在内异症内膜和正常内膜中的不同表现，为从雌激素和干细胞两个靶点探索内异症可能的干预措施奠定基础。

研究表明长链非编码RNAH19在肿瘤细胞侵袭、上皮-间质转化和干细胞性维持中起重要作用，但在内异症缺乏研究。组织纤维化可导致子宫内膜异位症相关症状如慢性盆腔痛和不孕症。我们预测H19/miR216a/ACTA2通路可能介导子宫内膜异位症在位内膜间质细胞的侵袭转移，在子宫内膜异位病灶纤维化形成中起作用。本研究检测了23例不孕合并子宫内膜异位症患者和23例不孕不合并子宫内膜异位症患者的在位子宫内膜间质细胞中H19和ACTA2表达并进行机制研究。结果表明H19和ACTA2均高表达且呈正相关。H19可通过竞争性结合miR216a-5p，进而促进ACYA2表达。我们得出结论是，雌激素可以通过调控H19/miR-216a-5p/ACTA2信号通路以调控子宫内膜异位症在位内膜间质细胞的侵袭和迁移能力。H19或ACTA2表达下调可抑制在位子宫内膜间质细胞的侵袭迁移能力。然而雌激素可通过上调H19表达促进其侵袭迁移能力。子宫内膜异位症纤维化和侵袭力研究对其发病机制研究和治疗有重要意义。