lncRNA RP11-5407.1促进人子宫内膜间质细胞蜕膜化的功能机制研究

Human endometrial decidualization determines embryonic growth and pregnancy maintenance. Studies have shown that lncRNAs are involved in the regulation of decidualization, but the mechanism is unknown. In the previous study, we found that lncRNA RP11-5407.1 is specifically expressed in endometrial stromal cells, and the expression in endometrial tissues of patients with repeated implantation failure is significantly decreased. It was further found that silencing of endogenous lncRNA RP11-5407.1 significantly inhibited endometrial stromal cells cytoskeleton remodeling and the expression of decidualization markers dPRL and IGFBP1 during decidualization in vitro. Preliminary mechanism studies have found that lncRNA RP11-5407.1 promotes the expression of the key molecule FOXO1A. Based on this, we speculate that lncRNA RP11-5407.1 promotes human endometrial decidualization and embryo implantation by regulating FOXO1A. This study will first clarify the nuclear and cytoplasmic localization of lncRNA rp11-5407.1 in human endometrial stromal cells, and then explore its regulatory mechanism on endometrial deciduation, so as to provide a basis for analyzing the regulatory mechanism of human endometrial deciduation and clinical embryo implantation failure.

人子宫内膜蜕膜化决定胚胎种植与妊娠维持。研究表明lncRNAs参与蜕膜化调控，但机制不明。前期我们研究发现lncRNA RP11-5407.1特异表达于子宫内膜间质细胞，且在反复种植失败患者子宫内膜组织中表达显著降低；进一步发现沉默内源性lncRNA RP11-5407.1后明显抑制体外诱导蜕膜化过程中子宫内膜间质细胞骨架重塑和蜕膜化标志分子dPRL和IGFBP1的表达，初步机制研究发现lncRNA RP11-5407.1促进蜕膜化关键分子FOXO1A的表达。据此推测lncRNA RP11-5407.1通过调节FOXO1A促进人子宫内膜蜕膜化和胚胎种植。本课题拟先明确lncRNA RP11-5407.1在人子宫内膜间质细胞中的核质定位情况，进而探究其对子宫内膜蜕膜化的调控机制，以期为解析人子宫内膜蜕膜化和临床胚胎种植失败的调控机制提供依据。

有效的子宫内膜蜕膜化对于成功怀孕是至关重要的，其决定了胚胎着床和妊娠维持。异常的子宫内膜蜕膜化是导致胚胎反复着床失败的重要原因之一。研究表明，复发性着床失败(Recurrent implantation failure, RIF) 患者子宫内膜样本中存在大量长链非编码RNA (long noncoding RNA, lncRNAs)异常表达。然而，lncRNA在RIF患者子宫内膜蜕膜化过程中的功能尚未被探索。在我们的这项研究中，我们发现lncRNA SAMD11-1:1(原名RP11-54O7.1)在RIF患者的子宫内膜中的表达量显著下降。通过敲低人子宫内膜间质细胞中内源性的lncSAMD11-1:1的表达后能够有效抑制间质细胞蜕膜化和体外小鼠囊胚的着床，而过表达lncSAMD11-1:1可促进间质细胞的蜕膜化和体外小鼠囊胚的着床，并有效改善RIF患者的间质细胞的蜕膜化。在机制上，lncSAMD11-1:1和磷脂酰肌醇-5-磷酸4-激酶2型α (phosphatidylinositol-5-phosphate 4-kinase type 2 alpha, PIP4K2A)在间质细胞蜕膜化过程中转移出细胞核并相互结合，从而抑制AKT的磷酸化，稳定FoxO1的核定位。这项研究表明lncSAMD11-1:1可能是一种在人类子宫内膜蜕膜化过程中发挥功能重要的新型lncRNA，同时lncSAMD11-1:1在子宫内膜中的异常表达可能是RIF的一个新的易发因素。