lncRNA-LEEME抑制孕激素受体B泛素化降解调控轻度子宫内膜异位症在位内膜孕激素敏感性的机制研究

The function and the mechanism of lncRNAs in progestrone receptor and its downstream signaling pathway is still unclear. In our previous studies, we identified the lncRNA-LEEME which could strengthen the progesterone sensitivity of the stromal cells in eutopic endometrium of mild endometriosis infertiler patients by using microarray analysis. Our results showed that lncRNA-LEEME could combine progestrone receptor PGR-B and suppress its phosphorylation and degradation via ubiquitination. Therefore, we hypothesize a decreased expression level of lncRNA-LEEME in the eutopic endometrium, which weakens the suppression effect for the phosphorylate modification of PGR-B by p42/p44MAPK, and accelerates the ubiquitination of PGR-B. The decreased progesterone sensitivity of stromal cells suppresses decidualization which affects embryo implantation and finally results in infertility. This study will provide evidence that the combination of lncRNA-LEEME and PGR-B modulates the downstream signaling pathway of progestrone receptor. And indentify the relationship between lncRNA-LEEME and the clinical features of endometriosis patients. Success of this study will provide original scientific basis for a predictor and candidate therapeutic target in patients of mild endometriosis combine infertility.

长链非编码RNA（lncRNA）在孕激素受体及其下游信号通路中的调控机制尚未阐明。我们预实验通过基因芯片鉴定出增强轻度子宫内膜异位症合并不孕患者在位内膜间质细胞孕激素敏感性的lncRNA-LEEME，初步证实lncRNA-LEEME结合并抑制孕激素受体PGR-B蛋白的磷酸化及泛素化降解。而在位内膜PGR-B低表达引起孕激素抵抗是内异症患者妊娠率低的重要原因。由此我们提出科学假说：在位内膜中lncRNA-LEEME表达水平降低，削弱了对p42/p44MAPK磷酸化修饰PGR-B的抑制，加速了PGR-B泛素化降解，使间质细胞孕激素敏感性降低、蜕膜化受阻，影响胚胎着床导致轻度内异症患者不孕。本研究拟采用体内外实验获得lncRNA-LEEME结合PGR-B调控孕激素受体下游信号通路的可靠证据，明确lncRNA-LEEME与患者临床特征的关系，为发现轻度内异症性不孕的预测指标和治疗靶点提供科学依据。

子宫在位内膜容受性差是轻度内异症患者妊娠率低的重要原因。我们通过基因芯片鉴定出lncRNA-EEME通过增强轻度内异症在位内膜间质细胞孕激素的敏感性改善子宫内膜的容受性，进一步探究是否由于lncRNA-EEME通过结合孕激素受体PGR-B，保护PGR-B的S294位点免受磷酸化进而减少PGR-B泛素化降解。本研究结果发现：轻度子宫内膜异位症在位内膜间质细胞中lncRNA-EEME低表达，对PGR-B的S294位点保护减弱，p42/p44MAPK加速PGR-B磷酸化进而泛素化降解，使间质细胞蜕膜化受阻，子宫内膜容受性降低，导致胚胎着床失败。本研究获得lncRNA-EEME结合PGR-B调控孕激素受体相关信号通路的可靠证据，明确了lncRNA-EEME与患者临床特征的关系，为发现轻度内异症患者妊娠率低的分子机制和治疗方案决策提供科学依据。