miR-133b挽救输卵管积水损害子宫内膜蜕膜化的机制研究

Hydrosalpinx impairs decidualization，is one of primary causes of female infertility. Previous studies have demonstrated that LIF plays important role in endometrial decidualization, which expression in the endometrium of patients with hydrosalpinx is decreased. However, the exact mechanisms by which hydrosalpinx fluid reduce the expression of LIF in human endometrium are unclear. Our studies showed that miR-133b promotes LIF expression in human endometrial stromal cells. We also found HF (hydrosalpinx fluid) as a negative regulator of human endometrial stromal cell decidualization, simultaneously, miR-133b promoted decidual maker genes PRL and IGFBP-1 as well as LIF expression. Using the online miRNA target gene prediction program miRanda, we found that KLF12 is potential miR-133b target. So, our hypothesis is that miR-133b reverses hydrosalpinx-induced impairment of decidualization by down-regulating KLF12. We will further to address the mechanism of hydrosalpinx-induced impairment of decidualization through miR-133b-mediated KLF12 expression. Our study might be providing more sufficient molecular mechanism for miR-133b as a new target to improve pregnancy rates of women with hydrosalpinx.

输卵管积水损害子宫内膜蜕膜化是导致女性不孕的主要原因之一。已有研究表明LIF在蜕膜化中起重要作用，且在输卵管积水患者子宫内膜中低表达。但输卵管积水导致LIF低表达的机制仍不清。我们在研究miR-133b改善输卵管积水抑制子宫内膜容受性标志分子HOXA10表达时发现miR-133b促进子宫内膜间质细胞中LIF的表达。预实验结果显示输卵管积水抑制子宫内膜蜕膜化，miR-133b促进蜕膜化的发生。miRNA靶基因生物信息学分析发现蜕膜化抑制因子KLF12为miR-133b的靶基因。因此，我们提出miR-133b抑制KLF12表达挽救输卵管积水介导的子宫内膜蜕膜化的损害。本项目旨在：获得miR-133b参与积水导致不孕的可靠证据；并从转录调控的角度探讨miR-133b靶向调控KLF12参与子宫内膜蜕膜化的分子机制。期望miR-133b成为提高输卵管积水患者受孕成功率治疗的新靶点提供充分的科学依据。

子宫内膜蜕膜化缺陷致使输卵管积水患者胚胎种植失败的重要原因，但机制不明。我们证实输卵管积水损害子宫内膜间质细胞发生蜕膜化，并发现miR-133b在输卵管积水患者分泌中期子宫内膜组织中及输卵管积水处理的人子宫内膜间质细胞中的表达量显著减少；过表达miR-133b能促进子宫内膜间质细胞蜕膜化，而敲降内源性miR-133b能抑制子宫内膜间质细胞蜕膜化。miR-133b靶向下调蜕膜化抑制分子KLF12的表达，进而增加LIF的表达和LIF/STAT通路活性，促进子宫内膜蜕膜化的发生，初步阐明了输卵管积水患者子宫内膜蜕膜化损伤的分子机制。此外，我们也探究了临床复发性流产患者蜕膜组织中异常低表达的miR-133b通过调控SUMO1参与影响复发性流产患者子宫组织蜕膜的维持。这些研究为探索临床蜕膜化障碍（输卵管积水、复发性流产等）患者子宫内膜蜕膜化缺陷的发病机制和治疗提供新靶点和新方向。