Increased Krüppel-like factor 12 in recurrent implantation failure impairs endometrial decidualization by repressing Nur77 expression.
Increased Krüppel-like factor 12 in recurrent implantation failure impairs endometrial decidualization by repressing Nur77 expression.
复制标题
复发性着床失败中 kruppel 样因子 12 的增加通过抑制 Nur77 表达损害子宫内膜蜕膜化
DOI：
10.1186/s12958-017-0243-8
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发表时间：
2017-03-31
期刊：
影响因子：
--
通讯作者：
Sun H
中科院分区：
文献类型：
--
作者：
Huang C;Jiang Y;Zhou J;Yan Q;Jiang R;Cheng X;Xing J;Ding L;Sun J;Yan G;Sun H
蜕膜化是成功着床和妊娠建立的先决条件。蜕膜化受损在生育力低下中的关键作用已经确定。在人子宫内膜基质细胞 (hESC) 中，Krüppel 样因子 12 (KLF12) 和 Nur77 是蜕膜化的新型调节因子。我们研究了 KLF12 是否会损害复发性着床失败 (RIF) 患者的 hESC 蜕膜化。从 RIF 患者 (n = 34) 和生育对照 (n = 30) 中收集子宫内膜组织和 hESC 用于体外分析。使用从 RIF 子宫内膜组织中分离的原代 hESC 来评估 KLF12 和 Nur77 的生物学功能。此外，通过腺病毒介导的过表达研究了它们的分子机制。通过实时定量 PCR (qRT-PCR)、免疫染色和荧光素酶报告基因测定来检查基因表达调控。此外，还进行了囊胚样球体 (BLS) 和囊胚植入模型，以检查 KLF12 和 Nur77 在 hESC 胚胎扩增过程中的作用。 RIF患者的hESC表现出较差的蜕膜反应，主要特征是蜕膜催乳素（dPRL）分泌减少、转化受损和BLS扩张有限。此外，与可生育对照者相比，RIF 患者的子宫内膜组织中 KLF12 表达增加，尤其是在间质区。在这些组织中观察到 Nur77 表达的相反结果。 KLF12 通过降低 Nur77 表达来抑制 hESC 蜕膜化。从机制上讲，KLF12 与 Nur77 启动子区域的保守位点结合。 Nur77 过表达显着逆转 KLF12 介导的 dPRL 表达、蜕膜转化和 BLS/囊胚扩张的抑制。 KLF12 通过转录抑制 Nur77 损害子宫内膜蜕膜化，而 Nur77 过度表达可逆转 RIF 患者 hESC 较差的蜕膜反应。本文的在线版本 (doi:10.1186/s12958-017-0243-8) 包含补充材料，可供授权用户使用。
Decidualization is a prerequisite for successful implantation and the establishment of pregnancy. A critical role of impaired decidualization in subfertility has been established. In human endometrial stromal cells (hESCs), Krüppel-like factor 12 (KLF12) and Nur77 are novel regulators of decidualization. We investigated whether KLF12 impaired the decidualization of hESCs in recurrent implantation failure (RIF) patients. Endometrial tissues and hESCs were collected from RIF patients (n = 34) and fertile controls (n = 30) for in vitro analysis. Primary hESCs isolated from RIF endometrial tissues were used to evaluate the biological functions of KLF12 and Nur77. In addition, their molecular mechanisms were investigated by adenovirus-mediated overexpression. Gene expression regulation was examined by real-time-quantitative PCR (qRT-PCR), immunostaining and luciferase reporter assay. Further, blastocyst-like spheroid (BLS) and blastocyst implantation models were performed to examine the roles of KLF12 and Nur77 during embryo expansion on hESCs. hESCs from the RIF patients showed a poor decidual response, mainly characterized by decreased decidual prolactin (dPRL) secretion, impaired transformation and limited BLS expansion. In addition, KLF12 expression was increased in endometrial tissues from the RIF patients compared with those from the fertile controls, especially in stromal compartments. The opposite results were observed for Nur77 expression in these tissues. KLF12 repressed hESC decidualization by decreasing Nur77 expression. Mechanistically, KLF12 bound to a conserved site in the Nur77 promoter region. Nur77 overexpression significantly reversed the KLF12-mediated repression of dPRL expression, decidual transformation and BLS/blastocyst expansion. KLF12 impairs endometrial decidualization by transcriptionally repressing Nur77, and Nur77 overexpression reverses the poor decidual response of hESCs in RIF patients. The online version of this article (doi:10.1186/s12958-017-0243-8) contains supplementary material, which is available to authorized users.