Decreased expression of NR4A nuclear receptors in adenomyosis impairs endometrial decidualization
Decreased expression of NR4A nuclear receptors in adenomyosis impairs endometrial decidualization
复制标题
子宫腺肌病中 NR4A 核受体表达的减少会损害子宫内膜蜕膜化。
DOI：
10.1093/molehr/gaw042
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发表时间：
2016-09-01
影响因子：
4
通讯作者：
Yan, Guijun
中科院分区：
文献类型：
--
作者：
Jiang, Yue;Jiang, Ruiwei;Yan, Guijun
NR 4A受体如何驱动人子宫内膜间质细胞（hESCs）的蜕膜化？NR 4A受体通过转录激活FOXO 1A调节子宫内膜的蜕膜化，子宫腺肌病患者在位内膜NR 4A受体表达减少可能是子宫内膜蜕膜化受损和生育力低下的一种新机制，蜕膜化受损与生育力低下之间存在密切关系。在人子宫内膜间质细胞中，孤儿核受体NR 4A是一种新的蜕膜化调节因子。从在位子宫内膜组织中分离的原代hESC用于评估NR 4A受体的生物学功能。采用腺病毒介导的NR 4A过表达和靶向NR 4A和FOXO 1A的小干扰RNA来研究其分子机制。通过实时定量PCR、免疫染色和荧光素酶报告基因分析检测基因表达调控。采用体外人工蜕膜化实验研究NR 4A 1在体外诱导人胚胎干细胞（hESC）蜕膜化过程中的作用，NR 4A通过上调催乳素（PRL）和胰岛素样生长因子结合蛋白-1（IGFBP-1）的表达和转化来调控hESC的蜕膜化。子宫Nr 4a 1的缺失导致女性由于蜕膜化受损而生育力低下。从机制上讲，NR 4A与FOXO 1A启动子区域内的神经生长因子1B（NGFI-B）反应元件（NBRE）（-843至-813）结合并调节FOXO 1A表达。FOXO 1A的缺失显著抑制PRL和IGFBP-1的表达，如NR 4A所诱导的。此外，NR 4A和FOXO 1A的表达在子宫腺肌病子宫内膜组织中较生育对照组低，尤其是在间质区。异位NR 4A表达将子宫腺肌病hESC中的PRL和IGFBP-1表达恢复至接近正常水平。此外，PI 3 K/AKT信号通路参与诱导hESC在蜕膜化刺激下表达NR 4A，子宫腺肌病患者子宫内膜间质中p（Ser 473）-AKT水平显著升高。本研究得到了国家自然科学基金（81170570，G.J.Y.，2005）的资助，并获得了一个新的研究成果，即NR 4A受体激动剂的发现，将对子宫内膜异位症和子宫内膜异位症等蜕膜化不全性不孕症患者的治疗起到重要的作用。81370683，G.J.Y. 81501251，Y.J. 31571189，H.X.S.和81571402，G.J.Y.），江苏省临床医学科学专项基金（BL 2014003，H.X.S.）。作者没有利益冲突需要声明。
How do NR4A receptors drive decidualization of human endometrial stromal cells (hESCs)?NR4A receptors modulate endometrial decidualization by transcriptional activation of FOXO1A, and in adenomyosis patients, the reduced expression of NR4A receptors in the eutopic endometrium may represent a novel mechanism to explain impaired decidualization and subfertility.A close relationship between impaired decidualization and subfertility has been established. In human endometrial stromal cells, orphan nuclear receptor NR4A is a novel regulator of decidualization.Eutopic endometrial tissues and hESCs from fertile controls (n = 56) and adenomyosis patients (n = 27) were collected for in vitro analysis. Primary hESCs isolated from eutopic endometrial tissues were used to evaluate the biological function of NR4A receptors. Adenovirus-mediated overexpression of NR4A and small interfering RNAs targeting NR4A, and FOXO1A were used to investigate the molecular mechanisms. Gene expression regulation was examined by real-time-quantitative PCR, immunostaining, and luciferase reporter assay. Artificial decidualization assay was performed to investigate the role of NR4A1 during decidualization in vivo.NR4A modulates the decidualization of hESCs by upregulating prolactin (PRL) and insulin-like growth factor binding protein-1 (IGFBP-1) expression and transformation in vitro. Loss of uterine Nr4a1 results in female subfertility due to impaired decidualization. Mechanistically, NR4A binds to the nerve growth factor 1B (NGFI-B) -responsive element (NBRE) (-843 to -813) within the FOXO1A promoter region and regulates FOXO1A expression. Loss of FOXO1A significantly inhibits PRL and IGFBP-1 expression, as induced by NR4A. Moreover, the expression of NR4A and FOXO1A was lower in adenomyosis endometrial tissues compared to fertile controls, especially in stroma compartments. Ectopic NR4A expression rescued PRL and IGFBP-1 expression in adenomyotic hESCs to near-normal levels. Furthermore, PI3K/AKT signaling pathway involved in inducing NR4A expression under decidualization stimuli in hESCs and the level of p(Ser473)-AKT was significantly higher in stroma in endometrium from patients with adenomyosis.This is an in vitro study with a small sample size, utilizing stromal cell cultures from endometrial tissues of adenomyosis patients. Furthermore, results obtained should also be confirmed in a larger data set and with adenomyosis mouse models in vivo.Identification of a positive agonist of NR4A receptors will be critical for the improved treatment of patients with conditions of insufficient decidualization-associated infertility, such as adenomyosis and endometriosis.This study was supported by the National Natural Science Foundation of China (81170570, G.J.Y. 81370683, G.J.Y. 81501251, Y.J. 31571189, H.X.S. and 81571402, G.J.Y.), and a special grant for clinical medicine science of Jiangsu Province (BL2014003, H.X.S.). The authors have no conflicts of interest to declare.