Decreased expression of NR4A nuclear receptors in adenomyosis impairs endometrial decidualization

Yue Jiang, Ruiwei Jiang, Xi Cheng, Qun Zhang, Yali Hu, Hui Zhang, Yun Cao, Mei Zhang, Junxia Wang, Lijun Ding, Zhenyu Diao, Haixiang Sun (+1 others)
2016 Molecular human reproduction  
STUDY QUESTION: How do NR4A receptors drive decidualization of human endometrial stromal cells (hESCs)? SUMMARY ANSWER: 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. WHAT IS KNOWN ALREADY: A close relationship between impaired decidualization and subfertility has been
more » ... fertility has been established. In human endometrial stromal cells, orphan nuclear receptor NR4A is a novel regulator of decidualization. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: 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. MAIN RESULTS AND THE ROLE OF CHANCE: 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.
doi:10.1093/molehr/gaw042 pmid:27515096 fatcat:65errxqpfbh6xj54phjho2ii2u