Su Ren-Wei, Strug Michael R, Joshi Niraj R, Jeong Jae-Wook, Miele Lucio, Lessey Bruce A, Young Steve L, Fazleabas Asgerally T
Department of Obstetrics, Gynecology and Reproductive Biology (R.-W.S., M.R.S., N.R.J., J.-W.J., A.T.F.), Michigan State University, Grand Rapids, Michigan 49503; Cancer Institute (L.M.), Louisiana State University Health Sciences Center and Stanley S. Scott Cancer Center, New Orleans, Louisiana 70112; Greenville Health Systems (B.A.L.), University of South Carolina, Greenville, South Carolina 29605; and Department of Obstetrics and Gynecology (S.L.Y.), University of North Carolina, Chapel Hill, North Carolina 27599.
J Clin Endocrinol Metab. 2015 Mar;100(3):E433-42. doi: 10.1210/jc.2014-3720. Epub 2014 Dec 29.
Endometriosis is a common gynecological disease affecting one in 10 women of reproductive age and is a major cause of pelvic pain and impaired fertility. Endometrial stromal cells of women with endometriosis exhibit a reduced response to in vitro decidualization. NOTCH1 is critical for decidualization of both mouse and human uterine stromal cells.
This study aimed to determine whether decidualization failure in women with endometriosis is a consequence of impaired Notch signaling.
We investigated expression levels of Notch signaling components in the endometrium of women and baboons with or without endometriosis. We identified NOTCH1-regulated genes during decidualization of human uterine fibroblast (HuF) cells by microarray and quantified their expression levels in in vitro-decidualized endometrial stromal cells isolated from women with or without endometriosis.
Notch signaling receptors NOTCH1 and NOTCH4, ligands JAGGED2 and DLL4, as well as direct target genes HES5 and HEY1 were decreased in the eutopic endometrium of women and baboons with endometriosis. Notch signaling was decreased in stromal cells isolated from women with endometriosis, which was associated with impaired in vitro decidualization. Genes that were down-regulated by NOTCH1 silencing in decidualized HuF cells were also decreased in decidualized endometrial stromal cells of women with endometriosis. FOXO1 acts as a downstream target of Notch signaling and endometriosis is associated with decreased expression of NOTCH1-regulated, FOXO1-responsive genes during decidualization.
Decreased Notch signaling is associated with endometriosis and contributes to impaired decidualization through the down-regulation of FOXO1.
子宫内膜异位症是一种常见的妇科疾病，影响十分之一的育龄妇女，是盆腔疼痛和生育能力受损的主要原因。子宫内膜异位症患者的子宫内膜基质细胞对体外蜕膜化反应降低。NOTCH1对小鼠和人类子宫基质细胞的蜕膜化至关重要。
本研究旨在确定子宫内膜异位症患者蜕膜化失败是否是Notch信号受损的结果。
我们研究了有或没有子宫内膜异位症的女性和狒狒子宫内膜中Notch信号成分的表达水平。我们通过微阵列鉴定了人子宫成纤维细胞（HuF）细胞蜕膜化过程中NOTCH1调控的基因，并定量了从有或没有子宫内膜异位症的女性中分离出的体外蜕膜化子宫内膜基质细胞中这些基因的表达水平。
Notch信号受体NOTCH1和NOTCH4、配体JAGGED2和DLL4以及直接靶基因HES5和HEY1在患有子宫内膜异位症的女性和狒狒的在位内膜中减少。从子宫内膜异位症患者分离出的基质细胞中Notch信号减少，这与体外蜕膜化受损有关。在蜕膜化的HuF细胞中被NOTCH1沉默下调的基因在子宫内膜异位症患者的蜕膜化子宫内膜基质细胞中也减少。FOXO1作为Notch信号的下游靶点，子宫内膜异位症与蜕膜化过程中NOTCH1调控的、FOXO1反应性基因的表达降低有关。
Notch信号降低与子宫内膜异位症有关，并通过下调FOXO1导致蜕膜化受损。
