Abstract
We first reported that the Hippo-YAP signaling pathway plays a critical role in the pathogenesis of endometriosis (EMS). Autophagy is also related to the invasion ability of endometrial cells and is involved in the pathogenesis of EMS through multi-levels. However, the precise regulatory mechanism of YAP on autophagy in the eutopic endometrial stromal cells (ESCs) is still unclear. Primary eutopic ESCs of EMS patients (n = 12) and control patients without EMS (n = 9) were isolated and cultured to investigate the expressions of YAP and mTOR, the role of YAP in autophagy, and the effect of the YAP-autophagy signal on the decidualization of the eutopic ESCs. Endometriosis-related sequencing data (GSE51981) in the GEO database were used to find the genes significantly correlated with YAP. We found 155 genes with significant differences in the interaction with YAP in EMS from the dataset, and the autophagy pathway was significantly enriched. Following on from our previous studies of YAP knockdown, overexpression of YAP resulted in an increased expression of mTOR and decreased ratio of LC3-II/LC3-I and autophagy markers, in the eutopic ESCs; transmission electron microscope observation also showed fewer autophagosomes compared with the control cells. Furthermore, ESCs of the Rapamycin-treated group showed significant decidual-like changes with significantly increased decidual prolactin level at 72 h after in vitro decidualization. These results demonstrate that the increased YAP inhibited the level of autophagy by upregulating the mTOR signal in the eutopic ESCs of endometriosis. The YAP-autophagy signal plays an important role in the pathogenesis of endometriosis-associated infertility.
Highlights
Endometriosis (EMS) is a chronic inflammatory hormonedependent disease, characterized by the growth of the endometrium outside the uterus, affecting more than 190 million women worldwide and up to 10% of women of reproductive age [1,2,3]
We first found a significant correlation in the Yes-associated protein (YAP) interaction set of 155 genes through bioinformatics analysis, from the GSE51981 chip samples of endometriosis-associated research (Endometriosis vs. Non-Endometriosis), analyzed the GO enrichment analysis and KEGG pathway enrichment, and found that these genes interact with YAP and the enrichment of autophagy function significantly; YAP may be correlated with cell autophagy in EMS
In vitro cell experiments showed that the protein level of the negative regulator of autophagy, mammalian target of rapamycin (mTOR), was significantly increased in the eutopic endometrial stromal cells in EMS than in the normal endometrial stromal cells, while the ratio of autophagy marker protein LC3-II/LC3-I was significantly decreased in the eutopic ESCs than in the normal endometrial stromal cells
Summary
Endometriosis (EMS) is a chronic inflammatory hormonedependent disease, characterized by the growth of the endometrium outside the uterus, affecting more than 190 million women worldwide and up to 10% of women of reproductive age [1,2,3]. Chronic pelvic pain and infertility caused by the disease seriously affect women’s reproductive health and quality of life. The endometrium is a complex tissue with periodic changes, which is regulated by ovarian steroids, autocrine/ paracrine, and signaling pathways. Many studies have found that some signaling pathways play an important role in endometriosis, such as the over-activated MAPK pathway and PI3K/AKT pathway, which affect the role of progesterone and block the decidualization of endometrial stromal cells (ESCs) [11]. Abnormal regulation of endometrial signaling pathways, local inflammation, stromal differentiation, and improper endometrial reconstruction in EMS may lead to a condition of endometrium that is unacceptable for implanting embryos [8, 12]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
