Department of Reproductive Medicine, West China Second University Hospital of Sichuan University, Chengdu, China.
Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital of Sichuan University, Chengdu, China.
Front Endocrinol (Lausanne). 2022 Jan 31;13:813165. doi: 10.3389/fendo.2022.813165. eCollection 2022.
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 ( = 12) and control patients without EMS ( = 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 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.
我们首次报道 Hippo-YAP 信号通路在子宫内膜异位症（EMS）的发病机制中起关键作用。自噬也与子宫内膜细胞的侵袭能力有关，并通过多个层次参与 EMS 的发病机制。然而，YAP 对在位子宫内膜基质细胞（ESCs）中自噬的精确调节机制尚不清楚。分离培养 EMS 患者（n = 12）和无 EMS 对照组患者（n = 9）的原发性在位 ESCs，以研究 YAP 和 mTOR 的表达、YAP 在自噬中的作用，以及 YAP-自噬信号对在位 ESCs 蜕膜化的影响。使用 GEO 数据库中与 EMS 相关的测序数据（GSE51981），寻找与 YAP 显著相关的基因。我们从该数据集发现了 155 个与 YAP 相互作用差异显著的 EMS 相关基因，自噬途径显著富集。在我们之前对 YAP 敲低的研究基础上，过表达 YAP 导致在位 ESCs 中 mTOR 表达增加，LC3-II/LC3-I 比值和自噬标志物减少；透射电镜观察也显示与对照细胞相比自噬体更少。此外，雷帕霉素处理组的 ESCs 在蜕膜化 72 小时后表现出明显的蜕膜样变化，蜕膜催乳素水平显著升高。这些结果表明，在位子宫内膜异位症中 YAP 增加通过上调 mTOR 信号抑制自噬水平。YAP-自噬信号在子宫内膜异位症相关不孕的发病机制中起着重要作用。
