Abstract
Endometriosis (EMs) is one of the most frequent diseases of reproductive-age women and is characterized by the growth of endometrial tissues beyond the uterus. The enhanced proliferative and migratory potential of endometrial stromal cells (ESCs) plays an important role in the progression of EMs. Mounting studies have demonstrated that long noncoding RNAs (lncRNAs) exert an important role in regulating the development and progression of EMs. Given the aberrant expression of lncRNA ADAMTS9-AS1 in ectopic endometrium (ecEM), we investigated the biological effect of ADAMTS9-AS1 on ESC proliferation and migration and explored the underlying mechanism. The current data showed that ADAMTS9-AS1 expression was significantly upregulated in ecEM compared with eutopic endometrium (euEM) in patients with EMs and in a murine model of EMs. Functionally, ADAMTS9-AS1 knockdown in ectopic ESCs (EESCs) decreased cell viability and migration, whereas ADAMTS9-AS1 overexpression in normal ESCs (NESCs) enhanced cell viability and migration. More importantly, the effect of ADAMTS9-AS1 inhibition on decreasing ESC viability was significantly blocked by ferrostatin-1 (Fer-1, a ferroptosis inhibitor), and ADAMTS9-AS1 overexpression repressed erastin (a ferroptosis activator)-induced cell death. Furthermore, the regulatory role of ADAMTS9-AS1 in ferroptosis was defined and evidenced by increased reactive oxygen species (ROS) levels and malonyl dialdehyde (MDA) content and decreased expression of glutathione peroxidase 4 (GPX4) after ADAMTS9-AS1 inhibition. Mechanistically, ADAMTS9-AS1 functioned as a competing endogenous RNA (ceRNA) by sponging miR-6516-5p to derepress the expression of GPX4, the critical repressor of ferroptosis. Taken together, these results demonstrate that upregulated ADAMTS9-AS1 accelerates ESC proliferation and migration by regulating miR-6516-5p/GPX4-dependent ferroptosis and may be a potential target for the treatment of EMs.
Highlights
Endometriosis (EMs) is a common and polyfactorial disorder in which environmental, genetic, immunologic, and hormonal aberrations are correlated with the pathological process of E Ms1,2
The data from quantitative RT‐PCR (qPCR) analysis in seventeen paired ectopic endometrium (ecEM) and eutopic endometrium (euEM) tissues showed that the expression level of ADAMTS9-AS1 was significantly increased in ecEM compared to euEM (Fig. 1A)
Primary ectopic endometrial stromal cell (ESC) (EESCs) and normal ESCs (NESCs) were collected from the ecEM and euEM tissues, respectively, and the ADAMTS9-AS1 level was assessed
Summary
Endometriosis (EMs) is a common and polyfactorial disorder in which environmental, genetic, immunologic, and hormonal aberrations are correlated with the pathological process of E Ms1,2. Emerging evidence has revealed the role of lncRNAs in the pathogenesis of EMs. A total of 576 differentially expressed lncRNAs were identified in the ectopic endometrium (ecEM) of adenomyosis, of which 388 lncRNAs were increased and 188 lncRNAs were d ecreased[13]. Zhang et al demonstrated that the expression of lncRNA CCDC144NL-AS1 is upregulated in ectopic endometrial tissues compared with paired eutopic endometrial and normal endometrial (NE) tissues[14]. Functional studies further showed that CCDC144NL-AS1 inhibition decreases endometrial stromal cell (ESC) migration and invasion[14]. The levels of iron and lipid peroxide content are increased in the peritoneal fluid of women with EMs compared to those w ithout[23,24,25], the role of ferroptosis in EMs has not been systematically investigated. ADAMTS9-AS1 functioned as a competing endogenous RNA (ceRNA) by sponging miR-6516-5p to derepress the expression of GPX4
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