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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.

Titel:	Long noncoding RNA ADAMTS9-AS1 represses ferroptosis of endometrial stromal cells by regulating the miR-6516-5p/GPX4 axis in endometriosis.
Autor/in / Beteiligte Person:	Wan, Y ; Gu, C ; Kong, J ; Sui, J ; Zuo, L ; Song, Y ; Chen, J
Link:	Full Text Finder (Volltext)
Zeitschrift:	Scientific reports, Jg. 12 (2022-02-16), Heft 1, S. 2618
Veröffentlichung:	London : Nature Publishing Group, copyright 2011-, 2022
Medientyp:	academicJournal
ISSN:	2045-2322 (electronic)
DOI:	10.1038/s41598-022-04963-z
Schlagwort:	Animals Cell Movement genetics Cell Proliferation genetics Cells, Cultured Disease Models, Animal Endometriosis pathology Endometriosis therapy Female Humans Mice, Inbred BALB C Molecular Targeted Therapy Mice ADAMTS9 Protein physiology Endometriosis genetics Endometriosis physiopathology Endometrium cytology Endometrium physiology Ferroptosis genetics Ferroptosis physiology Gene Expression genetics MicroRNAs genetics MicroRNAs metabolism Phospholipid Hydroperoxide Glutathione Peroxidase genetics Phospholipid Hydroperoxide Glutathione Peroxidase metabolism RNA, Long Noncoding physiology Stromal Cells physiology
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't Language: English [Sci Rep] 2022 Feb 16; Vol. 12 (1), pp. 2618. <i>Date of Electronic Publication: </i>2022 Feb 16. MeSH Terms: ADAMTS9 Protein / physiology ; Endometriosis / genetics ; Endometriosis / physiopathology ; Endometrium / cytology ; Endometrium / physiology ; Ferroptosis / genetics ; Ferroptosis / physiology ; Gene Expression / genetics ; MicroRNAs / genetics ; MicroRNAs / metabolism ; Phospholipid Hydroperoxide Glutathione Peroxidase / genetics ; Phospholipid Hydroperoxide Glutathione Peroxidase / metabolism ; RNA, Long Noncoding / physiology ; Stromal Cells / physiology ; Animals ; Cell Movement / genetics ; Cell Proliferation / genetics ; Cells, Cultured ; Disease Models, Animal ; Endometriosis / pathology ; Endometriosis / therapy ; Female ; Humans ; Mice, Inbred BALB C ; Molecular Targeted Therapy ; Mice References: Deiana, D. et al. 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Long non-coding RNA H19 regulates Bcl-2, Bax and phospholipid hydroperoxide glutathione peroxidase expression in spontaneous abortion. Exp. Ther. Med. 21, 41 (2021). (PMID: 3327397110.3892/etm.2020.9473) Substance Nomenclature: 0 (MicroRNAs) ; 0 (RNA, Long Noncoding) ; EC 1.11.1.12 (Phospholipid Hydroperoxide Glutathione Peroxidase) ; EC 1.11.1.9 (glutathione peroxidase 4, mouse) ; EC 3.4.24.- (ADAMTS9 Protein) ; EC 3.4.24.- (Adamts9 protein, mouse) Entry Date(s): Date Created: 20220217 Date Completed: 20220314 Latest Revision: 20240226 Update Code: 20240226 PubMed Central ID: PMC8850595

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Long noncoding RNA ADAMTS9-AS1 represses ferroptosis of endometrial stromal cells by regulating the miR-6516-5p/GPX4 axis in endometriosis.