MicroRNA-210-3p Regulates Endometriotic Lesion Development by Targeting IGFBP3 in Baboons and Women with Endometriosis

Abstract

MicroRNAs (miRs) play an important role in the pathophysiology of endometriosis; however, the role of miR-210 in endometriosis remains unclear. This study explores the role of miR-210 and its targets, IGFBP3 and COL8A1, in ectopic lesion growth and development. Matched eutopic (EuE) and ectopic (EcE) endometrial samples were obtained for analysis from baboons and women with endometriosis. Immortalized human ectopic endometriotic epithelial cells (12Z cells) were utilized for functional assays. Endometriosis was experimentally induced in female baboons (n = 5). Human matched endometrial and endometriotic tissues were obtained from women (n = 9, 18–45 years old) with regular menstrual cycles. Quantitative reverse transcript polymerase chain reaction (RT-qPCR) analysis was performed for in vivo characterization of miR-210, IGFBP3, and COL8A1. In situ hybridization and immunohistochemical analysis were performed for cell-specific localization. Immortalized endometriotic epithelial cell lines (12Z) were utilized for in vitro functional assays. MiR-210 expression was decreased in EcE, while IGFBP3 and COL8A1 expression was increased in EcE. MiR-210 was expressed in the glandular epithelium of EuE but attenuated in those of EcE. IGFBP3 and COL8A1 were expressed in the glandular epithelium of EuE and were increased compared to EcE. MiR-210 overexpression in 12Z cells suppressed IGFBP3 expression and attenuated cell proliferation and migration. MiR-210 repression and subsequent unopposed IGFBP3 expression may contribute to endometriotic lesion development by increasing cell proliferation and migration.

Spatial Transcriptomic Analysis Identifies Epithelium-Macrophage Crosstalk in Endometriotic Lesions

“…Inflammatory cytokines are increased in the peritoneal fluid of women with endometriosis [30], likely influencing gene expression. Indeed, miRNAs, 9 Notch signaling, aromatase enzymes, prostaglandins, and progestin responsiveness are altered in lesions compared to matched endometrial tissues [31][32][33][34][35][36][37][38][39][40][41][42].…”

“…Further, patient rather than tissue type, that is lesion or endometrium, was the primary determinant of gene expression based on principal component and UMAP plots. The differences observed in macrophage gene expression are likely due to the presence of peritoneal and monocyte-derived macrophages in lesions, compared to tissue resident macrophages in the eutopic endometrium [43–45].…”

The Known, the Unknown and the Future of the Pathophysiology of Endometriosis

“…This miRNA has been shown to be downregulated in the ectopic endometrium of women and baboons with endometriosis, while IGFBP3 and COL8A1 expression was increased in the ectopic endometrial tissue. MiR-210 suppression was shown to contribute to endometriotic lesion development by increasing cell proliferation and migration [ 161 ].…”

Plasma microRNA expression in adolescents and young adults with endometriosis: the importance of hormone use

“…Compared to other RNA species, miRNAs are relatively RNAase-resistant, rendering them more stable against degradation ( 9 ). Recently research has expanded into elucidating miRNA profiles of endometriosis ( 10 – 12 ), and investigating how changes in miRNA expression may impact gene expression in ectopic endometrial tissue ( 13 , 14 ). While recent studies have reported promising results for the use of miRNA signatures in endometriosis diagnosis ( 15 – 19 ), gaps remain in our understanding of the relationship between miRNAs and endometriosis etiology ( 12 ).…”