Differentially-Expressed miRNAs in Ectopic Stromal Cells Contribute to Endometriosis Development: The Plausible Role of miR-139-5p and miR-375

Abstract

microRNA (miRNA) expression level alterations between endometrial tissue and endometriotic lesions indicate their involvement in endometriosis pathogenesis. However, as both endometrium and endometriotic lesions consist of different cell types in various proportions, it is not clear which cells contribute to variability in miRNA levels and the overall knowledge about cell-type specific miRNA expression in ectopic cells is scarce. Therefore, we utilized fluorescence-activated cell sorting to isolate endometrial stromal cells from paired endometrial and endometrioma biopsies and combined it with high-throughput sequencing to determine miRNA alterations in endometriotic stroma. The analysis revealed 149 abnormally expressed miRNAs in endometriotic lesions, including extensive upregulation of miR-139-5p and downregulation of miR-375 compared to eutopic cells. miRNA transfection experiments in the endometrial stromal cell line ST-T1b showed that the overexpression of miR-139-5p resulted in the downregulation of homeobox A9 (HOXA9) and HOXA10 expression, whereas the endothelin 1 (EDN1) gene was regulated by miR-375. The results of this study provide further insights into the complex molecular mechanisms involved in endometriosis pathogenesis and demonstrate the necessity for cell-type-specific analysis of ectopic tissues to understand the interactions between different cell populations in disease onset and progression.

Role of Non-coding RNAs in the Pathogenesis of Endometriosis

“…They reported downregulation of miR-375 in these cells compared to eutopic cells. This miRNA has been shown to regulate expression of the endothelin 1 (EDN1) gene (30). Yang et al have shown down-regulation of miR-200b, miR-15a-5p, miR-19b-1-5p, miR-146a-5p, and miR-200c while up-regulation of VEGFA in endometriotic tissues.…”

“…Another technical development which has facilitated identification of this process has been the cell sorting technique. This technique has paved the way for cell-type-specific analysis of ectopic tissues to recognize the interactions between different cell types during the course of disease (30).…”

Endometriosis Associated Infertility: A Critical Review and Analysis on Etiopathogenesis and Therapeutic Approaches

“…Recent findings of Rekker et al (2018), suggested that changing the miRNA expression patterns of the endometrial stromal cells could to be involved in the pathogenesis of endometriosis [ 122 ]. In their endeavors, the research team discovered 21 miRNAs with such modified expressions, one of them being miR-139-5p.…”

“…In their endeavors, the research team discovered 21 miRNAs with such modified expressions, one of them being miR-139-5p. This miRNA has a direct implication in regulating the homeobox gene, presenting a suppressive outcome on both the HOXA9 and HOXA10 genes [ 122 , 123 ]. Boergese et al and several other researchers published studies in regard to miRNA and its expression in the lesions of endometriosis, with the summarized results being shown in Table 1 .…”

The differential expression of miRNAs between ovarian endometrioma and endometriosis-associated ovarian cancer

“…MicroRNAs have been implicated to play a vital role in development, differentiation, cell proliferation and apoptosis. Circulating micro-RNAs in endometriosis have been shown to be potential biomarkers of the disease [8], and Rekker K et al reported that circulating miR-141, miR-200a and miR-200c have altered plasma levels in patients with endometriosis and vary with blood collection time [9]. Cosar et al also revealed that miR-125b-5p can be a diagnostic marker for endometriosis and, in combination with miR-451a or miR3613-5b, improves the rate of a correct diagnosis of endometriosis [10].…”