MicroRNA 21a-5p overexpression impacts mediators of extracellular matrix formation in uterine leiomyoma

Abstract

BackgroundMicroRNAs (MiR) may promote fibroid development via altered expression of genes involved in cell proliferation and ECM formation, and evidence supports aberrant expression of MicroRNA (MiR) 21a-5p in fibroids. The purpose of this study was to investigate the functional significance of MiR 21a-5p overexpression in the pathobiology of leiomyomata (fibroids).MethodsA basic science experimental design using immortalized fibroid and myometrial cell lines derived from patient-matched specimens was used. Stable overexpression of MiR-21a-5p in an immortalized fibroid and patient matched myometrial cell line was achieved through lentiviral vector infection. Main outcome measures were MiR-21-5p overexpression, target gene and protein expression, collagen (COL1A1) production, cell proliferation, cell migration, and cell cycle stages of fibroid and myometrial immortalized cell lines.ResultsMiR-21a-5p was overexpressed to similar levels in fibroid and myometrial cell lines after lentiviral infection. Increased expression of miR-21 resulted in increased gene and protein expression of TGF-β3 in both fibroid and myometrial cells. Changes in expression of the ECM genes Fibronectin, Collagen 1A1, CTGF, Versican and DPT were seen in both fibroid and myometrial cells. Changes were also seen in Matrix Metalloproteinase (MMP) related genes including MMP 2, MMP 9, MMP 11 and Serpine 1 in both fibroid and myometrial cells. MiR-21 upregulation resulted in increased proliferation and migration in fibroid cells compared to myometrial cells.ConclusionsMiR-21a-5p overexpression results in changes in the expression of ECM mediators in both fibroid and myometrial cells, and increased cell proliferation in fibroid cells. These finding suggest a potential functional role of MiR-21a-5p in the development of uterine fibroids and warrant further investigation.Electronic supplementary materialThe online version of this article (10.1186/s12958-018-0364-8) contains supplementary material, which is available to authorized users.

MicroRNA-139-5p Regulates Fibrotic Potentials via Modulation of Collagen Type 1 and Phosphorylated p38 MAPK in Uterine Leiomyoma

“… 38 Therefore, our results suggest that the promotion of fibroblast connective tissue cell migration induced by suppression of miR-139-5p expression may contribute to fibrosis in uterine leiomyomas. Similar to our results, miR-150-5p and miR-21a-5p are also known to induce changes in cell migration in uterine leiomyomas, 16 35 but further research is warranted to determine the pathways regulated by these miRNAs.…”

“… 33 Several studies have investigated other miRNAs related to the changes associated with excessive ECM deposition observed in uterine fibroids. 34 35 Cardozo, et al 35 reported that miR-21a-5p overexpression modulated the expression of ECM genes in both fibroid and myometrial cells and increased cell proliferation and migration in fibroid cells. However, there was no significant difference in the expression level of miR-21-5p between the fibroid and myometrial cells.…”

The Role of miRNA and Related Pathways in Pathophysiology of Uterine Fibroids—From Bench to Bedside

“…Finally, the miR-21 upregulation resulted in the increased proliferation of UF cells. These findings emphasize the functional role of this family in UFs formation and growth and could provide the basis for further research [79].…”

“…The expression of TGF-β receptor type II is the target of miR-21 in UFs, so it may mediate its biological activities by binding to TGF-β receptors [29]. In a recent study by Cardozo et al (2018) [79], the overexpression of miR-21a-5p in an immortalized UF was achieved through vector infection. An increased expression of miR-21 resulted in the increased protein expression of TGF-β3 in UFs and myometrial cells.…”

MiR-150-5p May Contribute to Pathogenesis of Human Leiomyoma via Regulation of the Akt/p27Kip1 Pathway In Vitro

“…MiR-21 expression is also known to be dysregulated, having an impact on cellular apoptosis and translation in leiomyoma cells [24]. In addition, a recent study reported that miR-21 increases gene and protein expression of TGF-β3 and changes the expression of extracellular matrix genes such as fibronectin, collagen 1A1, CTGF, Versican, and DPT in vitro [25]. Interestingly, the dysregulation of miR-21 is known to be involved not only in leiomyoma but also in various OB/Gyn diseases such as endometrial cancer, endometriosis, preeclampsia, and fetal growth restriction through different mechanisms [26,27,28].…”