Abstract
Downregulated microRNA-142-3p signaling contributes to the pathogenesis of endometriosis, an invasive disease where the lining of the uterus grows at ectopic locations, by yet incompletely understood mechanisms. Using bioinformatics and in vitro assays, this study identifies cytoskeletal regulation and integrin signaling as two relevant categories of miR-142-3p targets. qPCR revealed that miR-142-3p upregulation in St-T1b cells downregulates Rho-associated protein kinase 2 (ROCK2), cofilin 2 (CFL2), Ras-related C3 botulinum toxin substrate 1 (RAC1), neural Wiskott-Aldrich syndrome protein (WASL), and integrin α-V (ITGAV). qPCR and Western-blotting showed miR-142-3p effect on WASL and ITGAV was significant also in primary endometriotic stroma cells. Luciferase reporter assays in ST-T1b cells then confirmed direct regulation of ITGAV and WASL. On the functional side, miR-142-3p upregulation significantly reduced ST-T1b cell size, the size of vinculin plaques, migration through fibronectin-coated transwell filters, and the ability of ST-T1b and primary endometriotic stroma cells to contract collagen I gels. These results suggest that miR-142-3p has a strong mechanoregulatory effect on endometrial stroma cells and its external administration reduces the invasive endometrial phenotype. Within the limits of an in vitro investigation, our study provides new mechanistic insights into the pathogenesis of endometriosis and provides a perspective for the development of miR-142-3p based drugs for inhibiting invasive growth of endometriotic cells.
Highlights
MicroRNAs are short non-coding RNAs that post-transcriptionally regulate cellular signaling by dampening the expression of their target mRNAs [1]
Our results suggest miR-142-3p contributes to the pathophysiology of endometriosis at ectopic locations by regulating the expression of the Rho GTPases that regulate cytoskeleton and of integrin signaling
The putative mRNAs targeted by miR142-3p were identified in silico using a conservative approach that relies on three algorithms MirTarget [31], Diana, and TargetScan
Summary
MicroRNAs are short non-coding RNAs that post-transcriptionally regulate cellular signaling by dampening the expression of their target mRNAs [1]. This highly conserved class of genes comprises more than 2000 species [2] that constitute around 1% of all predicted genes [1]. It is not surprising that altered microRNA gene expression has been shown to accompany and contribute to several human diseases [3], including those of the human reproductive system [5,6,7]. While the exact causes of the disease remain unknown, several studies confirmed that the phenotype of endometrial ectopic cells differs from that found in eutopic (eut) endometrium [5,9,10,11]. Ectopic (ect) endometrial cells are progesterone resistant [12], can produce estrogen [13], are contractile [14] and invasive [15]
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