miR-142-3p Reduces the Size, Migration and Contractility of Endometrial and Endometriotic Stromal Cells by Targeting Integrin- and Rho GTPase-related Pathways that Regulate Cytoskeletal Function

Abstract

Downregulated microRNA-142-3p signaling contributes to the pathogenesis of endometriosis [1] [2], 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 ROCK2, CFL2, RAC1, WASL and 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.

Integrin αvβ3 Induces HSP90 Inhibitor Resistance via FAK Activation in KRAS-Mutant Non-Small Cell Lung Cancer

“…2A). Because ITGB3 and ITGAv are well known to be regulated by miR-150 and miR-142, respectively [18][19][20], we confirmed that miR-150 and miR-142 were downregulated in our two AUY922 resistant NSCLC cell lines (Fig. 2B).…”

“…Previous studies have reported that TSPAN7 [ 24 ] and ITGB3 [ 20 ] are induced by microRNA-150 (miR 150) downregulation activity and that ITGAv is targeted of miR-142 [ 18 , 19 , 25 ]. Since both TSPAN7 and ITGB3 are co-direct targets of miR-150 [ 20 , 24 ], we examined whether this regulatory molecule controlled EMT and FAK activity through the blockade of TSPAN7 and ITGB3 expression, respectively.…”