MicroRNA-146a modulates TGF-β1-induced phenotypic differentiation in human dermal fibroblasts by targeting SMAD4

Abstract

During wound healing and tissue repair the dermal fibroblast-to-myofibroblast transdifferentiation plays an important role, transforming growth factor-β1 (TGF-β1) is considered to be the main stimuli factor of transdifferentiation. MicroRNAs (miRNAs) have recently emerged as key post-transcriptional regulators of gene expression. The involvement of miRNAs and their roles in TGF-β1-induced myofibroblast transdifferentiation remains to be determined in detail. The current study found that the expression of miR-146a was upregulated in human dermal fibroblasts cells in response to TGF-β1 stimulation in dose-dependent manner by quantitative RT-PCR. Bioinformatic analyses predict that signaling effectors mothers against decapentaplegic protein 4 (SMAD4) is a miR-146a target gene. Luciferase assay demonstrated that miR-146a mimics suppressed SMAD4 3'-UTR reporter construct activity. Furthermore, miR-146a overexpression in dermal fibroblast did not decrease target mRNA levels, but significantly reduced target protein expression. In addition, dermal fibroblasts transfected with miR-146a mimics exhibited attenuated TGF-β1 -induced α-smooth muscle actin (α-SMA) expression compared with the control. This study demonstrated that miR-146a may function as a novel negative regulator to modulate myofibroblast transdifferentiation during TGF-β1 induction by targeting SMAD4.

Advances in the role of oxytocin receptors in human parturition

“…Consistent with this, hsa-miR-146a-5p was found to attenuate the expression of α-smooth muscle actin, the major protein constituent of uterine smooth muscle and essential component of the contractile machinery in human dermal fibroblasts [64]. Changes in miR-200 expression have been reported in multiple types of cancers including pancreatic [66], prostate [67], breast [68] and ovarian cancer [69].…”

MicroRNA-146a Regulates Human Foetal Femur Derived Skeletal Stem Cell Differentiation by Down-Regulating SMAD2 and SMAD3

“…Various components of the TGF-β pathway; namely SMAD2, SMAD3, SMAD4, TGFB-induced factor homeobox 1 (TGIF1), BMP and activin membrane-bound inhibitor homolog (BAMBI) and activin A receptor type IC/I/Type II-like 1 (ACVR1C/ACVR1B/ACVRL1) were highlighted as potential targets of miR-146a, advocating the function of this miR in diaphyseal cells maybe mediated via attenuation of the TGF-β pathway [30]. miR-146 has previously been identified to modulate myofibroblast trans-differentiation during TGF-β1 induction by targeting SMAD4 [18], [36] and miR-146 may also be an important regulator during the inflammatory state of osteoarthritis, as IL-1β induced production of TNF-α, a pro-inflammatory cytokine known to play a role in osteoarthritis, was significantly reduced by miR-146 overexpression [19], [20], [37]. Furthermore, overexpression of miR-146a has been shown to protect the human bronchial epithelial from apoptosis and to promote cell proliferation through up-regulation of Bcl-XL and STAT3 phosphorylation [21], [38].…”

Exogenous oxytocin modulates human myometrial microRNAs

“…Consistent with this, hsa-miR-146a-5p has also been shown to attenuate the expression of asmooth muscle actin, which is the major protein constituent of uterine smooth muscle and essential component of the contractile machinery, in human dermal fibroblasts. 29 We recently have shown a proinflammatory role for oxytocin in human gestational tissues whereby specific stimulation of oxytocin by its ligand drives the sequential activation of MAPKinases and NF-kB and subsequent prostaglandin and proinflammatory Myocyte expression of hsa-miR-146a-5p, hsa-miR-146b-3p, hsa-miR196b-3p, and hsa-miR-876-5p after oxytocin exposure A, Hsa-miR-146a-5p expression in myocytes was reduced significantly after exposure to oxytocin (100 nmol/L) for 2 hours with no change in expression seen at 1 and 4 hours. B, Hsa-miR-146b-3p expression in myocytes was not altered by the addition of oxytocin.…”