MicroRNA-27a-3p Is a Negative Regulator of Lung Fibrosis by Targeting Myofibroblast Differentiation

Abstract

Although microRNAs (miRs) have been well recognized to play an important role in the pathogenesis of organ fibrosis, there is a lack of evidence as to whether miRs directly regulate the differentiation of myofibroblasts, the putative effector cells during pathological fibrogenesis. In this study, we found that levels of miR-27a-3p were up-regulated in transforming growth factor-b1-treated human lung fibroblasts in a Smad2/3-dependent manner and in fibroblasts isolated from lungs of mice with experimental pulmonary fibrosis. However, both basal and transforming growth factor-b1-induced expression of miR-27a-3p were reduced in lung fibroblasts from patients with idiopathic pulmonary fibrosis compared with that from normal control subjects. Overexpression of miR-27a-3p inhibited, whereas knockdown of miR-27a-3p enhanced, the differentiation of lung fibroblasts into myofibroblasts. We found that miR-27a-3p directly targeted the phenotypic marker of myofibroblasts, a-smooth muscle actin, and two key Smad transcription factors, Smad2 and Smad4. More importantly, we found that therapeutic expression of miR-27a-3p in mouse lungs through lentiviral delivery diminished bleomycin-induced lung fibrosis. In conclusion, our data suggest that miR-27a-3p functions via a negative-feedback mechanism in inhibiting lung fibrosis. This study also indicates that targeting miR27a-3p is a novel therapeutic approach to treat fibrotic organ disorders, including lung fibrosis.

Differential miRNA Expression in the Liver of Balb/c Mice Protected by Vaccination during Crisis of Plasmodium chabaudi Blood-Stage Malaria

“…Only during the crisis phase, vaccination-protected mice exhibit elevated levels of miR-122-5p, whereas the corresponding levels further decrease in non-vaccinated mice with lethal infections. Similar courses of miRNA expression levels are here found for miR-30a known to be involved in manifestation and resolution of liver fibrosis (Roy et al, 2015), for miR-27a described to be involved in fibrosis (Cui et al, 2016), and for mir-29b known to suppress transcription of genes encoding for extracellular matrix proteins (cf. Table 1) (Roderburg et al, 2011; Lambrecht et al, 2015; Kitano and Bloomston, 2016).…”

MicroRNA-27a Suppresses Detrusor Fibrosis in Streptozotocin-Induced Diabetic Rats by Targeting PRKAA2 Through the TGF-β1/Smad3 Signaling Pathway

“…Additionally, smooth muscle miRNAs, including miR-27a, a smooth muscle miRNA, influence detrusor contractility and the voiding pattern of unrestrained rats [34], and high miR-27a expression was reported to promote renal tubulointerstitial fibrosis [21]. Increasing evidence has shown that miRNAs play an indispensable role in the pathogenesis of organ fibrosis [35]. The endoplasmic reticulum, a major subcellular compartment, is a eukaryotic organelle involved in calcium homeostasis, lipid synthesis, and protein folding and maturation [36].…”

miR-27b inhibits fibroblast activation via targeting TGFβ signaling pathway

“…In the present study, we demonstrated that miR-27b was down-regulated in fibrotic lungs and fibroblasts from bleomycin-induced mouse pulmonary fibrosis model. In contrast, miR-27a-3p was found to be increased in the fibroblasts isolated from the lungs of the bleomycin-treated mice although the same authors found that miR-27a-3p was decreased in IPF fibroblasts compared to normal lung fibroblasts [15]. Additionally, TGFβ inhibited miR-27b expression in lung epithelial A549 cells [14], but increased miR-27a expression in MRC-5 fibroblasts [15].…”

“…In contrast, miR-27a-3p was found to be increased in the fibroblasts isolated from the lungs of the bleomycin-treated mice although the same authors found that miR-27a-3p was decreased in IPF fibroblasts compared to normal lung fibroblasts [15]. Additionally, TGFβ inhibited miR-27b expression in lung epithelial A549 cells [14], but increased miR-27a expression in MRC-5 fibroblasts [15]. The reasons for these differences remain to be determined, but could be due to the differences in transcription because miR-27a-3p and miR-27b are located in different chromosomes, chromosome19 and chromosome 9, respectively.…”

“…However, this study used lung epithelial cancer cell line A549 cells rather than pulmonary fibroblasts. During the course of this work, Cui et al published a study showing that transfection of miR-27a-3p mimic into a fetal lung fibroblast cell line MRC-5 inhibited COL1A2 and alpha-smooth muscle actin (α-SMA) and this result was confirmed in IPF fibroblasts [15]. The use of a miRNA mimic could result in overwhelmed expression of a miRNA since it by-pass the cellular regulatory system for the processing of a miRNA.…”