MiR‐448‐5p inhibits TGF‐β1‐induced epithelial‐mesenchymal transition and pulmonary fibrosis by targeting Six1 in asthma

Abstract

MicroRNAs (miRNAs) are small yet versatile gene tuners that regulate a variety of cellular processes, including cell growth and proliferation. The aim of this study was to explore how miR‐448‐5p affects airway remodeling and transforming growth factor‐β1 (TGF‐β1)‐stimulated epithelial‐mesenchymal transition (EMT) by targeting Sine oculis homeobox homolog 1 (Six1) in asthma. Asthmatic mice models with airway remodeling were induced with ovalbumin solution. MiRNA expression was evaluated using quantitative real‐time polymerase chain reaction. Transfection studies of bronchial epithelial cells were performed to determine the target genes. A luciferase reporter assay system was applied to identify whether Six1 is a target gene of miR‐448‐5p. In the current study, we found that miR‐448‐5p was dramatically decreased in lung tissues of asthmatic mice and TGF‐β1‐stimulated bronchial epithelial cells. In addition, the decreased level of miR‐448‐5p was closely associated with the increased expression of Six1. Overexpression of miR‐448‐5p decreased Six1 expression and, in turn, suppressed TGF‐β1‐mediated EMT and fibrosis. Next, we predicted that Six1 was a potential target gene of miR‐448‐5p and demonstrated that miR‐448‐5p could directly target Six1. An SiRNA targeting Six1 was sufficient to suppress TGF‐β1‐induced EMT and fibrosis in 16HBE cells. Furthermore, the overexpression of Six1 partially reversed the protective effect of miR‐448‐5p on TGF‐β1‐mediated EMT and fibrosis in bronchial epithelial cells. Taken together, the miR‐448‐5p/TGF‐β1/Six1 link may play roles in the progression of EMT and pulmonary fibrosis in asthma.

MiR-203a-3p regulates TGF-β1-induced epithelial–mesenchymal transition (EMT) in asthma by regulating Smad3 pathway through SIX1

“…In our study, we found that TGF-β1 elevated fibronectin and vimentin levels and reduced E-cadherin level in BEAS-2B and 16HBE cells, suggesting that TGF-β1 enhanced EMT in HBE cells, which was consistent with the previous studies [27,28]. TGF-β1-induced EMT can be modulated by many molecules, including miRNAs [20,21]. Until now, the role of many miRNAs in the development of asthma has been investigated.…”

“…SIX1 was reported to inhibit tumor invasion and might be a novel therapeutic target in pancreatic cancer [33]. Also, previous study indicated that SIX1 participated in TGF-β1-induced EMT in lung cancer tissues [20]. SIX1 level was up-regulated in asthma serum samples and induced by TGF-β1 treatment in human bronchial epithelial cells.…”

“…Although asthma is commonly diagnosed in childhood, it occurs in all age groups [3]. Ra et al reported that there was no significant difference between the prevalence rate of the elderly (>65) and that of the young people (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34) [4]. A lot of stimuli, including cold air and exercise, and other risk factors such as smoking, obesity and rhinitis contribute to asthma incidence [5][6][7].…”

“…Zeng et al reported that SIX1 enhanced epithelial-mesenchymal transition (EMT) in breast cancer by interaction with miR-204-5p [19]. Additionally, recent study has indicated that SIX1 was remarkably elevated in asthmatic mice and played a major role in transforming growth factor-β (TGF-β1)-induced EMT and pulmonary fibrosis in asthma [20]. It has been reported that dysregulation of the TGF-β1/Smad pathway is necessary for bronchial epithelial cell proliferation in asthma patients.…”

Alternatively activated macrophages; a double-edged sword in allergic asthma

“…However, the main action of TGF-β1 is the induction of fibrosis and airway remodeling. TGF-β1 is considered one of the potent inducers of epithelial-mesenchymal transition (EMT), which promote myofibroblasts derived from bronchial epithelial cells, mediated through phosphorylated SMAD3 signaling pathway [95,96]. Myofibroblasts express α-SMA, which mediate the contractile activity of fibroblastic cells, in addition to their production of collagen types I, III, IV and V [97].…”