Abstract
Silicosis is a serious occupational disease characterized by pulmonary chronic inflammation and progressive fibrosis. Epithelial-mesenchymal transition (EMT) of alveolar epithelial cells plays a vital role in silicosis. Recent studies discovered a variety of microRNAs (miRNAs) participating in fibrotic diseases. Here, we aimed to explore the function and mechanism of miRNA let-7d in the EMT process in silica-induced alveolar epithelial cells. To detect whether let-7d and its target HMGA2 were involved in silica-induced EMT, we established a silicosis mouse model and found that let-7d was down-regulated and HMGA2 was up-regulated in the silica-treated group. Then we applied an in vitro co-culture system to imitate the EMT process in A549 cells after silica treatment. The down-regulation of let-7d and up-regulation of HMGA2 were also observed in vitro. The knockdown of HMGA2 significantly inhibited the silica-induced EMT. Furthermore, we found that overexpression of let-7d could reduce the expression of HMGA2 and consequently inhibited the silica-induced EMT, whereas inhibition of let-7d increased the expression of HMGA2 and promoted the silica-induced EMT. In conclusion, let-7d negatively regulated silica-induced EMT and inhibited silica-induced pulmonary fibrosis, which might be partially realized by directly binding to HMGA2. Our data suggested that miRNA let-7d might have a potential protective effect in the fibrotic process and become a new therapeutic target for silicosis or other fibrotic diseases.
Highlights
Silicosis is an interstitial pulmonary brotic disease caused by inhalation of crystalline silica.[1]
The expression of epithelial marker E-cad decreased signi cantly, whereas the mesenchymal markers a-SMA and vimentin showed increased expression both at the mRNA (Fig. 1D) and protein levels (Fig. 1E). qRT-PCR revealed the down-regulation of let7d and the concomitant increase of HMGA2 in silica-treated mice (Fig. 1C and E), con rmed their potential relationship in silicosis in vivo
We further investigated the effects of let-7d overexpression on HMGA2 and silica-induced epithelial to mesenchymal transition (EMT) in A549 cells
Summary
Silicosis is an interstitial pulmonary brotic disease caused by inhalation of crystalline silica.[1]. Emerging evidence suggests epithelial to mesenchymal transition (EMT) plays a critical role in the occurrence and progression of pulmonary brosis.[4,5] During EMT, the epithelial cells lose their tight connection properties and acquire mesenchymal features, which is characterized by the decrease of E-cadherin (ECad) in epithelial cells and increased expression of mesenchymal proteins such as a-smooth muscle actin (aSMA).[6] EMT is MicroRNAs (miRNAs) are small, non-coding RNAs normally consisting of 19–22 nucleotides They could modulate gene expression both transcriptionally and posttranscriptionally and affect various biological processes.[10] miRNAs dysregulation has been reported to associate with various organs brotic disease.[8,11,12] Previous studies showed that miRNAs participated in the process of EMT and pulmonary brosis. MiR-448-5p inhibits TGF-b1-induced EMT and pulmonary brosis by targeting Six1.14 MiR-29c attenuates pulmonary brosis by regulating epithelial cell renewal and apoptosis.[15]
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