miR-let-7d attenuates EMT by targeting HMGA2 in silica-induced pulmonary fibrosis

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 silicainduced alveolar epithelial cells. To detect whether let-7d and its target HMGA2 were involved in silicainduced 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 upregulation 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. Fig. 7 Let-7d modulates the EMT by regulating the expression of HMGA2. A549 cells were transfected with 50 nM siR-HMGA2 alone, 100 nM let-7d inhibitor alone, or both co-transfected. The EMT-related genes were detected by qRT-PCR (A). The protein levels was detected by Western blot and quantification analysis was conducted and shown as a graph (B). Means AE SEM (n ¼ 3), *P < 0.05 versus siR-NC group, # P < 0.05 versus siR-HMGA2 group.19362 | RSC Adv., 2019,9,[19355][19356][19357][19358][19359][19360][19361][19362][19363][19364] This journal is

Epigenetic Regulation of EMP/EMT-Dependent Fibrosis

“…Interestingly, the overexpression of miR-26a reduced the EMT process triggered by TGF-β in adenocarcinoma A259 cells [ 153 ]. An interesting study has evidenced that, in mice exposed to silicone to induce pulmonary fibrosis, an overexpression of miRNA let-7d led to a reduction in HMGA2 expression and inhibition of EMT; while the suppression of miRNA let-7d augmented HMGA2 expression and triggered silica-induced EMT [ 154 ].…”

Epigenetic Changes and Functions in Pneumoconiosis

“…Through cell and animal experiments, the researchers found that overexpression of miR-29b attenuates or even reverses the EMT process induced by silica. Yu et al [ 97 , 108 ] discovered that THP-1 macrophages that phagocytose micron-sized silica particles can reduce the expression of let-7d increase the expression of HMGA2 and then promote the EMT process of A549 cells. Zhao and Qi et al [ 81 , 82 ] detected that the expression of miR-34a-5p decreased, and the expression of SMAD4 increased in murine models of silicosis and TGF- β –stimulated A549 cells.…”

The emerging role of epigenetic regulation in the progression of silicosis

“…And overexpression of miR-29b-2-5p or miR-34c-3p inhibited the EMT process and abrogated the profibrotic effect in vitro [ 51 ], indicating that the upregulation of miR-29b-2-5p and miR-34c-3p could play a protective role in silicosis. In addition, Yu et al found that let-7d negatively regulated silica-induced EMT and inhibited silica-induced pulmonary fibrosis, which might be partially achieved through direct binding to high mobility group protein 2 (HMGA2) [ 52 ].…”