LncRNA‐ATB regulates epithelial‐mesenchymal transition progression in pulmonary fibrosis via sponging miR‐29b‐2‐5p and miR‐34c‐3p

Dysregulation of non‐coding RNAs (ncRNAs) has been proved to play pivotal roles in epithelial‐mesenchymal transition (EMT) and fibrosis. We have previously demonstrated the crucial function of long non‐coding RNA (lncRNA) ATB in silica‐induced pulmonary fibrosis‐related EMT progression. However, the underlying molecular mechanism has not been fully elucidated. Here, we verified miR‐29b‐2‐5p and miR‐34c‐3p as two vital downstream targets of lncRNA‐ATB. As opposed to lncRNA‐ATB, a significant reduction of both miR‐29b‐2‐5p and miR‐34c‐3p was observed in lung epithelial cells treated with TGF‐β1 and a murine silicosis model. Overexpression miR‐29b‐2‐5p or miR‐34c‐3p inhibited EMT process and abrogated the pro‐fibrotic effects of lncRNA‐ATB in vitro. Further, the ectopic expression of miR‐29b‐2‐5p and miR‐34c‐3p with chemotherapy attenuated silica‐induced pulmonary fibrosis in vivo. Mechanistically, TGF‐β1‐induced lncRNA‐ATB accelerated EMT as a sponge of miR‐29b‐2‐5p and miR‐34c‐3p and shared miRNA response elements with MEKK2 and NOTCH2, thus relieving these two molecules from miRNA‐mediated translational repression. Interestingly, the co‐transfection of miR‐29b‐2‐5p and miR‐34c‐3p showed a synergistic suppression effect on EMT in vitro. Furthermore, the co‐expression of these two miRNAs by using adeno‐associated virus (AAV) better alleviated silica‐induced fibrogenesis than single miRNA. Approaches aiming at lncRNA‐ATB and its downstream effectors may represent new effective therapeutic strategies in pulmonary fibrosis.