Aberrant expression of miR-125a-3p promotes fibroblast activation via Fyn/STAT3 pathway during silica-induced pulmonary fibrosis

Abstract

Various miRNAs are dysregulated during initiation and progression of pulmonary fibrosis. However, their function remains limited in silicosis. Here, we observed that miR-125a-3p was downregulated in silica-induced fibrotic murine lung tissues. Ectopic miR-125a-3p expression with chemotherapy attenuated silica-induced pulmonary fibrosis. Further in vitro experiments revealed that TGF-β1 effectively decreased miR-125a-3p expression in fibroblast lines (NIH/3T3 and MRC-5). Overexpression of miR-125a-3p blocked fibroblast activation stimulated by TGF-β1. Mechanistically, miR-125a-3p could bind to the 3′-untranslated region of Fyn and inhibit its expression in both mRNA and protein levels, thus causing inactivation of Fyn downstream effector STAT3. Fyn and p-STAT3, as opposed to miR-125a-3p expression, were elevated in silica-induced fibrotic murine lung tissues and TGF-β1-treated fibroblast lines. Furthermore, Fyn knockdown or p-STAT3 suppression effectively attenuated fibroblast activation and ECM production. Taken together, miR-125a-3p is involved in fibrosis pathogenesis by fibroblast activation, suggesting that targeting miR-125a-3p/Fyn/STAT3 signaling pathway could be a potential therapeutic approach for pulmonary fibrosis.