Loss of miR-140 is a key risk factor for radiation-induced lung fibrosis through reprogramming fibroblasts and macrophages

• Published in: Scientific reports 2016-12, Vol.6 (1), p.39572-39572, Article 39572
• Main Authors: Duru, Nadire, Zhang, Yongshu, Gernapudi, Ramkishore, Wolfson, Benjamin, Lo, Pang-Kuo, Yao, Yuan, Zhou, Qun
• Format: Article
• Language: English
• Subjects: 13/109; 14/19; 14/32; 38/77; 38/90; 631/337/384/331; 631/80/304; 64/60; 692/4028/67/1059/485; 82/80; Cancer; Collagen; Fibroblasts; Fibronectin; Fibrosis; Humanities and Social Sciences; Lung cancer; Lungs; Macrophages; multidisciplinary; Post-radiation; Radiation therapy; Risk factors; Science; Smad3 protein; Thorax; Transforming growth factor-b1
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep39572

Radiation-induced lung fibrosis (RILF) is a common side effect for patients with thoracic cancer receiving radiation therapy. RILF is characterized by excessive collagen deposition mediated by TGF-β1 and its downstream factor SMAD3, but the exact molecular mechanism leading to fibrosis is yet to be determined. The present study investigated the impact of miR-140 on RILF development. Herein, we first found that loss of miR-140 is a marker of fibrotic lung tissue in vivo one-year post-radiation treatment. We showed that miR-140 knockout primary lung fibroblasts have a higher percentage of myofibroblasts compared to wild type primary lung fibroblasts, and that loss of miR-140 expression leads to increased activation of TGF-β1 signaling as well as increased myofibroblast differentiation. We also identified fibronectin as a novel miR-140 target gene in lung fibroblasts. Finally, we have shown that miR-140 deficiency promotes accumulation of M2 macrophages in irradiated lung tissues. These data suggest that miR-140 is a key protective molecule against RILF through inhibiting myofibroblast differentiation and inflammation.