Abstract
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.
Highlights
We have identified that loss of miR-140 is a key risk factor for RILF
We found a dramatic decrease in the expression of miR-140 in fibrotic lung tissues compared to non-fibrotic lung tissues one-year post-radiation treatment using the C57BL/6 mice irradiated with 13 Gy radiation
Using Sca1/CD49e murine myofibroblast markers we showed that myofibroblasts are significantly enriched in miR-140 knockout mice lung fibroblasts (MLFs) compared to wild type MLFs
Summary
We hypothesized that loss of miR-140 expression is one of the key risk factors for the development of fibrosis in lungs upon radiation treatment. Treatment with a total of 20 Gy of fractionated ionizing radiation (FIR) slightly decreased the myofibroblast population of wild type mice lung fibroblasts (MLFs), while it increased the myofibroblast population of miR-140 knockout MLFs. ; we identified fibronectin as a novel target of miR-140. We showed that fibrotic lung tissues, which exhibit loss of miR-140 expression, have a dramatic increase in alternative activation of macrophages. These data suggest that miR-140 plays a critical role for RILF development. Developing drugs that upregulate miR-140 might be a novel strategy for minimizing collateral tissue damage in thoracic cancer patients being treated with IR
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