title: Loss of miR-140 is a key risk factor for radiation-induced lung fibrosis through reprogramming fibroblasts and macrophages.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Nadire
authors.initials: N
authors.lastname: Duru
authors.affiliation: Department of Biochemistry and Molecular Biology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Yongshu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Ramkishore
authors.initials: R
authors.lastname: Gernapudi
authors.affiliation: Department of Biochemistry and Molecular Biology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wolfson
authors.affiliation: Department of Biochemistry and Molecular Biology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Pang-Kuo
authors.initials: PK
authors.lastname: Lo
authors.affiliation: Department of Biochemistry and Molecular Biology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Department of Biochemistry and Molecular Biology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Qun
authors.initials: Q
authors.lastname: Zhou
mesh_terms: D000818:Animals; D002469:Cell Separation; D065150:Cellular Reprogramming; D003094:Collagen / Q000737:chemistry; D005347:Fibroblasts / Q000166:cytology*; D005353:Fibronectins / Q000378:metabolism; D005434:Flow Cytometry; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D058628:Myofibroblasts / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000473:pathology; D011832:Radiation Injuries / Q000378:metabolism*; D012307:Risk Factors; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism
chemical_list: D005353:Fibronectins; C547828:MIRN140 microRNA, mouse; D035683:MicroRNAs; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D003094:Collagen