title: Induction of MiR-21 by Stereotactic Body Radiotherapy Contributes to the Pulmonary Fibrotic Response.
abstract: Radiation-induced lung fibrosis, the most serious effect of lung cancer radiotherapy on normal tissue, remains a major technical obstacle to the broader application of radiotherapy to patients with lung cancer. This study describes the use of an image-guided irradiation system in mice mimicking stereotactic body radiotherapy (SBRT) to examine the molecular features of chronic fibrotic response after radiation injury. MicroRNA (miR) array analysis of injured pulmonary tissue identified a set of miRs whose expression was significantly increased in damaged lung tissue. In particular, miR-21 expression was increased at the radiation injury site, concurrent with collagen deposition. Although the inhibition of miR-21 by its specific inhibitor anti-miR-21 only marginally affected endothelial-mesenchymal transition (EndMT) in lung endothelial cells, this inhibition significantly reduced collagen synthesis in lung fibroblasts. Furthermore, ectopic expression of miR-21 was sufficient to promote a fibrotic response in lung fibroblasts, enhancing Smad2 phosphorylation concurrent with Smad7 downregulation. These findings indicate that the induction of miR-21 expression is responsible for fibrotic responses observed in mesenchymal cells at the injury site through the potentiation of TGF-β signaling. Local targeting of miR-21 at the injured area could have potential therapeutic utility in mitigating radiation-induced lung fibrosis.
authors.affiliation: Department of Life Sciences, Sogang University, Seoul, Korea.
authors.forename: Ok-Seon
authors.initials: OS
authors.lastname: Kwon
authors.affiliation: Department of Life Sciences, Sogang University, Seoul, Korea.
authors.forename: Keun-Tae
authors.initials: KT
authors.lastname: Kim
authors.affiliation: College of Pharmacy and Wonkwang Oriental Medicines Research Institute, Wonkwang University, Jeonbuk, Korea.
authors.forename: Eunioo
authors.initials: E
authors.lastname: Lee
authors.affiliation: College of Pharmacy and Wonkwang Oriental Medicines Research Institute, Wonkwang University, Jeonbuk, Korea.
authors.forename: Myoungjae
authors.initials: M
authors.lastname: Kim
authors.affiliation: Laboratory of Radiation Effect, Division of Radiation effect, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
authors.forename: Seo-Hyun
authors.initials: SH
authors.lastname: Choi
authors.affiliation: Department of Biochemistry and Molecular and Cellular Biology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, D.C., United States of America.
authors.forename: Henghong
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular and Cellular Biology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, D.C., United States of America.
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Fornace
authors.affiliation: Department of Radiation Oncology, Severance Hospital, Yonsei University, Seoul, Korea.
authors.forename: Jae-Ho
authors.initials: JH
authors.lastname: Cho
authors.affiliation: School of Pharmacy, Ewha University Seoul, Korea.
authors.forename: Yun-Sil
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Burn Institute, Hangang Sacred Heart Hospital, College of Medicine, Hallym University, Seoul, Korea.
authors.forename: Ji-Seon
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Laboratory of Radiation Effect, Division of Radiation effect, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
authors.forename: Yoon-Jin
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Department of Life Sciences, Sogang University, Seoul, Korea.
authors.forename: Hyuk-Jin
authors.initials: HJ
authors.lastname: Cha
mesh_terms: D000818:Animals; D002460:Cell Line; D003094:Collagen / Q000096:biosynthesis; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D004727:Endothelium / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D008297:Male; D008648:Mesoderm / Q000473:pathology; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy*; D011839:Radiation, Ionizing; D016634:Radiosurgery; D014162:Transfection; D015854:Up-Regulation / Q000235:genetics
chemical_list: D003094:Collagen; D035683:MicroRNAs; C524940:MIRN21 microRNA, human; C531950:MIRN21 microRNA, mouse