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Induction of MiR-21 by Stereotactic Body Radiotherapy Contributes to the Pulmonary Fibrotic Response

 Ok-Seon Kwon  ;  Keun-Tae Kim  ;  Eunioo Lee  ;  Myoungjae Kim  ;  Seo-Hyun Choi  ;  Henghong Li  ;  Albert J. Fornace  ;  Jae-Ho Cho  ;  Yun-Sil Lee  ;  Ji-Seon Lee  ;  Yoon-Jin Lee  ;  Hyuk-Jin Cha 
 PLOS ONE, Vol.11(5) : e0154942, 2016 
Journal Title
Issue Date
Animals ; Cell Line ; Collagen/biosynthesis ; Endothelial Cells/metabolism ; Endothelial Cells/pathology ; Endothelium/pathology ; Fibroblasts/metabolism ; Fibroblasts/pathology ; Humans ; Lung/metabolism ; Lung/pathology ; Lung/radiation effects ; Male ; Mesoderm/pathology ; Mice, Inbred C57BL ; MicroRNAs/genetics* ; MicroRNAs/metabolism ; Pulmonary Fibrosis/genetics* ; Pulmonary Fibrosis/pathology ; Pulmonary Fibrosis/radiotherapy* ; Radiation, Ionizing ; Radiosurgery* ; Transfection ; Up-Regulation/genetics
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.
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Radiation Oncology (방사선종양학교실) > 1. Journal Papers
Yonsei Authors
Cho, Jae Ho(조재호) ORCID logo https://orcid.org/0000-0001-9966-5157
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