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Metformin Alleviates Radiation-Induced Skin Fibrosis via the Downregulation of FOXO3.

Authors
 Kim J.-M.  ;  Yoo H.  ;  Kim J.-Y.  ;  Oh S.H.  ;  Kang J.W.  ;  Yoo B.R.  ;  Han S.Y.  ;  Kim C.S.  ;  Choi W.H.  ;  Lee E.-J.  ;  Byeon H.J.  ;  Lee W.J.  ;  Lee Y.-S.  ;  Cho J 
Citation
 CELLULAR PHYSIOLOGY AND BIOCHEMISTRY, Vol.48(3) : 959-970, 2018 
Journal Title
 CELLULAR PHYSIOLOGY AND BIOCHEMISTRY 
ISSN
 1015-8987 
Issue Date
2018
MeSH
Animals ; Cells, Cultured ; Class Ia Phosphatidylinositol 3-Kinase/genetics ; Class Ia Phosphatidylinositol 3-Kinase/metabolism ; Down-Regulation/drug effects* ; Down-Regulation/radiation effects ; Fibroblasts/cytology ; Fibroblasts/drug effects ; Fibroblasts/metabolism ; Fibrosis ; Forkhead Box Protein O3/antagonists & inhibitors ; Forkhead Box Protein O3/genetics ; Forkhead Box Protein O3/metabolism* ; Metformin/pharmacology* ; Mice ; Mice, Inbred C57BL ; NIH 3T3 Cells ; Oxidative Stress/drug effects ; RNA Interference ; RNA, Small Interfering/metabolism ; Radiation Injuries, Experimental/pathology ; Radiation Injuries, Experimental/prevention & control ; Radiation, Ionizing ; STAT3 Transcription Factor/genetics ; STAT3 Transcription Factor/metabolism ; Skin/drug effects ; Skin/pathology ; Skin/radiation effects ; Transforming Growth Factor beta/metabolism ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism
Keywords
FOXO3 ; Metformin ; PIK3r1 ; Radiation-induced skin fibrosis
Abstract
BACKGROUND/AIMS: Radiation-induced skin fibrosis is a common side effect of clinical radiotherapy. Our previous next-generation sequencing (NGS) study demonstrated the reduced expression of the regulatory α subunit of phosphatidylinositol 3-kinase (PIK3r1) in irradiated murine skin. Metformin has been reported to target the PIK3-FOXO3 pathway. In this study, we investigated the effects of metformin on radiation-induced skin fibrosis. METHODS: Metformin was orally administered to irradiated mice. Skin fibrosis was analyzed by staining with H&E and Masson's trichrome stain. The levels of cytokines and chemokines associated with fibrosis were analyzed by immunohistochemistry and quantitative RT-PCR. The roles of PIK3rl and FOXO3 in radiation-induced skin fibrosis were studied by overexpressing PIK3rl and transfecting FOXO3 siRNA in NIH3T3 cells and mouse-derived dermal fibroblasts (MDF). RESULTS: The oral administration of metformin significantly reduced radiation-induced skin thickening and collagen accumulation and significantly reduced the radiation-induced expression of FOXO3 in murine skin. Additionally, the overexpression of PIK3r1 reduced the radiation-induced expression of FOXO3, while FOXO3 silencing decreased the radiation-induced expression of TGFβ in vitro. CONCLUSIONS: The results indicated that metformin suppresses radiation-induced skin injuries by modulating the expression of FOXO3 through PIK3r1. Collectively, the data obtained in this study suggested that metformin could be a potent therapeutic agent for alleviating radiation-induced skin fibrosis.
Files in This Item:
T201802537.pdf Download
DOI
10.1159/000491964
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Dermatology (피부과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Plastic and Reconstructive Surgery (성형외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Radiation Oncology (방사선종양학교실) > 1. Journal Papers
Yonsei Authors
Oh, Sang Ho(오상호) ORCID logo https://orcid.org/0000-0002-4477-1400
Lee, Won Jai(이원재) ORCID logo https://orcid.org/0000-0003-3056-0503
Cho, Jae Ho(조재호) ORCID logo https://orcid.org/0000-0001-9966-5157
Choi, Won Hoon(최원훈)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/163201
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