Metformin Alleviates Radiation-Induced Skin Fibrosis via the Downregulation of FOXO3.
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.
['Kim|Jin-Mo|JM|', 'Yoo|Hyun|H|', 'Kim|Jee-Youn|JY|', 'Oh|Sang Ho|SH|', 'Kang|Jeong Wook|JW|', 'Yoo|Byung Rok|BR|', 'Han|Song Yee|SY|', 'Kim|Cha Soon|CS|', 'Choi|Won Hoon|WH|', 'Lee|Eun-Jung|EJ|', 'Byeon|Hyeong Ju|HJ|', 'Lee|Won Jai|WJ|', 'Lee|Yun-Sil|YS|', 'Cho|Jaeho|J|']
D000818:Animals D002478:Cells, Cultured D058543:Class Ia Phosphatidylinositol 3-Kinase D015536:Down-Regulation D005347:Fibroblasts D005355:Fibrosis D000071316:Forkhead Box Protein O3 D008687:Metformin D051379:Mice D008810:Mice, Inbred C57BL D041681:NIH 3T3 Cells D018384:Oxidative Stress D034622:RNA Interference D034741:RNA, Small Interfering D011833:Radiation Injuries, Experimental D011839:Radiation, Ionizing D050796:STAT3 Transcription Factor D012867:Skin D016212:Transforming Growth Factor beta D016159:Tumor Suppressor Protein p53
Metformin Radiation-induced skin fibrosis FOXO3 PIK3r1