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

Jin Mo Kim, Hyun Yoo, Jee Youn Kim, Sang Ho Oh, Jeong Wook Kang, Byung Rok Yoo, Song Yee Han, Cha Soon Kim, Won Hoon Choi, Eun Jung Lee, Hyeong Ju Byeon, Won Jai Lee, Yun Sil Lee, Jaeho Cho

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13 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)959-970
Number of pages12
JournalCellular Physiology and Biochemistry
Volume48
Issue number3
DOIs
Publication statusPublished - 2018 Aug 1

Bibliographical note

Funding Information:
This study was supported by a grant from the ? orea Institute of Radiological and ?edical Sciences (?IRA?S), funded by ?inistry of Science ICT (?SIT), Republic of ? orea ( 猃礃猃猃爃瘃眃眃眃礁 猃礃猃猃爃瘃眃眃甃稁 猃礃猃猃爃瘃眃眃眃瘂thIe. TRhade iasttuiodny was also funded by Technology Research and Development Program (NRF-球爃猃礀ဃ琀A 琀A 礀A 爃球爃猃笃砃猃琁 球爃猃眀ဃ琀A 琀A 礀A 爃甃爃瘃瘃稃甃猂I, and the Basic Science Research Program (NRF-球爃猃砀R 猀A 砀A 甀A 猃猃笃甃球球球码 球爃猃礀R 猀D 猀A 猀B 爃甃爃球礃稃稃猂I through the National Foundation of ? orea, funded by the ?inistry of Education, by the Convergence of Conventional ?edicine and Traditional ? orean ?edicine R&D program funded by the ?inistry of Health & Welfare through the ? orea Health Industry Development Institute (HI 猃眀C 爃球猃瘂I. Also, a faculty research grant from the Yonsei University College of ?edicine ( 码球爃猃码爃猃眃稂I supported the study.

Funding Information:
This study was supported by a grant from the Korea Institute of Radiological and Medical Sciences (KIRAMS), funded by Ministry of Science ICT (MSIT), Republic of Korea (1711045557; 1711045538; 1711045554). The study was also funded by the Radiation Technology Research and Development Program (NRF-2017M2A2A7A02019612, 2015M2A2A7A03044831), and the Basic Science Research Program (NRF-2016R1A6A3A11932226, 2017R1D1A1B03027881) through the National Research Foundation of Korea, funded by the Ministry of Education, by the Convergence of Conventional Medicine and Traditional Korean Medicine R&D program funded by the Ministry of Health & Welfare through the Korea Health Industry Development Institute (HI15C0214). Also, a faculty research grant from the Yonsei University College of Medicine (6-2016-0158) supported the study.

Publisher Copyright:
© 2018 The Author(s). Published by S. Karger AG, Basel.

All Science Journal Classification (ASJC) codes

  • Physiology

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