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

doi:10.1159/000491964

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

Research output: Contribution to journal › Article › peer-review

9 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 language	English
Pages (from-to)	959-970
Number of pages	12
Journal	Cellular Physiology and Biochemistry
Volume	48
Issue number	3
DOIs	https://doi.org/10.1159/000491964
Publication status	Published - 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.

All Science Journal Classification (ASJC) codes

Physiology

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Kim, Jin Mo ; Yoo, Hyun ; Kim, Jee Youn ; Oh, Sang Ho ; Kang, Jeong Wook ; Yoo, Byung Rok ; Han, Song Yee ; Kim, Cha Soon ; Choi, Won Hoon ; Lee, Eun Jung ; Byeon, Hyeong Ju ; Lee, Won Jai ; Lee, Yun Sil ; Cho, Jaeho. / Metformin Alleviates Radiation-Induced Skin Fibrosis via the Downregulation of FOXO3. In: Cellular Physiology and Biochemistry. 2018 ; Vol. 48, No. 3. pp. 959-970.

@article{8f28471fe51a49e88727b3718ac7bcee,

title = "Metformin Alleviates Radiation-Induced Skin Fibrosis via the Downregulation of FOXO3",

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.",

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

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.",

year = "2018",

month = aug,

day = "1",

doi = "10.1159/000491964",

language = "English",

volume = "48",

pages = "959--970",

journal = "Cellular Physiology and Biochemistry",

issn = "1015-8987",

publisher = "S. Karger AG",

number = "3",

}

Metformin Alleviates Radiation-Induced Skin Fibrosis via the Downregulation of FOXO3. / Kim, Jin Mo; Yoo, Hyun; Kim, Jee Youn; Oh, Sang Ho; Kang, Jeong Wook; Yoo, Byung Rok; Han, Song Yee; Kim, Cha Soon; Choi, Won Hoon; Lee, Eun Jung; Byeon, Hyeong Ju; Lee, Won Jai; Lee, Yun Sil; Cho, Jaeho.

In: Cellular Physiology and Biochemistry, Vol. 48, No. 3, 01.08.2018, p. 959-970.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Metformin Alleviates Radiation-Induced Skin Fibrosis via the Downregulation of FOXO3

AU - Kim, Jin Mo

AU - Yoo, Hyun

AU - Kim, Jee Youn

AU - Oh, Sang Ho

AU - Kang, Jeong Wook

AU - Yoo, Byung Rok

AU - Han, Song Yee

AU - Kim, Cha Soon

AU - Choi, Won Hoon

AU - Lee, Eun Jung

AU - Byeon, Hyeong Ju

AU - Lee, Won Jai

AU - Lee, Yun Sil

AU - Cho, Jaeho

N1 - 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.

PY - 2018/8/1

Y1 - 2018/8/1

N2 - 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.

AB - 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.

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