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 journalArticle

5 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

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Metformin
Fibrosis
Down-Regulation
Radiation
Skin
Phosphatidylinositol 3-Kinase
Background Radiation
Chemokines
Small Interfering RNA
Oral Administration
Collagen
Radiotherapy
Fibroblasts
Immunohistochemistry
Staining and Labeling
Cytokines
Polymerase Chain Reaction

All Science Journal Classification (ASJC) codes

  • Physiology

Cite this

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.
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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",
year = "2018",
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doi = "10.1159/000491964",
language = "English",
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Kim, JM, Yoo, H, Kim, JY, Oh, SH, Kang, JW, Yoo, BR, Han, SY, Kim, CS, Choi, WH, Lee, EJ, Byeon, HJ, Lee, WJ, Lee, YS & Cho, J 2018, 'Metformin Alleviates Radiation-Induced Skin Fibrosis via the Downregulation of FOXO3', Cellular Physiology and Biochemistry, vol. 48, no. 3, pp. 959-970. https://doi.org/10.1159/000491964

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 journalArticle

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

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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