TGF-β regulates isoform switching of FGF receptors and epithelial–mesenchymal transition

Authors

  • Takuya Shirakihara,

    1. Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
    2. Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan
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  • Kana Horiguchi,

    1. Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
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  • Keiji Miyazawa,

    1. Department of Biochemistry, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan
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  • Shogo Ehata,

    1. Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
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  • Tatsuhiro Shibata,

    1. Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan
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  • Ikuo Morita,

    1. Department of Cellular Physiological Chemistry and Global Center of Excellence (GCOE) Program, International Research Center for Molecular Science in Tooth and Bone Diseases, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
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  • Kohei Miyazono,

    Corresponding author
    1. Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
    • Corresponding authors: Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Tel.: +81 35841 3345; Fax: +81 35841 3354; E-mail: miyazono@m.u-tokyo.ac.jpDepartment of Biochemistry, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3899, Japan. Tel.: +81 55273 9496; Fax: +81 55273 6784; E-mail: msaitoh-ind@umin.ac.jp

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  • Masao Saitoh

    Corresponding author
    1. Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
    2. Department of Biochemistry, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan
    3. Department of Cellular Physiological Chemistry and Global Center of Excellence (GCOE) Program, International Research Center for Molecular Science in Tooth and Bone Diseases, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
    • Corresponding authors: Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Tel.: +81 35841 3345; Fax: +81 35841 3354; E-mail: miyazono@m.u-tokyo.ac.jpDepartment of Biochemistry, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3899, Japan. Tel.: +81 55273 9496; Fax: +81 55273 6784; E-mail: msaitoh-ind@umin.ac.jp

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Abstract

The epithelial–mesenchymal transition (EMT) is a crucial event in wound healing, tissue repair, and cancer progression in adult tissues. Here, we demonstrate that transforming growth factor (TGF)-β induced EMT and that long-term exposure to TGF-β elicited the epithelial–myofibroblastic transition (EMyoT) by inactivating the MEK-Erk pathway. During the EMT process, TGF-β induced isoform switching of fibroblast growth factor (FGF) receptors, causing the cells to become sensitive to FGF-2. Addition of FGF-2 to TGF-β-treated cells perturbed EMyoT by reactivating the MEK-Erk pathway and subsequently enhanced EMT through the formation of MEK-Erk-dependent complexes of the transcription factor δEF1/ZEB1 with the transcriptional corepressor CtBP1. Consequently, normal epithelial cells that have undergone EMT as a result of combined TGF-β and FGF-2 stimulation promoted the invasion of cancer cells. Thus, TGF-β and FGF-2 may cooperate with each other and may regulate EMT of various kinds of cells in cancer microenvironment during cancer progression.

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