title: TGF-β regulates isoform switching of FGF receptors and epithelial-mesenchymal transition.
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.
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Shirakihara
authors.forename: Kana
authors.initials: K
authors.lastname: Horiguchi
authors.forename: Keiji
authors.initials: K
authors.lastname: Miyazawa
authors.forename: Shogo
authors.initials: S
authors.lastname: Ehata
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Shibata
authors.forename: Ikuo
authors.initials: I
authors.lastname: Morita
authors.forename: Kohei
authors.initials: K
authors.lastname: Miyazono
authors.forename: Masao
authors.initials: M
authors.lastname: Saitoh
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000429:Alcohol Oxidoreductases / Q000378:metabolism; D017398:Alternative Splicing / Q000187:drug effects* / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology* / Q000502:physiology; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D020033:Protein Isoforms; D017468:Receptors, Fibroblast Growth Factor; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D016222:Fibroblast Growth Factor 2; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein