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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Actins / genetics
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Actins / metabolism
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Alcohol Oxidoreductases / metabolism
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Alternative Splicing / drug effects*
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Alternative Splicing / genetics
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Cell Differentiation / drug effects
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Cell Differentiation / genetics
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Cell Differentiation / physiology
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Cells, Cultured
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DNA-Binding Proteins / metabolism
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Epithelial-Mesenchymal Transition / drug effects*
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Epithelial-Mesenchymal Transition / genetics
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Epithelial-Mesenchymal Transition / physiology
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Fibroblast Growth Factor 2 / metabolism
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Fibroblast Growth Factor 2 / pharmacology
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Gene Expression Regulation, Neoplastic / drug effects
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Homeodomain Proteins / metabolism
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Humans
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Models, Biological
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Myofibroblasts / drug effects
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Myofibroblasts / metabolism
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Myofibroblasts / physiology
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Neoplasm Invasiveness
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Neoplasms / genetics
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Neoplasms / metabolism
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Neoplasms / pathology
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Protein Binding / drug effects
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Protein Binding / genetics
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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Protein Isoforms / physiology
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Receptors, Fibroblast Growth Factor / genetics*
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Receptors, Fibroblast Growth Factor / metabolism*
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Signal Transduction / genetics
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Transcription Factors / metabolism
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Transforming Growth Factor beta / pharmacology*
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Transforming Growth Factor beta / physiology
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Zinc Finger E-box-Binding Homeobox 1
Substances
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ACTA2 protein, human
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Actins
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DNA-Binding Proteins
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Homeodomain Proteins
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Protein Isoforms
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Receptors, Fibroblast Growth Factor
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Transcription Factors
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Transforming Growth Factor beta
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ZEB1 protein, human
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Zinc Finger E-box-Binding Homeobox 1
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Fibroblast Growth Factor 2
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Alcohol Oxidoreductases
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C-terminal binding protein