Abstract
Krüppel-like factor 4 (KLF4) was closely associated with epithelial-mesenchymal transition and stemness in colorectal cancer stem cells (CSCs)-enriched spheroid cells. Nonetheless, the underlying molecular mechanism is unclear. This study showed that KLF4 overexpression was accompanied with stemness and mesenchymal features in Lgr5+ CD44+ EpCAM+ colorectal CSCs. KLF4 knockdown suppressed stemness, mesenchymal features and activation of the TGF-β1 pathway, whereas enforced KLF4 overexpression activated TGF-β1, phosphorylation of Smad 2/3 and Snail expression, and restored stemness and mesenchymal phenotypes. Furthermore, TGF-β1 pathway inhibition invalidated KLF4-facilitated stemness and mesenchymal features without affecting KLF4 expression. The data from the current study are the first to demonstrate that KLF4 maintains stemness and mesenchymal properties through the TGF-β1/Smad/Snail pathway in Lgr5+ CD44+ EpCAM+ colorectal CSCs.
Keywords:
Krüppel-like factor 4; TGF-β1; cancer stem cell; colorectal cancer; snail.
© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Carcinogenesis / drug effects
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Carcinogenesis / metabolism
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Carcinogenesis / pathology
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Cell Line, Tumor
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Colorectal Neoplasms / metabolism*
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Colorectal Neoplasms / pathology*
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Epithelial Cell Adhesion Molecule / metabolism
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Humans
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Hyaluronan Receptors / metabolism
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Imidazoles / pharmacology
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Kruppel-Like Factor 4
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Kruppel-Like Transcription Factors / metabolism*
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Mesoderm / pathology*
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Neoplastic Stem Cells / drug effects
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Neoplastic Stem Cells / metabolism*
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Neoplastic Stem Cells / pathology*
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Phenotype
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Quinoxalines / pharmacology
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Receptors, G-Protein-Coupled / metabolism
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Signal Transduction* / drug effects
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Smad Proteins / metabolism*
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Snail Family Transcription Factors / metabolism*
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Transforming Growth Factor beta1 / metabolism*
Substances
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6-(2-tert-butyl-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline
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CD44 protein, human
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Epithelial Cell Adhesion Molecule
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Hyaluronan Receptors
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Imidazoles
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KLF4 protein, human
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Kruppel-Like Factor 4
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Kruppel-Like Transcription Factors
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LGR5 protein, human
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Quinoxalines
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Receptors, G-Protein-Coupled
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Smad Proteins
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Snail Family Transcription Factors
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Transforming Growth Factor beta1