Abstract
EGF receptor (EGFR) overexpression correlates with metastasis in a variety of carcinomas, but the underlying mechanisms are poorly understood. We demonstrated that EGF disrupted cell-cell adhesion and caused epithelial-to-mesenchymal transition (EMT) in human tumor cells overexpressing EGFR, and also induced caveolin-dependent endocytosis of E-cadherin, a cell-cell adhesion protein. Chronic EGF treatment resulted in transcriptional downregulation of caveolin-1 and induction of the transcriptional repressor Snail, correlating with downregulation of E-cadherin expression. Caveolin-1 downregulation enhanced beta-catenin-TCF/LEF-1 transcriptional activity in a GSK-3beta-independent manner. Antisense RNA-mediated reduction of caveolin-1 expression in EGFR-overexpressing tumor cells recapitulated these EGF-induced effects and enhanced invasion into collagen gels. We propose that EGF-induced negative regulation of caveolin-1 plays a central role in the complex cellular changes leading to metastasis.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Cadherins / metabolism*
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Caveolae / metabolism
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Caveolin 1
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Caveolins / metabolism*
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Cell Adhesion
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Cell Movement
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Cell Nucleus / metabolism
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Cytoskeletal Proteins / metabolism*
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DNA-Binding Proteins / metabolism
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Down-Regulation / drug effects
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Endocytosis / physiology
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Epidermal Growth Factor / metabolism*
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ErbB Receptors / metabolism
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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Humans
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Intercellular Junctions / metabolism
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Neoplasm Metastasis
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RNA, Antisense / metabolism
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Signal Transduction
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Snail Family Transcription Factors
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Trans-Activators / metabolism*
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Transcription Factors / metabolism
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Transcriptional Activation / physiology
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Tumor Cells, Cultured
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beta Catenin
Substances
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CAV1 protein, human
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CTNNB1 protein, human
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Cadherins
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Caveolin 1
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Caveolins
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Cytoskeletal Proteins
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DNA-Binding Proteins
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RNA, Antisense
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Snail Family Transcription Factors
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Trans-Activators
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Transcription Factors
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beta Catenin
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Epidermal Growth Factor
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ErbB Receptors
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Glycogen Synthase Kinase 3