Abstract
The epithelial-mesenchymal transition (EMT) is crucial for the invasion and metastasis of many epithelial tumors including colorectal carcinoma (CRC). In the present study, a scattering and fibroblastic morphology with reduced intercellular contacts was found in the SW480 colon cancer cells overexpressing the gene encoding thymosin beta4 (Tbeta4), which was accompanied by a loss of E-cadherin as well as a cytosolic accumulation of beta-catenin, two most prominent markers of EMT. Whereas E-cadherin downregulation was likely to be accounted by a ZEB1-mediated transcriptional repression, the accumulation of beta-catenin was a result of glycogen synthase kinase-3beta inactivation mediated by integrin-linked kinase (ILK) and/or its downstream effector, Akt. Intriguingly, ILK upregulation in Tbeta4-overexpressing SW480 cells seemed to be attributed mainly to a stabilization of this kinase by complexing with particularly interesting new Cys-His protein (PINCH) more efficiently. In the meantime, a strong correlation between the expression levels of Tbeta4, ILK and E-cadherin in CRC patients was also revealed by immunohistochemical analysis. Taken together, these data suggest a novel role of Tbeta4 in promoting CRC progression by inducing an EMT in tumor cells via upregulating ILK and consequentially its signal transduction.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Cadherins / metabolism
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Casein Kinase I / metabolism
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Colonic Neoplasms / enzymology*
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Colonic Neoplasms / pathology
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Colorectal Neoplasms / metabolism*
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Colorectal Neoplasms / secondary
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DNA-Binding Proteins / metabolism
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Enzyme Inhibitors / pharmacology
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Epithelial Cells / metabolism*
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Fibroblasts / cytology
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Fibroblasts / metabolism
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Fibroblasts / pathology
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Glycogen Synthase Kinase 3 / metabolism
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Humans
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Immunoenzyme Techniques
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LIM Domain Proteins
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Membrane Proteins
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Mesoderm / cytology*
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Mesoderm / metabolism
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Mice
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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RNA, Antisense / pharmacology
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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Thymosin / antagonists & inhibitors
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Thymosin / genetics
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Thymosin / pharmacology*
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transcription, Genetic
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Transfection
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Tumor Cells, Cultured
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Up-Regulation
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Zinc Finger E-box-Binding Homeobox 1
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beta Catenin / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Cadherins
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DNA-Binding Proteins
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Enzyme Inhibitors
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Homeodomain Proteins
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LIM Domain Proteins
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LIMS1 protein, human
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Membrane Proteins
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Phosphoinositide-3 Kinase Inhibitors
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RNA, Antisense
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RNA, Messenger
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Transcription Factors
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ZEB1 protein, human
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Zinc Finger E-box-Binding Homeobox 1
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beta Catenin
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thymosin beta(4)
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Thymosin
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integrin-linked kinase
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Casein Kinase I
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Protein Serine-Threonine Kinases
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Glycogen Synthase Kinase 3