Abstract
CDX2 is an intestine-specific tumor suppressor gene encoding homeodomain-containing transcription factor, which is involved in a variety of developmental, proliferating, and differentiating processes. Moreover, the expression of CDX2 is reduced in a subset of primary colorectal cancers. In contrast, cyclooxygenase-2 (COX-2) is often up-regulated in human colorectal cancers. However, the molecular relationship between CDX2 down-regulation and COX-2 up-regulation is unknown. Here we show that CDX2 down-regulates COX-2 promoter activity by interacting with NF-kappaB. The ectopic expression of CDX2 was found to suppress PMA-induced COX-2 promoter activity in a dose-dependent manner. In addition, the treatment of colorectal cancer cells with PMA resulted in significant reduction in the level of endogenous CDX2 and a significant increase in the level of endogenous COX-2, in a dose-dependent manner. Furthermore, CDX2 was found to co-immunoprecipitate with the p65 subunit of NF-kappaB and to inhibit p65-induced NF-kappaB minimal promoter activity in colon cancer cells. These results suggest that reduced CDX2 expression may be involved in colorectal carcinogenesis by enhancing NF-kappaB-mediated inflammatory genes such as COX-2.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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CDX2 Transcription Factor
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Caco-2 Cells
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Cell Line
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Colorectal Neoplasms / enzymology
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Colorectal Neoplasms / genetics
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Colorectal Neoplasms / metabolism*
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Cyclooxygenase 2
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Dose-Response Relationship, Drug
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / genetics
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Genes, Reporter / genetics
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Homeodomain Proteins / biosynthesis*
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Homeodomain Proteins / genetics
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Humans
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Immunoglobulin kappa-Chains / metabolism
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Interferon Type I / metabolism
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Isoenzymes / biosynthesis*
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Isoenzymes / genetics
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Luciferases / metabolism
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Membrane Proteins
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NF-kappa B / metabolism
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Plasmids / genetics
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Promoter Regions, Genetic
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Prostaglandin-Endoperoxide Synthases / biosynthesis*
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Prostaglandin-Endoperoxide Synthases / genetics
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Tetradecanoylphorbol Acetate / antagonists & inhibitors
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Tetradecanoylphorbol Acetate / pharmacology
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Trans-Activators / pharmacology
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Transfection
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eIF-2 Kinase / metabolism
Substances
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CDX2 Transcription Factor
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Homeodomain Proteins
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Immunoglobulin kappa-Chains
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Interferon Type I
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Isoenzymes
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Membrane Proteins
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NF-kappa B
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Trans-Activators
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interferon kappa
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Luciferases
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Cyclooxygenase 2
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PTGS2 protein, human
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Prostaglandin-Endoperoxide Synthases
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eIF-2 Kinase
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Tetradecanoylphorbol Acetate