Abstract
Mutational inactivation of the human tumour suppressor gene adenomatous polyposis coli (APC) results in constitutive activation of beta-catenin/T cell factor-4 (Tcf-4) mediated transcription of target genes. Up-regulation of cyclooxygenase-2 (COX-2) protein is frequently found in human colorectal cancer (CRC). We analysed 38 CRC for mutations in APC and beta-catenin and found an association between APC mutations and elevated COX-2 levels. Furthermore, APC mutations were predominantly observed in tumour tissues from the rectum compared to tumours of colonic origin. Western blot analysis revealed that nuclear beta-catenin levels were generally higher in tumours with APC mutations compared to tumours with wild type APC. However, there was also a higher level of nuclear beta-catenin in tumour compared to normal tissue, but nuclear Tcf-4 protein was constitutively expressed in tumour and normal tissue and showed no differences. An identified putative Tcf-4 binding element in the COX-2 promoter may partly explain the enhanced level of COX-2 and support the idea that COX-2 may be a downstream target of the APC/beta-catenin/Tcf-4 pathway.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / enzymology
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Adenocarcinoma / genetics*
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Adenocarcinoma / pathology
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Adult
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Aged
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Aged, 80 and over
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Cecal Neoplasms / enzymology
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Cecal Neoplasms / genetics
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Cecal Neoplasms / pathology
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Cell Nucleus / enzymology
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Cyclooxygenase 2
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Cytoskeletal Proteins / genetics*
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Female
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Gene Expression
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Genes, APC*
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Humans
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Isoenzymes / biosynthesis
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Isoenzymes / genetics*
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Male
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Membrane Proteins
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Middle Aged
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Mutation*
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Prostaglandin-Endoperoxide Synthases / biosynthesis
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Prostaglandin-Endoperoxide Synthases / genetics*
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Rectal Neoplasms / enzymology
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Rectal Neoplasms / genetics*
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Rectal Neoplasms / pathology
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Sigmoid Neoplasms / enzymology
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Sigmoid Neoplasms / genetics*
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Sigmoid Neoplasms / pathology
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TCF Transcription Factors
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Trans-Activators*
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Transcription Factor 7-Like 2 Protein
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Transcription Factors / biosynthesis
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beta Catenin
Substances
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CTNNB1 protein, human
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Cytoskeletal Proteins
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Isoenzymes
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Membrane Proteins
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TCF Transcription Factors
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TCF7L2 protein, human
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Trans-Activators
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Transcription Factor 7-Like 2 Protein
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Transcription Factors
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beta Catenin
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Cyclooxygenase 2
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PTGS2 protein, human
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Prostaglandin-Endoperoxide Synthases