title: Enhanced expression of cyclooxygenase-2 and nuclear beta-catenin are related to mutations in the APC gene in human colorectal cancer.
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.
authors.affiliation: Department of Biomedicine and Surgery, Division of Cell Biology, Faculty of Health Sciences, Linköping, Sweden. jan.dimberg@hhj.hj.se
authors.forename: J
authors.initials: J
authors.lastname: Dimberg
authors.forename: A
authors.initials: A
authors.lastname: Hugander
authors.forename: A
authors.initials: A
authors.lastname: Sirsjö
authors.forename: P
authors.initials: P
authors.lastname: Söderkvist
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002430:Cecal Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D002467:Cell Nucleus / Q000201:enzymology; D051546:Cyclooxygenase 2; D003598:Cytoskeletal Proteins / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D017491:Genes, APC; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D009154:Mutation; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000235:genetics*; D012004:Rectal Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D012811:Sigmoid Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D051820:TCF Transcription Factors; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000096:biosynthesis; D051176:beta Catenin
chemical_list: C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D007527:Isoenzymes; D008565:Membrane Proteins; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D051176:beta Catenin; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases