Enhanced expression of cyclooxygenase-2 and nuclear beta-catenin are related to mutations in the APC gene in human colorectal cancer

Anticancer Res. 2001 Mar-Apr;21(2A):911-5.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / enzymology
  • Adenocarcinoma / genetics*
  • Adenocarcinoma / pathology
  • Adult
  • Aged
  • Aged, 80 and over
  • Cecal Neoplasms / enzymology
  • Cecal Neoplasms / genetics
  • Cecal Neoplasms / pathology
  • Cell Nucleus / enzymology
  • Cyclooxygenase 2
  • Cytoskeletal Proteins / genetics*
  • Female
  • Gene Expression
  • Genes, APC*
  • Humans
  • Isoenzymes / biosynthesis
  • Isoenzymes / genetics*
  • Male
  • Membrane Proteins
  • Middle Aged
  • Mutation*
  • Prostaglandin-Endoperoxide Synthases / biosynthesis
  • Prostaglandin-Endoperoxide Synthases / genetics*
  • Rectal Neoplasms / enzymology
  • Rectal Neoplasms / genetics*
  • Rectal Neoplasms / pathology
  • Sigmoid Neoplasms / enzymology
  • Sigmoid Neoplasms / genetics*
  • Sigmoid Neoplasms / pathology
  • TCF Transcription Factors
  • Trans-Activators*
  • Transcription Factor 7-Like 2 Protein
  • Transcription Factors / biosynthesis
  • beta Catenin

Substances

  • CTNNB1 protein, human
  • Cytoskeletal Proteins
  • Isoenzymes
  • Membrane Proteins
  • TCF Transcription Factors
  • TCF7L2 protein, human
  • Trans-Activators
  • Transcription Factor 7-Like 2 Protein
  • Transcription Factors
  • beta Catenin
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases