Correlation of beta-catenin localization with cyclooxygenase-2 expression and CpG island methylator phenotype (CIMP) in colorectal cancer

Neoplasia. 2007 Jul;9(7):569-77. doi: 10.1593/neo.07334.


The WNT/beta-catenin (CTNNB1) pathway is commonly activated in the carcinogenic process. Cross-talks between the WNT and cyclooxygenase-2 (COX-2 or PTGS2)/prostaglandin pathways have been suggested. The relationship between beta-catenin activation and microsatellite instability (MSI) in colorectal cancer has been controversial. The CpG island methylator phenotype (CIMP or CIMP-high) with widespread promoter methylation is a distinct epigenetic phenotype in colorectal cancer, which is associated with MSI-high. However, no study has examined the relationship between beta-catenin activation and CIMP status. Using 832 population-based colorectal cancer specimens, we assessed beta-catenin localization by immunohistochemistry. We quantified DNA methylation in eight CIMP-specific promoters [CACNA1G, CDKN2A(p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1] by real-time polymerase chain reaction (MethyLight). MSI-high, CIMP-high, and BRAF mutation were associated inversely with cytoplasmic and nuclear beta-catenin expressions (i.e., beta-catenin activation) and associated positively with membrane expression. The inverse relation between beta-catenin activation and CIMP was independent of MSI. COX-2 overexpression correlated with cytoplasmic beta-catenin expression (even after tumors were stratified by CIMP status), but did not correlate significantly with nuclear or membrane expression. In conclusion, beta-catenin activation is inversely associated with CIMP-high independent of MSI status. Cytoplasmic beta-catenin is associated with COX-2 overexpression, supporting the role of cytoplasmic beta-catenin in stabilizing PTGS2 (COX-2) mRNA.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Colorectal Neoplasms / enzymology
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism*
  • CpG Islands*
  • Cyclooxygenase 2 / analysis
  • Cyclooxygenase 2 / metabolism*
  • DNA Methylation*
  • Female
  • Humans
  • Male
  • Membrane Proteins / analysis
  • Membrane Proteins / metabolism*
  • Microsatellite Instability
  • Phenotype
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins B-raf / genetics
  • RNA Stability
  • RNA, Messenger / metabolism
  • Up-Regulation
  • beta Catenin / analysis
  • beta Catenin / metabolism*


  • CTNNB1 protein, human
  • Membrane Proteins
  • RNA, Messenger
  • beta Catenin
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf