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PMID: 17710160 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Neoplasia (New York, N.Y.) ·Vol. 9 ·No. 7 ·2007-07-00 ·Pages 569-77

Kawasaki T, Nosho K, Ohnishi M, Suemoto Y, Kirkner GJ, Dehari R, Meyerhardt JA, Fuchs CS, Ogino S

Abstract

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.

MeSH Terms
Colorectal Neoplasms/enzymology,genetics,metabolism CpG Islands Cyclooxygenase 2/analysis,metabolism DNA Methylation Female Humans Male Membrane Proteins/analysis,metabolism Microsatellite Instability Phenotype Promoter Regions, Genetic Proto-Oncogene Proteins B-raf/genetics RNA Stability RNA, Messenger/metabolism Up-Regulation beta Catenin/analysis,metabolism
Chemicals
CTNNB1 protein, human Membrane Proteins RNA, Messenger beta Catenin Cyclooxygenase 2 PTGS2 protein, human BRAF protein, human Proto-Oncogene Proteins B-raf
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Kawasaki Takako
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Nosho Katsuhiko
Ohnishi Mutsuko
Suemoto Yuko
Kirkner Gregory J
Dehari Reiko
Meyerhardt Jeffrey A
Fuchs Charles S
Ogino Shuji
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Article Info
Journal
Neoplasia (New York, N.Y.)
Abbr.
Neoplasia
ISSN
1476-5586
DOI
10.1593/neo.07334
Published
2007-07-00
Pages
569-77
Language
English
Region
United States
NLM ID
100886622
PMCID
PMC1939932
Subset
IM
Grants
NCI NIH HHS · P01 CA055075 · United States
NCI NIH HHS · P01 CA087969 · United States
NCI NIH HHS · P01 CA55075 · United States
NCI NIH HHS · P01 CA87969 · United States
External Links
PubMed source DOI: 10.1593/neo.07334 PMC Full Text View journal details
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