Correlation of beta-catenin localization with cyclooxygenase-2 expression and CpG island methylator phenotype (CIMP) in colorectal cancer.
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.
Kawasaki
Takako
T
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Nosho
Katsuhiko
K
Ohnishi
Mutsuko
M
Suemoto
Yuko
Y
Kirkner
Gregory J
GJ
Dehari
Reiko
R
Meyerhardt
Jeffrey A
JA
Fuchs
Charles S
CS
Ogino
Shuji
S
D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D018899:CpG Islands; D051546:Cyclooxygenase 2 / Q000032:analysis / Q000378:metabolism*; D019175:DNA Methylation; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000032:analysis / Q000378:metabolism*; D053842:Microsatellite Instability; D010641:Phenotype; D011401:Promoter Regions, Genetic; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D015854:Up-Regulation; D051176:beta Catenin / Q000032:analysis / Q000378:metabolism*
C495270:CTNNB1 protein, human; D008565:Membrane Proteins; D012333:RNA, Messenger; D051176:beta Catenin; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
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