Kawasaki Takako, Nosho Katsuhiko, Ohnishi Mutsuko, Suemoto Yuko, Kirkner Gregory J, Dehari Reiko, Meyerhardt Jeffrey A, Fuchs Charles S, Ogino Shuji
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
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.
WNT/β-连环蛋白（CTNNB1）通路在致癌过程中通常被激活。有人提出WNT与环氧合酶-2（COX-2或PTGS2）/前列腺素通路之间存在相互作用。β-连环蛋白激活与结直肠癌微卫星不稳定性（MSI）之间的关系一直存在争议。具有广泛启动子甲基化的CpG岛甲基化表型（CIMP或高CIMP）是结直肠癌中一种独特的表观遗传表型，与高MSI相关。然而，尚无研究探讨β-连环蛋白激活与CIMP状态之间的关系。我们使用832份基于人群的结直肠癌标本，通过免疫组织化学评估β-连环蛋白的定位。我们通过实时聚合酶链反应（MethyLight）对8个CIMP特异性启动子[CACNA1G、CDKN2A（p16）、CRABP1、IGF2、MLH1、NEUROG1、RUNX3和SOCS1]中的DNA甲基化进行定量。高MSI、高CIMP和BRAF突变与细胞质和细胞核β-连环蛋白表达（即β-连环蛋白激活）呈负相关，与膜表达呈正相关。β-连环蛋白激活与CIMP之间的负相关独立于MSI。COX-2过表达与细胞质β-连环蛋白表达相关（即使在根据CIMP状态对肿瘤进行分层后），但与细胞核或膜表达无显著相关性。总之，β-连环蛋白激活与高CIMP呈负相关，且独立于MSI状态。细胞质β-连环蛋白与COX-2过表达相关，支持细胞质β-连环蛋白在稳定PTGS2（COX-2）mRNA中的作用。
