Promoter hypermethylation of cyclooxygenase-2 in gastric carcinoma

Overexpression of cyclooxygenase-2 (COX-2) is associated with loss of apoptosis, enhancement of proliferation and tumorigenesis. The role of promoter methylation in the transcriptional silencing of cox-2 gene in human gastric cancer is less determined. We investigated 5 gastric cancer cell lines and 58 primary gastric carcinomas for the presence of promoter hypermethylation in cox-2 gene. Combined methylation-specific polymerase chain reaction analysis and bisulfite sequencing analysis revealed that the cox-2 promoter was methylated in 2 of the gastric cancer cell lines. Treatment with 5-aza-2'-deoxycytidine, a DNA methyltransferase inhibitor, induced COX-2 expression in the methylated gastric cancer cell line. Among the 58 primary gastric cancers, hypermethylation was detected in 25 (43.1%) cases. However, none of the normal gastric tissues showed methylation in cox-2. Promoter hypermethylation was associated with loss of protein expression as determined by immunostaining (p=0.005). Our results indicate that hypermethylation of the CpG island in the cox-2 gene is a major mechanism that mediates transcriptional silencing in a subset of gastric cancers. Thus, gastric cancers with methylation in cox-2 may not be good candidates for treatment with specific COX-2 inhibitors.