Here, we demonstrated that COX-2/PGE2 contributes to gastric carcinogenesis, at least in part, by inducing DNMT3B expression, as evidenced by 1) PGE2 treatment directly enhances DNMT3B expression and activity in gastric normal and cancer cells in vitro; 2) transgenic COX-2 expressing mice have elevated expression of DNMT3B and activity in vivo; and 3) the significant correlation between COX-2 and DNMT3B expression in human GC. This evidence concerns the gene PTGS2 and gastric cancer.