We have published that proton pump inhibitor could prevent colitis-associated cancer (Kim et al, Cancer Prevention Res, 2010), but question remains how PPI-induced hypergastrinemia contributed to significant cancer preventive outcomes in spite of proliferative and antiapoptotic action of gastrin beyond a central role of acid secretion. Therefore, there might be counterbalance or unexpected augmentation in cancer preventive action of PPI and gastrin, for which we investigated the effects of gastrin alone or combination with PPI on either colitis associated cancer or intestinal polyposis. Treatment of HCT116 cells with 100nM gastrin led to significantly increased proliferation, confirming trophic effects of gastrin and exogenous gastrin significantly increased the number of intestinal polyposis in Min mice as well as promoted carcinogenesis in two-stage colitic cancer mice. Gastrin treatment induced the progression of G1/S phase and increased the expressions of CDK4 and cyclin D1 as well as increased nuclear translocation of β-catenin associated with increased levels of Tcf4 and Lef1, whereas the inhibition of gastrin receptor by either YM022 or transient transfection of siRNA CCK-2R abrogated these cellular proliferations. Based on these mechanisms that pantoprazole treatment significantly abolished the gastrin-induced proliferation through attenuating gastrin induced β-catenin signaling accompanied with significant subG1 increments, combination of gastrin and PPI led to paradoxically significant prevention of colitis-associated cancer as well as significantly decreased intestinal polyposis. Our study can explain why in spite of longstanding PPI administration, the risk of colon cancer did not increase as Cohort study had documented and imposes anticipating cancer preventive action of PPI.