P-cadherin is frequently up-regulated in solid tumors such as gastric, colon, lung, pancreatic and breast cancers. Although P-cadherin promotes cadherin-mediated cell adhesion, the gastric cancer-linked regulation of P-cadherin has not been extensively investigated. In this study, we found epigenetic regulation of P-cadherin in human gastric cancer cells that was induced by treatment with DNA demethylating drug and histone deacetylase inhibitor. Silencing P-cadherin by using siRNA induces apoptosis in gastric cells and blocks expression of Tie-2, an angiogenic receptor tyrosine kinase. In contrast, ectopically expressed P-cadherin by generating P-cadherin stable cell line enhances Tie-2 expression and cell mobility. We also demonstrated that inhibition of P-cadherin by PF-03732010, a fully humanized anti-P-cadherin IgG1 monoclonal antibody, suppressed cell migration in vitro and tumor growth in BALB/c nude mice bearing SNU620 gastric cancer xenograft. The data reported here are the first to reveal that the inhibition of P-cadherin decreases tumor cell migration and blocks a tumorigenesis by down-regulation of Tie-2 in gastric cancer. This demonstrates the potential for P-cadherin to be used as a target for treatment of gastric cancer.