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Aquaporins (AQP) play important roles in water and glycerol transport. We examined whether AQP3 is expressed in primary squamous cell carcinoma (SCC) such as esophageal and oral cancer and lymph node metastasis, and whether AQP3 is a potential target for tumor therapy. A high level expression of AQP3 was observed in tumor areas of human primary SCC such as esophageal and lingual cancers, and lymph node metastasis, but was not observed in normal areas. Treatment with pan-AQP inhibitor caused apoptotic cell death on the SCC cell lines in a concentration-dependent manner. Small interfering RNA (siRNA) specific for AQP3 also inhibited cell adhesion and growth of SCC, but not those of adenocarcinoma cell lines and fibroblasts. Expression of integrin α5 and β1, counter adhesion molecules for fibronectin, was inhibited by treatment with AQP3-siRNA. The phosphorylation of focal adhesion kinase (FAK) was decreased by treatment with AQP3-siRNA, which then caused decreases in phosphorylation of Erk and MAPK. These results indicate that the decreases in integrins and the inhibition of cell adhesion might cause inhibition of the FAK signaling pathways. Combination of AQP3-siRNA with cisplatin, a major anti-cancer drug, strongly inhibited the growth of SCC. Cell death caused by the inhibition of AQP3 was a result of direct interference with cell adhesion involving intracellular FAK-MAPK signaling pathways. These results imply a potentially important and novel role for the inhibition of AQP3 function via the use of specific siRNA in the treatment of SCC. (Cancer Sci 2011; 102: 1128–1136)