Squamous cell carcinoma antigen (SCCA) has been used for the management of squamous cell carcinoma, especially for evaluating therapeutic effects and monitoring recurrence. It has been reported that SCCA has several biological activities and influences behavior of cancer cells. E-cadherin is a cell adhesion molecule and plays important roles in the process of cancer invasion and metastasis. Our previous studies have shown that blockage of E-cadherin action by anti-E-cadherin antibody treatment suppresses SCCA production in squamous cell carcinoma cells. This finding strongly suggests that E-cadherin regulates SCCA expression. The present study was, therefore, undertaken to investigate the correlation between E-cadherin and SCCA2. For this purpose, E-cadherin cDNA was transfected into squamous cell carcinoma cell lines, SiHa and SKG IIIa. Overexpression of E-cadherin increased SCCA2 expression together with cell aggregation. We also examined the involvement of phosphatidylinositol 3-kinase (PI3K)-Akt pathway, which is one of major signaling pathways from E-cadherin. E-cadherin transfection increased phosphorylated Akt expression concomitantly with the increase in SCCA2 expression, and the increased SCCA2 expression was inhibited by a PI3K inhibitor. In conclusion, SCCA2 is up-regulated by E-cadherin through PI3K-Akt pathway, suggesting that SCCA2, as well as E-cadherin, may be involved in the regulation of cancer behavior.