Abstract In previous studies, we demonstrated that dysregulation of manganese superoxide dismutase (SOD2) is a frequent event in tongue squamous cell carcinoma (TSCC) and is associated with lymph node metastasis. Here, we further investigated the mechanism of SOD2-mediated cell migration and invasion in paired TSCC cell lines with different metastatic potential. The UM1 and UM2 are paired cell lines from a single TSCC patient, where UM1 is more aggressive than UM2 in term of cell migration and invasion. Compared to UM2 cells, UM1 cells exhibited significantly higher SOD2 activity, increased intracellular H2O2 and higher levels of Snail, MMP-1 and pERK1/2 protein, and lower level of E-cadtherin protein. Upon knockdown of SOD2 by RNA interference, UM1 cells displayed significantly reduced cell migration and invasion abilities. This is accompanied by reductions in SOD2 activities, intracellular H2O2, levels of Snail, MMP-1 and pERK1/2 proteins, as well as increase in the level of E-cadtherin protein. Cell migration and invasion of the UM2 and the SOD2 shRNA-treated UM1 cells were enhanced by H2O2 treatment. This H2O2-mediated cell migration and invasion is accompanied by increased levels of Snail, MMP-1 and pERK1/2 protein, and decreased level of E-cadtherin protein. Thus, we conclude that the SOD2-dependent production of H2O2 contributes to both cell migration and invasion of TSCC via the Snail signaling pathway through increased Snail, MMP-1 and pERK1/2 expression, and the repression of the E-cadtherin. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5322. doi:1538-7445.AM2012-5322