Snail regulates the motility of oral cancer cells via RhoA/Cdc42/p-ERM pathway

The transcriptional factor Snail has been reported to possess properties related to cancer progression; however, the mechanism for it is not fully understood. Our data showed that Snail knockdown by small interfering RNA in two OSCC cell lines, WSU-HN6 and CAL27, significantly inhibited cell migration and invasion which also resulted in decreased cell motility, such as impaired cell spreading on type I collagen substrate, reduced filopodia, and premature assembly of stress fibers. In addition, Snail-silencing decreased Cdc42 activity but increased RhoA activity, accompanied by the downregulation in both p-ERM expression and cell motility. Meanwhile, endogenous p-ERM was found specifically co-precipitated with activated Cdc42, but not RhoA, and this co-association was decreased by Snail-silencing. The small molecule inhibitors of Rho-associated kinase (Y27632) markedly enhanced Cdc42 activity and the association of p-ERM with activated Cdc42, increasing cell motility remarkably. Using immunohistochemistry, Snail and p-ERM overexpressions were found in OSCC tissues correlated with nodal metastasis and shorter survival. Taken together, these results demonstrate that Snail regulates cell motility through RhoA/Cdc42/p-ERM pathway and may serve as a biomarker to predict prognosis for OSCC patients. Although RhoA and Cdc42 are concurrently regulated downstream of Snail, there is a direct interplay between them, which indicates RhoA has to be inactivated at some point in cell motility cycle.