Migfilin Regulates Esophageal Cancer Cell Motility through Promoting GSK-3β-Mediated Degradation of β-Catenin

Migfilin, a protein component of focal adhesions, has been implicated in regulation of cell-extracellular matrix adhesion and motility but the underlying mechanisms are not fully elucidated. In this study, we have determined the functions of migfilin in esophageal cancer cells and the mechanisms involved. We show that the expression level of migfilin is negatively associated with clinical metastasis, and enforced expression of migfilin suppressed cell motility through decreased free beta-catenin level. Overexpression of migfilin resulted in destabilization of beta-catenin in concomitance with reduction of its transcriptional activity. Knockdown of migfilin by siRNA, transfection of a mutant b-catenin at Ser37 which is a critical phosphorylation site of GSK-3 beta, GSK-3 beta inhibitor LiCl, or proteasome inhibitor MG132 reversed the migfilin-mediated beta-catenin degradation and transcription inhibition. Moreover, migfilin promoted beta-catenin degradation by reinforcing the association between beta-catenin and GSK-3 beta. In addition, exogenously expressed beta-catenin partially restored migfilin-induced suppression of cell invasion. Collectively, these results suggest that the expression level of migfilin in ESCCs is inversely correlated with clinical metastasis status, and migfilin inhibits ESCC cell invasion at least in part through promoting degradation of beta-catenin. Mol Cancer Res; 10(3); 273-81. (C)2012 AACR.