Involvement of the Wnt-beta-catenin pathway in invasion and migration of oral squamous carcinoma cells

Abstract

The Wnt/beta-catenin pathway plays a critical role in cell proliferation and oncogenesis. To clarify the role of cytoplasmic accumulation of beta-catenin in oral squamous cell carcinoma （SCC）, the cDNA of a mutant form of beta-catenin that lacks the entire region with the glycogen synthase kinase-3 beta （GSK-3 beta）-specific phosphorylation site was transfected into Ca9-22 cells whose beta-catenin had been expressed predominantly at the membrane, and permanent cell lines expressing aberrant beta-catenin in the cytoplasm and nucleus were produced. These transfectants, C1 and C5, proliferated at similar rates to the parental Ca9-22 cells, but the cell morphology changed from polygonal to spindle-shaped, and close cell-cell interaction was lost. These mutant betacatenin-expressing cells exhibited a significantly higher invasion/migration capacity than wild-type Ca9-22 cells. The transcriptional activities of this mutant beta-catenin form was enhanced in these cells, which could be demonstrated by an elevated level of the transcription factors T-cell factor （Tcf）/lymphoid enhancer factor （Lef）-dependent reporter gene activity, as well as by the up-regulation of Wnt/beta-catenin target gene matrix metalloproteinase （MMP）-7. Moreover, we observed the redistribution of E-cadherin, the rearrangement of actin filaments, and the elevation of active Rho family members, Cdc42 and Rac. These results suggest that aberrant cytoplasmic accumulation of beta-catenin can induce Tcf/Lef-mediated transcriptional activity, up-regulate MMP-7, and induce epithelial and mesenchymal transition （EMT）. This would enhance the invasion and migration of oral SCC cells.