Journal
INTERNATIONAL JOURNAL OF ONCOLOGY
Volume 37, Issue 5, Pages 1095-1103Publisher
SPANDIDOS PUBL LTD
DOI: 10.3892/ijo_00000761
Keywords
beta-catenin; cytoplasmic accumulation; cell invasion and migration; epithelial-mesenchymal transition; oral squamous cell carcinoma
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Funding
- Japanese Society for the Promotion of Science [19592293]
- Grants-in-Aid for Scientific Research [19592293] Funding Source: KAKEN
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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 beta-catenin-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 factor 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 Rae. 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.
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