56998

CTNNBIP1

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-3beta)-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 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.

The inhibitor of beta-catenin and TCF (ICAT) blocks the binding of TCF to beta-catenin and has been demonstrated as a suppressor of the Wnt/beta-catenin signaling pathway. It has been reported to exert a different function around a wide variety of cancers. However, its function and underlying mechanisms in human cervical cancer remains unknown. In the present study, the expression of ICAT in 41 human cervical cancer tissues and 30 normal cervical tissues was evaluated by immunohistochemical analysis. ICAT was found highly expressed in cancer tissues. ICAT overexpression significantly promoted SiHa cell proliferation in vitro by causing G1 arrest, and enhanced cell migration and invasion whereas, ICAT knockdown induced opposite effects in Caski cells which have higher expression of ICAT. Downregulation or overexpression of ICAT resulted in an altered expression of the epithelial-mesenchymal transition (EMT). Furthermore, immunoprecipitation assays revealed that ICAT pormoted cervical cancer EMT by competing in E-cadhenin binding to beta-caterin. Overexpression of ICAT in SiHa cells promoted tumor growth and EMT was also demonstrated by the xenograft mouse experiment. These results demonstrate that ICAT contributed to the progression of cervical cancer and may play a role in the regulation of EMT by distrupting the E-cadherin/beta-catenin complex. It may be a novel potential therapeutic target for therapy in human cervical cancer.