Gene expression of Wnt-1, 2, 3, 4, 5a, 6 and 7a was analyzed by RT-PCR in eleven squamous cell carcinoma (SCC) cell lines and compared with that in two normal oral keratinocyte strains. There appeared to be an inverse relationship between Wnt-4 and Wnt-5a expressions, i.e., Wnt-4 was not expressed in HOC719-NE, HOC313 or TSU cells, while Wnt-5a was strongly expressed only in these cells.
Abstractp63 is a member of the p53 family and regulates crucial events in the formation of epithelial structures, but the role of p63 in tumor is unclear. We found that Snail-induced epithelialto-mesenchymal transition (EMT) is accompanied by downregulation of p63 in human squamous cell carcinomas (SCC). #Np63A is the predominantly expressed p63 isoform in SCC cells. DNp63 promoter activity required a CAAT/enhancer binding protein (C/EBP) binding element and was reduced remarkably by Snail. Down-regulation of #Np63A and reduction of C/EBPA were observed in EMT phenotype cells, which exhibited invasive activity in vitro. p63 knockdown in cells enhanced invasive activity in the presence of E-cadherin. Conversely, forced expression of #Np63A blocked invasive activity of cells with the EMT phenotype. These findings indicate that Snail down-regulates #Np63A, leading to acquisition of the invasive phenotype by SCC. The invasive activity caused by down-regulation of #Np63A does not require down-regulation of E-cadherin.
These cell lines will be useful tools for studying the repair and regeneration of dental and periodontal tissues and various diseases including odontogenic tumors.
Epithelial-mesenchymal transition (EMT) is a crucial event in cancer progression. We previously reported that EMT up-regulates matrix metalloproteinase-2 (MMP-2) expression in squamous cell carcinoma (SCC) cells. In this study, we showed that Tet Off-induced expression of Snail or SIP1, and treatment with TGF-ß1 induced EMT in terms of down-regulation of E-cadherin, and up-regulation of vimentin and MMP-2 expression with morphological changes. In SCC cells, SIP1 expression was induced by Snail and TGF-ß1, but Snail expression was not induced by SIP1 or TGF-ß1. However, expression of Snail but not SIP1 was strongly increased by TGF-ß1 in highly invasive SCC cells with mesenchymal phenotypes. Analysis of the MMP-2 promoter revealed that an Ets-1 binding site, located between position-1255 and-1248 relative to the transcriptional start site, was critical for the activation by Snail, SIP1 and TGF-ß1 in SCC cells. Induced expression of Snail and SIP1 resulted in the increased expression of Ets-1 and DNA-binding activities of nuclear proteins to the Ets-1-binding site and strong Ets-1 expression was detected in highly invasive SCC cells. Furthermore, overexpression of Ets-1 induced the promoter-activation and expression of MMP-2 without EMT. These results indicate that EMT induces Ets-1 expression, which activates the MMP-2 promoter, but Ets-1 by itself has no activity to induce EMT in SCC cells.
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