ΔNp63α-dependent expression of Id-3 distinctively suppresses the invasiveness of human squamous cell carcinoma

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Abstract

p63 is a member of the p53 family and ΔNp63α is the dominant-expressing isoform of p63 in basal layer of normal stratified epithelium and human squamous cell carcinoma (SCC) cells. We have previously reported that down-regulation of p63 was accompanied with epithelial-to-mesenchymal transition (EMT) by Snail-expressing SCC cells, in which re-expression of ΔNp63α diminished their invasiveness (Higashikawa K, Yoneda S, Tobiume K, Taki M, Shigeishi H, Kamata N. Snail-induced down-regulation of ΔNp63α acquires invasive phenotype of human squamous cell carcinoma. Cancer Res 2007;67:9207–13). In this study, we found that ΔNp63α positively regulatedinhibitor of differentiation-3 (Id-3) expression. Id is a dominant negative regulator of E2A which is a transcriptional repressor of E-cadherin. Enforced expression of Id-3 was incapable of invoking E-cadherin expression in the SCC cells with EMT phenotype, whereas it significantly impaired their invasiveness with down-regulation ofmatrix-metalloproteinase-2 (MMP-2) expression. Reporter gene assay revealed that the Ets-1-inducedMMP-2promoter activity was suppressed by the Id-3, while the Id-3-dependentE-cadherinpromoter activity was remarkably reduced in the presence of Snail. Furthermore, knockdown ofp63in SCC cells significantly decreasedId-3expression, in which up-regulation ofMMP-2expression was concomitant with the acquired invasiveness. These findings propose a particular role of the off-signaling of the ΔNp63α-Id-3 axis incident to Snail-mediated EMT for the MMP-2-dependent invasiveness in SCC cells. © 2009 UICC

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