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 regulated inhibitor 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 of matrix‐metalloproteinase‐2 (MMP‐2) expression. Reporter gene assay revealed that the Ets‐1‐induced MMP‐2 promoter activity was suppressed by the Id‐3, while the Id‐3‐dependent E‐cadherin promoter activity was remarkably reduced in the presence of Snail. Furthermore, knockdown of p63 in SCC cells significantly decreased Id‐3 expression, in which up‐regulation of MMP‐2 expression 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