Snail-induced downregulation of deltaNp63 acquires invasive phenotype of human squamous cell carcinoma

P63是p53家族的成员，调控上皮结构形成的关键事件，但P63在肿瘤中的作用尚不清楚。我们发现蜗牛诱导的上皮-间质转化（EMT）伴随着p63在人类鳞状细胞癌（SCCs）中的下调。deltaNp63alpha是SCC细胞中主要表达的p63亚型。deltaNp63启动子的活性需要一个C/EBP结合元件，并且被Snail显著降低。emt表型细胞中deltaNp63alpha表达下调，C/EBPalpha表达降低，并在体外表现出侵袭性活性。在E-cadherin存在的情况下，细胞中p63的敲低增强了侵袭活性。相反，强制表达deltaNp63alpha会阻断EMT表型细胞的侵袭活性。这些发现表明，Snail下调deltaNp63alpha，导致SCC获得侵袭性表型。deltaNp63alpha下调引起的侵袭性活动不需要下调E-cadherin。

p63 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 epithelial-to-mesenchymal transition (EMT) is accompanied by downregulation of p63 in human squamous cell carcinomas (SCCs). deltaNp63alpha is the predominantly expressed p63 isoform in SCC cells. deltaNp63 promoter activity required a C/EBP binding element and was reduced remarkably by Snail. Downregulation of deltaNp63alpha and reduction of C/EBPalpha 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 deltaNp63alpha blocked invasive activity of cells with the EMT phenotype. These findings indicate that Snail downregulates deltaNp63alpha, leading to acquisition of the invasive phenotype by SCC. The invasive activity caused by downregulation of deltaNp63alpha does not require downregulation of E-cadherin.