Abstract
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 down-regulation of p63 in human squamous cell carcinomas (SCC). DeltaNp63alpha is the predominantly expressed p63 isoform in SCC cells. DeltaNp63 promoter activity required a CAAT/enhancer binding protein (C/EBP) binding element and was reduced remarkably by Snail. Down-regulation 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 down-regulates DeltaNp63alpha, leading to acquisition of the invasive phenotype by SCC. The invasive activity caused by down-regulation of DeltaNp63alpha does not require down-regulation of E-cadherin.
Highlights
In embryonic development, epithelial-to-mesenchymal transition (EMT) is the process of disaggregating structured epithelial units to enable cell motility and morphogenesis [1, 2]
Most forced DNp63a-expressing cells were unable to invade the gel layer and formed stratified layers on the collagen gel in in vitro three-dimensional cultures (Fig. 5C). These findings indicate that DNp63a prevents the invasiveness of squamous cell carcinoma (SCC) cells with the spontaneous EMT phenotype and, loss of p63 leads to acquisition of an invasive activity regardless of functional E-cadherin expression
We showed that Snail inhibits expression of DNp63a and that forced depletion of DNp63a enhances invasiveness of SCC cell, whereas reexpression of DNp63a in DNp63adeficient cell suppresses its invasive activity in vitro
Summary
Epithelial-to-mesenchymal transition (EMT) is the process of disaggregating structured epithelial units to enable cell motility and morphogenesis [1, 2]. Wound healing and progression of carcinomas to invasive and metastatic phenotypes involve localized EMT [3, 4]. The term ‘‘EMT’’ comprises a wide spectrum of changes in epithelial plasticity. Among these EMT subtypes, ‘‘complete EMT,’’ defined by a fibroblastoid phenotype, loss of E-cadherin, and gain of vimentin, a mesenchymal marker, was most closely correlated with local invasion [5]. Loss of E-cadherin expression is a primal molecular event that contributes to tumor invasion and metastasis [6]. A zinc finger transcription factor, triggers EMT through direct repression of E-cadherin [7, 8]. The reverse correlation of Snail and E-cadherin has been reported for various human cancers, including squamous cell carcinoma
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