Loss of p63 Leads to Increased Cell Migration and Up-regulation of Genes Involved in Invasion and Metastasis

Abstract

Abstractp63, a homologue of the tumor suppressor p53, is critical for the development and maintenance of squamous epithelia. p63 is specifically expressed in the basal layers of stratified epithelial tissues and is considered a specific marker for cells of this type. The role of p63 in tumorigenesis remains poorly defined. Numerous studies have highlighted the oncogenic potential of the predominant p63 isoform #Np63A; however, data suggest that other p63 proteins can act as tumor suppressors or alter the metastatic potential of tumors. #Np63A can act as a transcriptional repressor, but the link between the transcriptional functions of p63 and its biological role is still unclear. In this study, we used a loss-of-function approach to investigate the transcriptional programs controlled by p63. Disruption of p63 in squamous cell lines resulted in down-regulation of transcripts specifically expressed in squamous tissues and a significant alteration of keratinocyte differentiation. Interestingly, we found that disruption of p63 led to up-regulation of markers of nonepithelial tissues (mesenchyme and neural tissue) in both primary and immortalized squamous cells. Many of these up-regulated genes are associated with increased capacity for invasion and metastasis in tumors. Furthermore, loss of p63 expression was accompanied by a shift toward mesenchymal morphology and an increase in motility in primary keratinocytes and squamous cell lines. We conclude that loss of endogenous p63 expression results in up-regulation of genes associated with invasion and metastasis, and predisposes to a loss of epithelial and acquisition of mesenchymal characteristics. These findings have implications for the role of p63 in both development and tumorigenesis. (Cancer Res 2006; 66(15): 7589-97)

ΔNp63α is a common inhibitory target in oncogenic PI3K/Ras/Her2-induced cell motility and tumor metastasis

“…We previously showed that ΔNp63α inhibits cancer cell migration, invasion, and metastasis by upregulating expression of the metastasis suppressor CD82, a member of the tetraspanin family of proteins (47), as well as MAP kinase phosphatase 3 (MKP3), which negatively regulates Erk2 signaling to inhibit cancer cell migration, invasion, and metastasis (45). In addition, ΔNp63α has been shown to regulate N-cadherin, L1 adhesion molecule, and Wnt-5A, which play a role in regulating cell migration (65), and to repress cell invasion by inhibiting Ets-1-mediated matrix metallopeptidase 2 (MMP2) expression via Id-3 up-regulation (66). Hence, ΔNp63α may act as a master regulator in regulation of cell motility.…”

TP63 P2 promoter functional analysis identifies β-catenin as a key regulator of ΔNp63 expression

“…Indeed, beyond its dominantnegative effect on p53 suppressor function, DNp63 was found to favour angiogenesis and chemoresistance (Senoo et al, 2002;Wu et al, 2005;Rocco et al, 2006) and to regulate cell-adhesion processes (Carroll et al, 2006;Yang et al, 2006). Conversely, several studies reported a loss of p63 expression in metastatic stages (Barbieri et al, 2006;Adorno et al, 2009). These observations suggest a dual role of DNp63 in tumourigenesis with enhanced expression in the early stages of progression during which the epithelial cell fate is maintained, followed by loss of expression when cells acquire mesenchymal properties associated with metastatic potential.…”

Are interactions with p63 and p73 involved in mutant p53 gain of oncogenic function?

“…Third, downregulation of p63/p73 in p53-null MEFs stimulated DNA synthesis and transformation potential to levels similar to those in mutant p53 MEFs (Lang et al, 2004). It is relevant that loss of p63 has been recently shown to upregulate genes involved in invasion and metastasis (Barbieri et al, 2006). This could in part explain the reasons for the increased metastasis observed in mice expressing mutant p53.…”