Abstract
The TP63 gene codes for two major isoform types, TAp63 and ΔNp63, with probable opposite roles in tumorigenesis. The ΔNp63α protein is frequently amplified and overexpressed in different epithelial tumors. Accordingly, it has been considered a potential oncogene. Nonetheless, a possible metastatic suppressor activity has also been suggested based on the experimental observation that its expression is reduced or even absent in advanced invasive tumors. Such metastatic suppressor activities are often related to tumors bearing point mutated TP53 gene. However, its potential roles in TP53-deficient tumors are poorly characterized. Here we show that in spontaneous tumors, induced by the epidermal-specific Trp53 ablation, the reduction of ΔNp63 expression is an early event, whereas it is re-expressed in the lung metastatic lesions. Using knock down and ectopic expression approaches, we show that ΔNp63 expression opposes the epithelial-mesenchymal transition and reduces the metastatic potential of the cells. This process occurs through the modulation of ΔNp63-dependent downstream targets (including transcription factors and microRNAs) likely to play metastatic roles. Further, ΔNp63 also favors the expression of factors involved in iPS reprogramming, thus suggesting that it can also modulate specific stem cell traits in mouse epidermal tumor cells. Overall, our data assign antimetastatic roles to ΔNp63 in the context of p53 deficiency and epidermis.
Highlights
The TP63 gene forms, together with TP53 and TP73, the so-called p53 family
More recently we demonstrated the high metastatic capacity of these Trp53ΔEpi tumors, and we characterized a role for specific miRNAs in this process through a possible modulation of the epithelial mesenchymal transition (EMT) signaling pathway [37]
Immunohistochemical analyses revealed that the pattern of p63 expression in the skin of Trp53ΔEpi and Trp53ΔEpi;Rb1ΔEpi mice is undistinguishable from control wt mice (Fig. 1A, 1E), and remains expressed, mainly in the basal layer, in areas of epidermal dysplasia (Fig. 1B, 1E)
Summary
The TP63 gene forms, together with TP53 and TP73, the so-called p53 family. These genes produce multiple isoforms due to alternative splicing and alternative promoter usage [1]. In some aggressive metastatic epithelial tumors the expression of ΔNp63 is reduced and often lost, suggesting potential roles as metastasis suppressor [16,17,18,19,20,21] This is in agreement with the observed ability of ΔNp63 to bind and modulate the expression of a variety of genes, including transcription factors, adhesion and signaling molecules, and several miRNAs [14, 20, 22,23,24,25]. Further research is clearly needed to ascertain the actual oncogenic and/or metastatic suppressor roles of ΔNp63 in order to consider possible targeted therapies
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