Abstract
Beside a role in normal development/differentiation, high p63 immunoreactivity is also frequently observed in squamous cell carcinoma (SCC). Due to the complexity of the gene, the role of each p63 isotype in tumorigenesis is still confusing. Constitutively produced or induced in inflammatory conditions, human beta-defensins (HβDs) are cationic peptides involved in host defenses against bacteria, viruses and fungi. Here, we investigated both the role of p63 proteins in the regulation of HβDs and the implication of these antimicrobial peptides in tumor (lymph)angiogenesis. Thus, in contrast to TAp63 isotypes, we observed that ΔNp63 proteins (α, β, γ) induce HβD1, 2 and 4 expression. Similar results were observed in cancer tissues and cell lines. We next demonstrated that ΔNp63-overexpressing SCC are associated with both a poor prognosis and a high tumor vascularisation and lymphangiogenesis. Moreover, we showed that HβDs exert a chemotactic activity for (lymphatic) endothelial cells in a CCR6-dependent manner. The ability of HβDs to enhance (lymph)angiogenesis in vivo was also evaluated. We observed that HβDs increase the vessel number and induce a significant increase in relative vascular area compared to negative control. Taken together, the results of this study suggest that ΔNp63-regulated HβD could promote tumor (lymph)angiogenesis in SCC microenvironment.
Highlights
Member of the p53 family, TP63 gene gives rise to transcripts that encode either full-length isoforms containing an amino-transactivation (TA) domain (TAp63) or truncated isoforms that lacks this TA domain (ΔNp63)
We investigated the involvement of chemokine receptor CCR6 on the capacity of vascular endothelial cells to migrate toward HβDs
Whatever the tumor location, the overall survival rate for squamous cell carcinoma (SCC) is low, largely due to the capacity of cancer cells to disseminate via blood and/or lymphatic circulations
Summary
Member of the p53 family, TP63 gene gives rise to transcripts that encode either full-length isoforms containing an amino-transactivation (TA) domain (TAp63) or truncated isoforms that lacks this TA domain (ΔNp63) Both TA and ΔN transcripts undergo C-terminal alternative splicing to yield six further carboxyl-terminal isotypes (α, β, γ) [1]. The implication of p63 proteins in epithelial stratification [2], differentiation [3] and in the maintenance of the proliferative potential of epithelial stems cells [4] has been well established In addition to their role in normal development and homeostasis, the large majority of squamous malignancies display p63 immunoreactivity suggesting that, similar to p53, p63 is acting during tumorigenesis [5]. Other data show www.impactjournals.com/oncotarget that the p63 gene, especially TAp63 isoforms, could act as a tumor suppressor [12,13,14], p63 is rarely mutated in human cancer in contrast to classic tumor suppressor genes
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