δ Np63 isoform-mediated ß-defensin family up-regulation is associated with (lymph)angiogenesis and poor prognosis in patients with squamous cell carcinoma

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 (HßDs) 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 HßDs and the implication of these antimicrobial peptides in tumor (lymph)angiogenesis. Thus, in contrast to TAp63 isotypes, we observed that δ Np63 proteins (a, ß, γ ) induce HßD1, 2 and 4 expression. Similar results were observed in cancer tissues and cell lines. We next demonstrated that δ Np63-overexpressing SCC are associated with both a poor prognosis and a high tumor vascularisation and lymphangiogenesis. Moreover, we showed that HßDs exert a chemotactic activity for (lymphatic) endothelial cells in a CCR6-dependent manner. The ability of HßDs to enhance (lymph)angiogenesis in vivo was also evaluated. We observed that HßDs 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 δ Np63-regulated HßD could promote tumor (lymph)angiogenesis in SCC microenvironment.