ΔNp63 isoform-mediated β-defensin family up-regulation is associated with (lymph)angiogenesis and poor prognosis in patients with squamous cell carcinoma.

// Meggy Suarez-Carmona 1,2,* , Pascale Hubert 1,* , Arnaud Gonzalez 3 , Anaelle Duray 4 , Patrick Roncarati 1 , Charlotte Erpicum 2 , Jacques Boniver 1 , Vincent Castronovo 3 , Agnes Noel 2 , Sven Saussez 4 , Olivier Peulen 3 , Philippe Delvenne 1,** and Michael Herfs 1,** 1 Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, Liege, Belgium 2 Laboratory of Tumor and Developmental Biology, GIGA-Cancer, University of Liege, Liege, Belgium 3 Metastasis Research Laboratory, GIGA-Cancer, University of Liege, Liege, Belgium 4 Laboratory of Anatomy, Faculty of Medicine and Pharmacy, University of Mons, Mons, Belgium * These authors contributed equally to this work ** These authors share last authorship Correspondence: Michael Herfs, email: // Keywords : p63, defensins, (lymph)angiogenesis, prognosis, squamous cell carcinoma Received : January 17, 2014 Accepted : March 19, 2014 Published : March 21, 2014 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.