ΔNp63 isoform-mediated β-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 (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.

Altered α‐defensin 5 expression in cervical squamocolumnar junction: implication in the formation of a viral/tumour‐permissive microenvironment

“…Previous studies demonstrated that other α ‐defensins (HNP1–3) inhibit endothelial cell adhesion and migration . In contrast, β ‐defensins have some pro‐angiogenic abilities . In the current study, we showed that blood vessel outgrowth from aortic rings is inhibited under the influence of high doses of HD‐5.…”

ΔNp63-driven recruitment of myeloid-derived suppressor cells promotes metastasis in triple-negative breast cancer

“…Furthermore, reduced tumor cell proliferation (marked by Ki67) was observed in tumors from ΔNp63-KD HCC1806 cells and ΔNp63-KD SUM159 cells compared with control cells, suggesting that reduced proliferation may be responsible for reduced tumor growth in ΔNp63-KD cells (Supplemental Figure 5, G and H). Angiogenesis positively correlates with metastasis, and ΔNp63 promotes tumor angiogenesis in pediatric neuroblastoma, osteosarcoma, and squamous cell carcinoma (34)(35)(36). Therefore, we assessed the expression of CD31 and CD34, markers for angiogenesis, as well as smooth muscle actin (SMA) (37) in HCC1806 and SUM159 primary tumors.…”

Genome-Wide Association Study and Transcriptome Analysis Provide New Insights into the White/Red Earlobe Color Formation in Chicken

“…TP63 is also an active gene involving tumorgenesis [33]. In squamous cell carcinoma (SCC), ΔNp63, the predominant isoform of TP63, its over-expression in vitro and in vivo could up-regulate human beta-defensin (HβD), thus promoting tumor angiogenesis in SCC microenvironment [34]. Importantly, RNA-seq study between the white earlobes and the red earlobes indicated that, TP63 was significantly down-regulated in white earlobes compared to that in red ones.…”