ΔNp63 promotes pediatric neuroblastoma and osteosarcoma by regulating tumor angiogenesis
Menée in vitro, in vivo et sur des échantillons de tumeurs primitives et de métastases pulmonaires prélevés sur des patients pédiatriques atteints d'un ostéosarcome ou d'un neuroblastome, cette étude met en évidence des mécanismes par lesquels, en régulant l'angiogenèse tumorale, un variant d'épissage du gène p63 (ΔNp63) favorise la croissance tumorale et le processus métastatique
The tumor suppressor gene p53 and its family members p63/p73 are critical determinants of tumorigenesis. ΔNp63 is a splice variant of p63 which lacks the N-terminal transactivation domain. It is thought to antagonize p53-, p63- and p73-dependent translation, thus blocking their tumor suppressor activity. In our studies of the pediatric solid tumors neuroblastoma and osteosarcoma, we find overexpression of ΔNp63; however, there is no correlation of ΔNp63 expression with p53 mutation status. Our data suggest that ΔNp63 itself endows cells with a gain of function that leads to malignant transformation, a function independent of any p53 antagonism. Here, we demonstrate that ΔNp63 overexpression, independent of p53, increases secretion of interleukin-6 (IL-6) and interleukin-8 (IL-8), leading to elevated phosphorylation of STAT-3 (Tyr-705). We show that elevated phosphorylation of STAT-3 leads to stabilization of HIF-1α protein, resulting in VEGF secretion. We also show human clinical data suggesting a mechanistic role for ΔNp63 in osteosarcoma metastasis. In summary, our study reveals the mechanism by which ΔNp63, as a master transcription factor, modulates tumor angiogenesis.