ΔNp63 Promotes Pediatric Neuroblastoma and Osteosarcoma by Regulating Tumor Angiogenesis

The tumor suppressor gene p53 and its family members p63/p73 are critical determinants of tumorigenesis. Delta Np63 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 Delta Np63; however, there is no correlation of Delta Np63 expression with p53 mutation status. Our data suggest that Delta Np63 itself endows cells with a gain-of-function that leads to malignant transformation, a function independent of any p53 antagonism. Here, we demonstrate that Delta Np63 overexpression, independent of p53, increases secretion of interleukin (IL)-6 and IL-8, leading to elevated phosphorylation of STAT3 (Tyr-705). We show that elevated phosphorylation of STAT3 leads to stabilization of hypoxia-inducible factor 1 alpha (HIF-1 alpha) protein, resulting in VEGF secretion. We also show human clinical data, which suggest a mechanistic role for DNp63 in osteosarcoma metastasis. In summary, our studies reveal the mechanism by which Delta Np63, as a master transcription factor, modulates tumor angiogenesis. (C)2013 AACR.