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Cancer Res. 2014 Jan 1;74(1):320-9. doi: 10.1158/0008-5472.CAN-13-0894. Epub 2013 Oct 23.

ΔNp63 promotes pediatric neuroblastoma and osteosarcoma by regulating tumor angiogenesis.

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1
Authors' Affiliations: Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital; and Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio.

Abstract

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 (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 1α (HIF-1α) protein, resulting in VEGF secretion. We also show human clinical data, which suggest a mechanistic role for ΔNp63 in osteosarcoma metastasis. In summary, our studies reveal the mechanism by which ΔNp63, as a master transcription factor, modulates tumor angiogenesis.

PMID:
24154873
PMCID:
PMC3950294
DOI:
10.1158/0008-5472.CAN-13-0894
[Indexed for MEDLINE]
Free PMC Article
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