title: ΔNp63 promotes pediatric neuroblastoma and osteosarcoma by regulating tumor angiogenesis.
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.
authors.affiliation: 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.
authors.forename: Hemant K
authors.initials: HK
authors.lastname: Bid
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Roberts
authors.forename: Maren
authors.initials: M
authors.lastname: Cam
authors.forename: Anthony
authors.initials: A
authors.lastname: Audino
authors.forename: Raushan T
authors.initials: RT
authors.lastname: Kurmasheva
authors.forename: Jiayuh
authors.initials: J
authors.lastname: Lin
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houghton
authors.forename: Hakan
authors.initials: H
authors.lastname: Cam
mesh_terms: D000293:Adolescent; D000818:Animals; D001859:Bone Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002648:Child; D004195:Disease Models, Animal; D005260:Female; D064593:Heterografts; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D009447:Neuroblastoma / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism; D012516:Osteosarcoma / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: C081876:CKAP4 protein, human; D008565:Membrane Proteins; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53