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?Np63 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. ?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 ?Np63; however, there is no correlation of ?Np63 expression with p53 mutation status. Our data suggest that ?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 ?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? (HIF-1?) protein, resulting in VEGF secretion. We also show human clinical data, which suggest a mechanistic role for ?Np63 in osteosarcoma metastasis. In summary, our studies reveal the mechanism by which ?Np63, as a master transcription factor, modulates tumor angiogenesis.

SUBMITTER: Bid HK

PROVIDER: S-EPMC3950294 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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ΔNp63 promotes pediatric neuroblastoma and osteosarcoma by regulating tumor angiogenesis.

Bid Hemant K HK Roberts Ryan D RD Cam Maren M Audino Anthony A Kurmasheva Raushan T RT Lin Jiayuh J Houghton Peter J PJ Cam Hakan H

Cancer research 20131023 1

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 ...[more]

PMID: 24154873

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Project description:Angiogenesis is involved in many pathological and physiological processes and is mainly driven by hypoxia. Karyopherin subunit alpha 2 (KPNA2), a member of the nuclear transport protein family, was recently shown to be induced by hypoxia in various types of tumours, so we aimed to investigate the role and mechanism of KPNA2 in angiogenesis under hypoxia. After overexpression or knockdown of KPNA2 in human umbilical vein endothelial cells (HUVEC) by adenovirus vector infection, the tube formation, proliferation and migration of HUVEC under hypoxia were detected by tubule formation assay, 5-ethynyl-2'-deoxyuridine (EdU) staining and Transwell assay, respectively. After overexpression or knockdown of KPNA2 in a murine hindlimb ischemia model by local injection of purified adenovirus vector into the gastrocnemius muscle, blood flow changes were examined with a laser Doppler system. Changes in KPNA2-binding proteins under hypoxia were detected by immunoprecipitation-mass spectrometry (IP-MS) and co-immunoprecipitation (Co-IP). The effect of KPNA2 on signal transducer and activator of transcription 3 (STAT3) was detected by Western blotting and quantitative RT‒PCR. KPNA2 was upregulated in the HUVEC hypoxia model and murine hindlimb ischemia model. Overexpression of KPNA2 increased the proliferation, migration and tube formation of HUVEC under hypoxia, while knockdown of KPNA2 reduced the proliferation, migration and tube formation of HUVEC. Overexpression of KPNA2 promoted the restoration of blood flow in the murine hindlimb ischemia model, while knockout of KPNA2 inhibited the restoration of blood flow in the murine hindlimb ischemia model. Mechanistically, hypoxia promoted the binding of STAT3 to KPNA2. Overexpression of KPNA2 promoted STAT3 phosphorylation and then upregulated vascular endothelial growth factor (VEGF) and angiopoietin 2(ANGPT2), whereas knockdown of KPNA2 inhibited STAT3 phosphorylation and then downregulated VEGF and ANGPT2. Our study demonstrates that hypoxia promotes the binding of STAT3 to KPNA2 and KPNA2 promotes angiogenesis under hypoxia by promoting the binding of STAT3 and JAK1 and regulating STAT3 phosphorylation.

Dataset Information

?Np63 promotes pediatric neuroblastoma and osteosarcoma by regulating tumor angiogenesis.

Publications

ΔNp63 promotes pediatric neuroblastoma and osteosarcoma by regulating tumor angiogenesis.

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