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Oncostatin-M induction of vascular endothelial growth factor expression in astroglioma cells

Oncogene volume 22, pages 8117–8124 (2003)Cite this article

Abstract

Oncostatin-M (OSM), a hematopoietic cytokine, and vascular endothelial growth factor (VEGF), a quintessential angiogenic signal, are coexpressed in development, cancer and inflammation. Here, we report that OSM treatment of human astroglioma cell lines increases VEGF levels by ∼threefold. Interleukin-1β (IL-1β), in combination with OSM, induces up to sevenfold higher VEGF expression, without significantly inducing VEGF on its own. Specifically examining the OSM contribution to VEGF expression, neutralizing antibodies to OSM receptor subunits gp130 and OSMRβ, but not LIFRβ, inhibited OSM induction of VEGF, indicating that the OSM-specific receptor OSMRβ/gp130 transduces the OSM signal for VEGF synthesis. OSM induction of VEGF promoter activity maps to the (−1171, −786) region of the VEGF promoter, which contains a STAT-3-binding site. STAT-3 is indeed essential for this response, since overexpression of a dominant-negative STAT-3 blocks OSM induction of VEGF promoter activity, as well as endogenous VEGF expression. Finally, we demonstrate that OSM is expressed in glioblastoma multiforme tumor biopsies, a particularly malignant form of brain tumor. This novel mechanism of VEGF regulation in astroglioma cells may be active in pathophysiological states where both OSM and IL-1β are present.

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Abbreviations

VEGF:

vascular endothelial growth factor

OSM:

oncostatin-M

HIF:

hypoxia-inducible factor

IL-1β:

interleukin-1β

MAPK:

mitogen-activated protein kinase

STAT:

signal transducer and activator of transcription

COX:

cyclooxygenase

LIF:

leukemia inhibitory factor

PGE:

prostaglandin E

DN:

dominant negative

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Acknowledgements

We thank Dr Yu-Tzu Tai (Dana-Farber Cancer Institute, Boston, MA, USA) for the human VEGF promoter construct, Dr B Mosley (Immunex Corporation, Seattle, WA, USA) for the neutralizing anti-OSMRβ antibody, Dr M Hibi (Osaka University Medical School, Osaka, Japan) for the DN-STAT-3 construct and Ms Xiang Xu (University of Alabama at Birmingham, Birmingham, AL, USA) for her technical expertise. This work was supported in part by National Institutes of Health Grants NS39954 and MH63650 (ENB), CA97247 (ENB and CLG), and CA59958 and CA97110 (CLG). The support of the University of Alabama at Birmingham Medical Scientist Training Program to PR is acknowledged. CYF was supported by a GAANN Fellowship P200A000124-02.

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  1. Department of Cell Biology, University of Alabama at Birmingham, Birmingham, 35294, AL, USA

    Pavle Repovic & Etty N Benveniste

  2. Department of Pathology, University of Alabama at Birmingham, Birmingham, 35294, AL, USA

    Constance Y Fears & Candece L Gladson

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  1. Pavle Repovic
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Correspondence to Etty N Benveniste.

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Repovic, P., Fears, C., Gladson, C. et al. Oncostatin-M induction of vascular endothelial growth factor expression in astroglioma cells. Oncogene 22, 8117–8124 (2003). https://doi.org/10.1038/sj.onc.1206922

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