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Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis

Oncogene volume 21, pages 2000–2008 (2002)Cite this article

Abstract

Non-receptor and receptor tyrosine kinases, such as Src and EGF receptor (EGFR), are major inducers of vascular endothelial growth factor (VEGF), one of the most potent mediators of angiogenesis. While tyrosine kinases signal through multiple pathways, signal transducer and activation of transcription 3 (Stat3) is a point of convergence for many of these and is constitutively activated with high frequency in a wide range of cancer cells. Here, we show that VEGF expression correlates with Stat3 activity in diverse human cancer cell lines. An activated Stat3 mutant (Stat3C) up-regulates VEGF expression and stimulates tumor angiogenesis. Stat3C-induced VEGF up-regulation is abrogated when a Stat3-binding site in the VEGF promoter is mutated. Furthermore, interrupting Stat3 signaling with dominant-negative Stat3 protein or Stat3 antisense oligonucleotide in tumor cells down-regulates VEGF expression. Consistent with an important role of Stat3 in VEGF up-regulation induced by various oncogenic tyrosine kinases, v-Src-mediated VEGF expression is inhibited when Stat3 signaling is blocked. Moreover, chromatin immunoprecipitation assays indicate that Stat3 protein binds to the VEGF promoter in vivo and mutation of a Stat3-binding site in the VEGF promoter abrogates v-Src-induced VEGF promoter activity. These studies provide evidence that the VEGF gene is regulated directly by Stat3 protein, and indicate that Stat3 represents a common molecular target for blocking angiogenesis induced by multiple signaling pathways in human cancers.

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Abbreviations

Stat3:

signal transducer and activation of transcription 3

VEGF:

vascular endothelial growth factor

IL-6:

interleukin-6

EGF:

epithelial growth factor

EMSA:

electrophoretic mobility shift assay

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Acknowledgements

This work was supported by National Institutes of Health (CA75243, CA89693, CA55652 and CA82533) and by the Dr Tsai-Fan Yu Cancer Research Endowment. We would like to thank Anita Larson for assisting with preparation of the manuscript, Dr Judith Abraham for providing the VEGF promoter and Wenbiao Liu for technical support. This work has been supported in part by the Molecular Biology Core Facility and Biostatistics Core Facility at the H Lee Moffitt Cancer Center and Research Institute.

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Authors and Affiliations

  1. Department of Oncology, Immunology Program, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida College of Medicine, Tampa, 33612, Florida, FL, USA

    Guilian Niu, Kenneth L Wright, Shumin Zhang & Hua Yu

  2. Department of Oncology, Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida College of Medicine, Tampa, 33612, Florida, FL, USA

    Mei Huang, James Turkson, Dominic Sinibaldi & Richard Jove

  3. Department of Oncology, Clinical Investigations Program, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida College of Medicine, Tampa, 33612, Florida, FL, USA

    Lanxi Song, Eric Haura, Domenico Coppola & Richard Heller

  4. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, MD, USA

    Tianhong Wang & Drew Pardoll

  5. Department of Surgical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, 77030, Texas, TX, USA

    Lee M Ellis

  6. Antisense Drug Discovery, Isis Pharmaceuticals, Inc., Carlsbad, 92008, California, CA, USA

    James Karras

  7. Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, 10021, NY, USA

    Jacqueline Bromberg

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  1. Guilian Niu
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  11. Richard Heller
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Correspondence to Richard Jove or Hua Yu.

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Niu, G., Wright, K., Huang, M. et al. Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 21, 2000–2008 (2002). https://doi.org/10.1038/sj.onc.1205260

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