Abstract
Vascular endothelial growth factor (VEGF) upregulation is induced by many receptor and intracellular oncogenic proteins commonly activated in cancer, rendering molecular targeting of VEGF expression a complex challenge. While VEGF inducers abound, only two major transcription activators have been identified for its promoter: hypoxia inducible factor-1 (HIF-1) and signal transducer and activator of transcription (Stat3). Both HIF-1 expression and Stat3 activity are upregulated in diverse cancers. Here, we provide evidence that Stat3 is required for both basal and growth signal-induced expression of HIF-1. Moreover, induction of VEGF by diverse oncogenic growth stimuli, including IL-6R, c-Src, Her2/Neu, is attenuated in cells without Stat3 signaling. We further demonstrate that Stat3 regulates expression of Akt, which is required for growth signal-induced HIF-1 upregulation. Targeting Stat3 with a small-molecule inhibitor blocks HIF-1 and VEGF expression in vitro and inhibits tumor growth and angiogenesis in vivo. Furthermore, tumor cells' in vivo angiogenic capacity induced by IL-6R, which simultaneously activates Jak/STAT and PI3K/Akt pathways, is abrogated when Stat3 is inhibited. Activation of Stat3 signaling by various growth signaling is prevalent in diverse cancers. Results presented here demonstrate that Stat3 is an effective target for inhibiting tumor VEGF expression and angiogenesis.
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Acknowledgements
We thank Drs Shizuo Akira and Kiyoshi Takeda for Stat3flox mice, and the Molecular Imaging Core and Analytic Microscopy Core at Moffitt Cancer Center and Research Institute for their assistance. This work was supported by National Institutes of Health Grants CA78038, CA82533 (R Jove) and CA75243, CA89693 (H Yu), and by the Dr Tsai-fan Yu Cancer Research Endowment.
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Xu, Q., Briggs, J., Park, S. et al. Targeting Stat3 blocks both HIF-1 and VEGF expression induced by multiple oncogenic growth signaling pathways. Oncogene 24, 5552–5560 (2005). https://doi.org/10.1038/sj.onc.1208719
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DOI: https://doi.org/10.1038/sj.onc.1208719
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