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Opposite functions of HIF-α isoforms in VEGF induction by TGF-β1 under non-hypoxic conditions

Oncogene volume 30, pages 1213–1228 (2011)Cite this article

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Abstract

Transforming growth factor (TGF)-β1 has biphasic functions in prostate tumorigenesis, having a growth-inhibitory effect in the early stages, but in the late stages promoting tumor angiogenesis and metastasis. We demonstrate here that tumor-producing TGF-β1 induces vascular endothelial growth factor (VEGF) in prostate cancer cells, and hypoxia-inducible factor (HIF)-1α and HIF-2α has opposite functions in TGF-β1 regulation of VEGF expression under non-hypoxic conditions. The promoter response of VEGF to TGF-β1 was upregulated by the transfection of HIF-2α or siHIF-1α but downregulated by HIF-1α and siHIF-2α. Both HIF-1α and HIF-2α were induced by TGF-β1 at mRNA and protein levels, however, their nuclear translocation was differentially regulated by TGF-β1, suggesting its association with their opposite effects. VEGF induction by TGF-β1 occurred in a Smad3-dependent manner, and the Smad-binding element 2 (SBE2, −992 to −986) and hypoxia response element (−975 to −968) in the VEGF promoter were required for the promoter response to TGF-β1. Smad3 cooperated with HIF-2α in TGF-β1 activation of VEGF transcription and Smad3 binding to the SBE2 site was greatly impaired by knockdown of HIF-2α expression. Moreover, the VEGF promoter response to TGF-β1 was synergistically elevated by co-transfection of Smad3 and HIF-2α but attenuated by HIF-1α in a dose-dependent manner. Additionally, TGF-β1 was found to increase the stability of VEGF transcript by facilitating the cytoplasmic translocation of a RNA-stabilizing factor HuR. Collectively, our data show that tumor-producing TGF-β1 induces VEGF at the both transcription and post-transcriptional levels through multiple routes including Smad3, HIF-2α and HuR. This study thus suggests that autocrine TGF-β1 production may contribute to tumor angiogenesis via HIF-2α signaling under non-hypoxic conditions, providing a selective growth advantage for prostate tumor cells.

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Abbreviations

TGF-β1:

transforming growth factor-β1

VEGF:

vascular endothelial growth factor

HIF:

hypoxia-inducible factor

NF-κB:

nuclear factor-κB

PI3K:

phosphoinositide-3-kinase

RT–PCR:

reverse transcription–PCR

siRNA:

short-interfering RNA

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Acknowledgements

This work was supported in part by grants from National Research Foundation of Korea (0000794 and 0001197), the Korea Research Foundation (2008-314-C00247) and the National Cancer Center (0820070), Republic of Korea.

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Authors and Affiliations

  1. School of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea

    K S Chae, M J Kang, J H Lee, B K Ryu, M G Lee, N G Her, T K Ha, J Han, Y K Kim & S G Chi

  2. Department of Biology Education, Teacher's College, Kyungpook National University, Daegu, Republic of Korea

    K S Chae

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  1. K S Chae
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Chae, K., Kang, M., Lee, J. et al. Opposite functions of HIF-α isoforms in VEGF induction by TGF-β1 under non-hypoxic conditions. Oncogene 30, 1213–1228 (2011). https://doi.org/10.1038/onc.2010.498

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