Opposite functions of HIF-α isoforms in VEGF induction by TGF-Β1 under non-hypoxic conditions

K. S. Chae, M. J. Kang, J. H. Lee, B. K. Ryu, M. G. Lee, N. G. Her, T. K. Ha, J. Han, Yoon Ki Kim, Sung-Gil Chi

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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.

Original languageEnglish
Pages (from-to)1213-1228
Number of pages16
JournalOncogene
Volume30
Issue number10
DOIs
Publication statusPublished - 2011 Mar 10

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Keywords

  • HIF-2α
  • HuR
  • prostate cancer
  • Smad3
  • TGF-β1
  • VEGF

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Chae, K. S., Kang, M. J., Lee, J. H., Ryu, B. K., Lee, M. G., Her, N. G., Ha, T. K., Han, J., Kim, Y. K., & Chi, S-G. (2011). Opposite functions of HIF-α isoforms in VEGF induction by TGF-Β1 under non-hypoxic conditions. Oncogene, 30(10), 1213-1228. https://doi.org/10.1038/onc.2010.498