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, Y. K. Kim, S. G. Chi

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34 Citations (Scopus)

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

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    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