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Heterogeneous Effects of Direct Hypoxia Pathway Activation in Kidney Cancer

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Listed:
  • Rafik Salama
  • Norma Masson
  • Peter Simpson
  • Lina Katrin Sciesielski
  • Min Sun
  • Ya-Min Tian
  • Peter John Ratcliffe
  • David Robert Mole

Abstract

General activation of hypoxia-inducible factor (HIF) pathways is classically associated with adverse prognosis in cancer and has been proposed to contribute to oncogenic drive. In clear cell renal carcinoma (CCRC) HIF pathways are upregulated by inactivation of the von-Hippel-Lindau tumor suppressor. However HIF-1α and HIF-2α have contrasting effects on experimental tumor progression. To better understand this paradox we examined pan-genomic patterns of HIF DNA binding and associated gene expression in response to manipulation of HIF-1α and HIF-2α and related the findings to CCRC prognosis. Our findings reveal distinct pan-genomic organization of canonical and non-canonical HIF isoform-specific DNA binding at thousands of sites. Overall associations were observed between HIF-1α-specific binding, and genes associated with favorable prognosis and between HIF-2α-specific binding and adverse prognosis. However within each isoform-specific set, individual gene associations were heterogeneous in sign and magnitude, suggesting that activation of each HIF-α isoform contributes a highly complex mix of pro- and anti-tumorigenic effects.

Suggested Citation

  • Rafik Salama & Norma Masson & Peter Simpson & Lina Katrin Sciesielski & Min Sun & Ya-Min Tian & Peter John Ratcliffe & David Robert Mole, 2015. "Heterogeneous Effects of Direct Hypoxia Pathway Activation in Kidney Cancer," PLOS ONE, Public Library of Science, vol. 10(8), pages 1-19, August.
    • Handle: RePEc:plo:pone00:0134645
    DOI: 10.1371/journal.pone.0134645
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    1. Caryn S. Ross-Innes & Rory Stark & Andrew E. Teschendorff & Kelly A. Holmes & H. Raza Ali & Mark J. Dunning & Gordon D. Brown & Ondrej Gojis & Ian O. Ellis & Andrew R. Green & Simak Ali & Suet-Feung C, 2012. "Differential oestrogen receptor binding is associated with clinical outcome in breast cancer," Nature, Nature, vol. 481(7381), pages 389-393, January.
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