Format

Send to

Choose Destination
PLoS One. 2015 Aug 11;10(8):e0134645. doi: 10.1371/journal.pone.0134645. eCollection 2015.

Heterogeneous Effects of Direct Hypoxia Pathway Activation in Kidney Cancer.

Author information

1
The Henry Wellcome Building for Molecular Physiology, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.

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.

PMID:
26262842
PMCID:
PMC4532367
DOI:
10.1371/journal.pone.0134645
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center