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Heterogeneous Effects of Direct Hypoxia Pathway Activation in Kidney Cancer.

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-1? and HIF-2? 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-1? and HIF-2? 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-1?-specific binding, and genes associated with favorable prognosis and between HIF-2?-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-? isoform contributes a highly complex mix of pro- and anti-tumorigenic effects.

SUBMITTER: Salama R

PROVIDER: S-EPMC4532367 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Heterogeneous Effects of Direct Hypoxia Pathway Activation in Kidney Cancer.

Salama Rafik R Masson Norma N Simpson Peter P Sciesielski Lina Katrin LK Sun Min M Tian Ya-Min YM Ratcliffe Peter John PJ Mole David Robert DR

PloS one 20150811 8

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 expres ...[more]

PMID: 26262842

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Project description:BackgroundHypoxia training enhances the endurance capacity of athletes. This response may in part be attributed to the hypoxia-induced increase in antioxidant capacity in skeletal muscles. Nuclear factor erythroid 2-related factor 2 (Nrf2), a key transcription factor which regulates the expression of genes via binding to the antioxidant-response element (ARE) of these genes, plays a crucial role in stimulating the body's defense system and potentially responds to hypoxia. Meanwhile, hypoxia-inducible factor-1? (HIF-1?) is an important player in protecting cells from hypoxic stress. The purpose of this study was to investigate the effects of acute hypoxia exposure with different durations on the activation of Nrf2-ARE pathway and a possible regulatory role of HIF-1? in these responses.MethodsC57BL/6J mice were allocated into the non-hypoxia 0-hour, 6-hour, 24-hour, and 48-hour hypoxic exposure (11.2% oxygen) groups. The quadriceps femoris was collected immediately after hypoxia. Further, to investigate the possible role of HIF-1?, C2C12 myoblasts with HIF-1? knockdown by small interfering RNA (siRNA) and the inducible HIF-1? transgenic mice were employed.ResultsThe results showed that 48-hour hypoxia exposure up-regulated protein expression of Nrf2, Nrf2/ARE binding activity and the transcription of antioxidative genes containing ARE (Sod1 and others) in mouse skeletal muscle. Moreover, HIF-1? siRNA group of C2C12 myoblasts showed a remarkable inhibition of Nrf2 protein expression and nuclear accumulation in hypoxia exposure for 72 hours compared with that in siRNA-Control group of the cells. In addition, HIF-1? transgenic mice gave higher Nrf2 protein expression, Nrf2/ARE binding activity and expressions of Nrf2-mediated antioxidative genes in their skeletal muscle, compared with those in the wild-type mice.ConclusionsThe findings suggested that the acute hypoxia exposure could trigger the activation of Nrf2-ARE pathway, with longer duration associated with higher responses, and HIF-1? expression might be involved in promoting the Nrf2-mediated antioxidant responses in skeletal muscle.

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Heterogeneous Effects of Direct Hypoxia Pathway Activation in Kidney Cancer.

Publications

Heterogeneous Effects of Direct Hypoxia Pathway Activation in Kidney Cancer.

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