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Obstructive Sleep Apnea Activates HIF-1 in a Hypoxia Dose-Dependent Manner in HCT116 Colorectal Carcinoma Cells

1
Charles Perkins Centre, Faculty of Medicine and Health, Northern Clinical School, The University of Sydney, Sydney NSW 2006, Australia
2
Department of Respiratory and Sleep Medicine, Royal North Shore Hospital, Sydney 2065, Australia
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(2), 445; https://doi.org/10.3390/ijms20020445
Received: 20 December 2018 / Revised: 17 January 2019 / Accepted: 18 January 2019 / Published: 21 January 2019
(This article belongs to the Special Issue Sleep Apnea and Intermittent Hypoxia)
Obstructive sleep apnea (OSA) affects a significant proportion of the population and is linked to increased rates of cancer development and a worse cancer outcome. OSA is characterized by nocturnal intermittent hypoxia and animal models of OSA-like intermittent hypoxia show increased tumor growth and metastasis. Advanced tumors typically have regions of chronic hypoxia, activating the transcription factor, HIF-1, which controls the expression of genes involved in cancer progression. Rapid intermittent hypoxia from OSA has been proposed to increase HIF-1 activity and this may occur in tumors. The effect of exposing a developing tumor to OSA-like intermittent hypoxia is largely unknown. We have built a cell-based model of physiological OSA tissue oxygenation in order to study the effects of intermittent hypoxia in HCT116 colorectal cancer cells. We found that HIF-1α increases following intermittent hypoxia and that the expression of HIF-target genes increases, including those involved in glycolysis, the hypoxic pathway and extracellular matrix remodeling. Expression of these genes acts as a ‘hypoxic’ signature which is associated with a worse prognosis. The total dose of hypoxia determined the magnitude of change in the hypoxic signature rather than the frequency or duration of hypoxia-reoxygenation cycles per se. Finally, transcription of HIF1A mRNA differs in response to chronic and intermittent hypoxia suggesting that HIF-1α may be regulated at the transcriptional level in intermittent hypoxia and not just by the post-translational oxygen-dependent degradation pathway seen in chronic hypoxia. View Full-Text
Keywords: intermittent hypoxia; obstructive sleep apnea; HIF-1; cancer; hypoxia intermittent hypoxia; obstructive sleep apnea; HIF-1; cancer; hypoxia
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Martinez, C.-A.; Kerr, B.; Jin, C.; Cistulli, P.A.; Cook, K.M. Obstructive Sleep Apnea Activates HIF-1 in a Hypoxia Dose-Dependent Manner in HCT116 Colorectal Carcinoma Cells. Int. J. Mol. Sci. 2019, 20, 445.

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