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

• Main Authors: Chloe-Anne Martinez, Bernadette Kerr, Charley Jin, Peter A. Cistulli, Kristina M. Cook
• Format: Article
• Language: English
• Published: MDPI AG 2019-01-01
• Series: International Journal of Molecular Sciences
• Subjects: intermittent hypoxia; obstructive sleep apnea; HIF-1; cancer; hypoxia
• Online Access: https://www.mdpi.com/1422-0067/20/2/445

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-1&#945; 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 &#8216;hypoxic&#8217; 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 <i>HIF1A</i> mRNA differs in response to chronic and intermittent hypoxia suggesting that HIF-1&#945; 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.