Sleep and cancer: a cell culture model of sleep apnoea alters gene expression in the hypoxic, inflammatory and circadian rhythm pathways

Martinez C, Kerr B, Kataria N, Cistulli P and Cook KM

University of Sydney, Charles Perkins Centre, Sydney, NSW.

Obstructive sleep apnoea (OSA) affects a significant proportion of the population and is characterised by episodic upper airway obstruction resulting in systemic intermittent hypoxia. Recent epidemiological studies have shown OSA is associated with higher rates of cancer development and cancer mortality. Animal models of OSA have found increased metastasis and tumour growth. However, the molecular mechanisms associated with the altered tumour behaviour seen in OSA is poorly understood. Hypoxia inducible factor (HIF) is a transcription factor that can influence cancer growth and metabolism. In OSA, increased activity of HIF and NF-κB transcriptional activity is proposed to occur systemically and hence may affect tumours. However, we have yet to understand how HIF or NF-κB may be activated by rapid oxygen fluctuations, as compared to chronic tumour hypoxia, and how this may lead to altered cancer outcomes. We have established a cell-based model of OSA tissue oxygenation in order to study the effects of rapid, intermittent cycles of hypoxia in HCT116 colorectal cancer cells. Using quantitative rtPCR and western blotting, we found that HIF-1α increases during cycles of intermittent hypoxia and that expression of HIF target genes increase in response. We have also seen changes in inflammatory gene expression and changes in the pathways that regulate circadian rhythm. Inflammation and disruption of circadian rhythm have both been linked to cancer. Finally, we identified that the HIF-mediated response appears to be different in rapid intermittent hypoxia when compared to chronic tumour hypoxia. These differences may be the key to understanding how rapid intermittent hypoxia, as occurs in OSA, may influence tumour growth and metastasis.