Accelerated tumor growth under intermittent hypoxia is associated with hypoxia-inducible factor-1-dependent adaptive responses to hypoxia
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Dae Wui Yoon1,*, Daeho So2,*, Sra Min1,2, Jiyoung Kim1,2, Mingyu Lee1,2, Roza Khalmuratova1, Chung-Hyun Cho1,2,3, Jong-Wan Park1,2,3,4 and Hyun-Woo Shin1,2,3,4,5
1Obstructive Upper Airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul 03080, Korea
2Department of Biomedical Science, Seoul National University Graduate School, Seoul 03080, Korea
3Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 03080, Korea
4Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea
5Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul 03080, Korea
*These authors have contributed equally to this work
Hyun-Woo Shin, email: [email protected]
Keywords: obstructive sleep apnea, cancer, hypoxia-inducible factor, intermittent hypoxia, hypoxia adaptation
Received: February 28, 2017 Accepted: May 29, 2017 Published: June 27, 2017
Mounting evidence has revealed a causative role of intermittent hypoxia (IH) in cancer progression in mouse models of obstructive sleep apnea (OSA), but most studies have focused on the effects of IH following tumor implantation using an exposure to single IH frequency. Thus, we aimed to investigate 1) the potential effect of IH on the initial tumor growth in patients with OSA without an interaction with other mechanisms induced by IH in mice and 2) the influence of the IH frequency on tumor growth, which were tested using pre-conditioning with IH (Pre-IH) and 2 different IH frequencies, respectively. Pre-IH was achieved by alternatively maintaining melanoma cells between normoxia (10 min, 21% O2) and hypoxia (50 min, 1% O2) for 7 days (12 cycles per day) before administering them to mice. The conditions for IH-1 and IH-2 were 90 s of 12% FiO2 followed by 270s of 21% FiO2 (10 cycles/h), and 90 s of 12% FiO2 and 90 s of 21% FiO2 (20 cycles/h), respectively, for 8 h per day. Tumor growth was significantly higher in the Pre-IH group than in the normoxia group. In addition, the IH-2 group showed more accelerated tumor growth compared to the normoxia and IH-1 groups. Immunohistochemistry and gene-expression results consistently showed the up-regulation of molecules associated with HIF-1α-dependent hypoxic adaptation in tumors of the Pre-IH and IH-2 groups. Our findings reveal that IH increased tumor progression in a frequency-dependent manner, regardless of whether it was introduced before or after in vivo tumor cell implantation.
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