Sleep Disorders: Sleep Disorders: Effects of Intermittent Hypoxia |

Relevant Mechanism of Intermittent Hypoxia-Induced Melanoma Lung Metastases in a Murine Model of Sleep Apnea FREE TO VIEW

Lian Li, PhD; Fangyuan Ren; Jie Cao; Baoyuan Chen, MD
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Tianjin Medical University General Hospital, Tianjin, China

Copyright 2016, American College of Chest Physicians. All Rights Reserved.

Chest. 2016;149(4_S):A556. doi:10.1016/j.chest.2016.02.581
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SESSION TITLE: Sleep Disorders: Effects of Intermittent Hypoxia

SESSION TYPE: Original Investigation Slide

PRESENTED ON: Sunday, April 17, 2016 at 04:00 PM - 05:00 PM

PURPOSE: Obstructive sleep apnea (OSA) has been recently associated with tumor incidence and cancer-related mortality. Intermittent hypoxia (IH) mimicking OSA contributes to tumor growth and metastasis in a mouse model. The aim of this study was to investigate the hypothesis that IH exposure enhances melanoma metastasis to the lung via increases of HIF-1α and its target proteins associated with metastasis, as well as changes of epithelial-mesenchymal (EMT) / mesenchymal-epithelial transition (MET)-related proteins and oxidative stress-responsive and inflammatory transcription factors.

METHODS: C57BL/6J male mice (8-week-old) were injected with B16F10 melanoma cells via the tail vein. Then these animals were exposed to 3 weeks of IH (30 s of 5 % O2-60 s of 21% O2) (6 h/day, 7 days/week) (n=8), continuous hypoxia (CH) (5% O2) (2 h/day, 7 days/week) (n=8) or room air (RA) (n=8). Number of lung metastatic colonies was assessed. HIF-1α and its target proteins, VEGF and MMP-9, EMT/MET-related proteins, N-cadherin (mesenchymal marker) and E-cadherin (epithelial marker), as well as oxidative stress-responsive and inflammatory transcription factors, Nrf2 and NF-κB P65 were measured by western blotting.

RESULTS: The number of melanoma lung metastases was the highest in IH group. Compared with RA group, the protein level of HIF-1α, VEGF and MMP-9 were significantly increased in IH group. Moreover, the protein level of N-cadherin was the lowest in IH group, when the highest in IH group for E-cadherin. Simultaneously, the protein levels of Nrf2 and NF-κB P65 were the highest in IH group.

CONCLUSIONS: These results confirmed that IH mimicking OSA indeed enhanced melanoma metastasis to the lung. The relevant mechanism is ascribed to HIF-1α increasing its transcriptional regulation of metastasis-related proteins in part, like VEGF and MMP-9, but mainly metastasis-related MET event probably regulated by oxidative and inflammatory transcription factors.

CLINICAL IMPLICATIONS: This study may provide new theory and experimental evidence to prevent the occurrence of cancer and effective interventions for cancer treatment.

DISCLOSURE: The following authors have nothing to disclose: Lian Li, Fangyuan Ren, Jie Cao, Baoyuan Chen

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