Abstract
BackgroundAn adverse role for obstructive sleep apnea (OSA) in cancer aggressiveness and mortality has recently emerged from clinical and animal studies, and the reasons have not been fully determined. Cancer stem cells (CSCs) are regarded as the main cause of carcinoma metastasis. So far, the relationship between OSA and lung CSCs has not been explored.MethodIn the present study, we established an orthotopic mouse model of primary lung cancer and utilized chronic intermittent hypoxia (CIH) exposure to mimic OSA status.ResultsWe observed that CIH endows lung cancer with greater metastatic potential, evidenced by increased tumor growth, tumor seeding, and upregulated CSC-related gene expression in the lungs. Notably, the transcription factor BTB and CNC homology 1 (Bach1), a key factor in responding to conditions of oxidative stress, is increased in lung cancer after CIH exposure in vitro and in vivo. Meanwhile, exposing lung cancer cells to CIH promoted cell proliferation, clonal diversity, induced stem-like cell marker expression, and gave rise to CSCs at a relatively higher frequency. Furthermore, the increase of mitochondrial ROS (mtROS) and CSC-marker expression induced by CIH exposure was abolished in Bach1 shRNA-treated lung cancer cells.ConclusionsOur results indicated that CIH promoted lung CSC-like properties by activating mtROS, which was partially mediated by Bach1.
Highlights
An adverse role for obstructive sleep apnea (OSA) in cancer aggressiveness and mortality has recently emerged from clinical and animal studies, and the reasons have not been fully determined
We observed that chronic intermittent hypoxia (CIH) endows lung cancer with greater metastatic potential, evidenced by increased tumor growth, tumor seeding, and upregulated Cancer stem cells (CSCs)-related gene expression in the lungs
The increase of mitochondrial Reactive oxygen species (ROS) and CSC-marker expression induced by CIH exposure was abolished in BTB and CNC homology 1 (Bach1) shRNA-treated lung cancer cells
Summary
An adverse role for obstructive sleep apnea (OSA) in cancer aggressiveness and mortality has recently emerged from clinical and animal studies, and the reasons have not been fully determined. Cancer stem cells (CSCs) are regarded as the main cause of carcinoma metastasis. The relationship between OSA and lung CSCs has not been explored. Obstructive sleep apnea (OSA) is a highly prevalent disorder characterized by repetitive occlusion of the upper airway during sleep that results in chronic intermittent hypoxia (CIH) [1]. The cancer stem cells (CSCs) involved in the lung cancer process have been explored and well established [10]. (See figure on page.) Fig. 1 Lung cancer in CIH-treated mice has greater CSC-like potential. C The representative images of cancer loci in lungs from Tumor + Nor and Tumor + CIH groups. D The number of cancer loci observed in the lungs of mice. CIH chronic intermittent hypoxia, Nor normoxia, CSC cancer stem cell
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