Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China.
Clinical Center for Sleep Breathing Disorder and Snoring, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
Respir Res. 2021 Feb 17;22(1):58. doi: 10.1186/s12931-021-01655-6.
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. So far, the relationship between OSA and lung CSCs has not been explored.
In the present study, we established an orthotopic mouse model of primary lung cancer and utilized chronic intermittent hypoxia (CIH) exposure to mimic OSA status.
We 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.
Our results indicated that CIH promoted lung CSC-like properties by activating mtROS, which was partially mediated by Bach1.
阻塞性睡眠呼吸暂停（OSA）在癌症侵袭性和死亡率方面的不良作用最近已从临床和动物研究中显现出来，但原因尚未完全确定。癌症干细胞（CSC）被认为是癌转移的主要原因。到目前为止，OSA 与肺 CSC 之间的关系尚未被探索。
在本研究中，我们建立了原发性肺癌的原位小鼠模型，并利用慢性间歇性低氧（CIH）暴露来模拟 OSA 状态。
我们观察到 CIH 赋予肺癌更大的转移潜力，表现为肿瘤生长、肿瘤播种和肺部 CSC 相关基因表达的上调。值得注意的是，转录因子 BTB 和 CNC 同源性 1（Bach1），一种对氧化应激条件反应的关键因子，在体外和体内 CIH 暴露后肺癌中增加。同时，CIH 暴露促进肺癌细胞增殖、克隆多样性，诱导干细胞样细胞标志物表达，并以相对较高的频率产生 CSC。此外，CIH 暴露引起的线粒体 ROS（mtROS）增加和 CSC 标志物表达在 Bach1 shRNA 处理的肺癌细胞中被消除。
我们的结果表明，CIH 通过激活 mtROS 促进肺 CSC 样特性，其中 Bach1 部分介导。
