Shengyu Hao1,2, Xiaodan Zhu1,2, Zilong Liu1, Xiaodan Wu1,2, Shanqun Li3,4, Pan Jiang5,6, Liyan Jiang7,8. 1. Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China. 2. Clinical Center for Sleep Breathing Disorder and Snoring, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. 3. Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China. li.shanqun@zs-hospital.sh.cn. 4. Clinical Center for Sleep Breathing Disorder and Snoring, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. li.shanqun@zs-hospital.sh.cn. 5. Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China. jppanpan@126.com. 6. Clinical Center for Sleep Breathing Disorder and Snoring, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. jppanpan@126.com. 7. Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China. jiang_liyan2000@126.com. 8. Clinical Center for Sleep Breathing Disorder and Snoring, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. jiang_liyan2000@126.com.
Abstract
BACKGROUND: 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. METHOD: 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. RESULTS: 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. CONCLUSIONS: Our results indicated that CIH promoted lung CSC-like properties by activating mtROS, which was partially mediated by Bach1.
BACKGROUND: 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. METHOD: 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. RESULTS: 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. CONCLUSIONS: Our results indicated that CIH promoted lung CSC-like properties by activating mtROS, which was partially mediated by Bach1.
Authors: Fernando Santamaria-Martos; Ivan Benítez; Cristina Girón; Ferran Barbé; Miguel-Angel Martínez-García; Luis Hernández; Josep M Montserrat; Eduardo Nagore; Antonio Martorell; Francisco Campos-Rodriguez; Jaime Corral; Valentin Cabriada; Jorge Abad; Olga Mediano; Maria F Troncoso; Irene Cano-Pumarega; Ana Maria Fortuna Gutierrez; Trinidad Diaz-Cambriles; Maria Somoza-Gonzalez; Isaac Almendros; Ramon Farre; David Gozal; Manuel Sánchez-de-la-Torre Journal: Eur Respir J Date: 2018-03-15 Impact factor: 16.671
Authors: Sonya Burgess; Craig P Juergens; Wesley Yang; Ibrahim M Shugman; Hanan Idris; Tuan Nguyen; Alison McLean; Melissa Leung; Liza Thomas; Kristy P Robledo; Christian Mussap; Sidney Lo; John French Journal: Int J Cardiol Date: 2020-08-14 Impact factor: 4.164