OncoTargets and Therapy (Mar 2019)
Hypoxic non-small-cell lung cancer cell-derived exosomal miR-21 promotes resistance of normoxic cell to cisplatin
Abstract
Caijun Dong,1 Xingwang Liu,2 Huisheng Wang,3 Jutao Li,4 Lei Dai,5 Jun Li,6 Zhen Xu1 1Department of Cardiothoracic Surgery, Ningbo No. 2 Hospital, Ningbo, Zhejiang, People’s Republic of China; 2Sports Medicine Center, Department of Sports Medicine and Arthroscopy Surgery, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China; 3Department of Orthopedics, The People’s Hospital of China Medical University, Shenyang, People’s Republic of China; 4Department of Hand and Foot Surgery I, Dalian Municipal Central Hospital Affiliated of Dalian Medical University, Liaoning, People’s Republic of China; 5Department of Thyroid Surgery, Ningbo No. 2 Hospital, Ningbo, Zhejiang, People’s Republic of China; 6Department of General Surgery II, Taihe Hospital, Shiyan, Hubei, People’s Republic of China Purpose: To explore the effects of hypoxic non-small-cell lung cancer (NSCLC)-derived exosomes on NSCLC resistance to cisplatin.Materials and methods: Exosomes were isolated by differential centrifugation and characterized by transmission electron microscope and Western blotting. Quantitative real-time PCR was used to measure miR-21 levels. MTT assays and colony formation assays were performed to investigate the effects of hypoxia-induced exosomes on cisplatin resistance.Results: Hypoxic NSCLC cell-derived exosomes facilitate normoxic cell resistance to cisplatin. In addition, hypoxia enhanced the miR-21 expression in NSCLC cells and cell-derived exosomes. Interestingly, changes in miR-21 levels in the hypoxia-induced exosomes affected the sensitivity of recipient cells to cisplatin. Mechanically, exosomal miR-21 promoted cisplatin resistance by downregulating phosphatase and tensin homolog (PTEN). The expression of miR-21 in tumor cell lines and clinical NSCLC tumor samples was positively correlated with hypoxia-inducible factor-1α and negatively correlated with PTEN. Moreover, high miR-21 expression was associated with shorter median survival period in patients undergoing pharmacotherapy, but no association was observed in patients who were not under pharmacotherapy.Conclusion: Exosomal miR-21 derived from hypoxic NSCLC cells may promote cisplatin resistance, which indicates that exosomal miR-21 might be a potential biomarker and therapeutic target to address NSCLC chemoresistance. Keywords: non-small-cell lung cancer, exosomes, miR-21, cisplatin resistance, PTEN
