Local blockage of self-sustainable erythropoietin signaling suppresses tumor progression in non-small cell lung cancer

// Lei He 1, * , Shouzhen Wu 2, * , Qiang Hao 1, * , Elhadji M. Dioum 3, 4 , Kuo Zhang 1 , Cun Zhang 1 , Weina Li 1 , Wei Zhang 1 , Yingqi Zhang 1 , Jiming Zhou 1 , Zhijun Pang 1 , Lijuan Zhao 1 , Xiaowen Ma 1 , Meng Li 1 and Qiuyang Zhang 3, 5 1 State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi’an, China 2 Shaanxi Institute of Pediatric Diseases, Xi’an Children’s Hospital, Xi’an, China 3 Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA 4 Current/Present address: Diabetes Department, Nestle Institute of Health Science, EPFL Campus, Lausanne, Switzerland 5 Current/Present address: Center for Esophageal Research, Baylor University Medical Center, Dallas, Texas, USA * These authors have contributed equally to this work Correspondence to: Qiuyang Zhang, email: qiuyangd.zhang@gmail.com Meng Li, email: limeng@fmmu.edu.cn Keywords: serum EPO, cell cycle, proliferation, NSCLC, hypoxia Received: March 08, 2017    Accepted: June 30, 2017    Published: July 18, 2017 ABSTRACT Functional significance of co-expressed erythropoietin (EPO) and its receptor (EPOR) in non-small cell lung cancer (NSCLC) had been under debate. In this study, co-overexpression of EPO/EPOR was confirmed to be positively associated with poor survival in NSCLC. The serum EPO in 14 of 35 enrolled NSCLC patients were found elevated significantly and decreased to normal level after tumor resection. With primary tumor cell culture and patient-derived tumor xenograft (PDX) mouse model, the EPO secretion from the tumors of these 14 patients was verified. Then, we proved the patient derived serum EPO was functionally active and had growth promotion effect in EPO/EPOR overexpressed but not in EPO/EPOR under-expressed NSCLC cells. We also illustrated EPO promoted NSCLC cell proliferation through an EPOR/Jak2/Stat5a/cyclinD1 pathway. In xenograft mouse model, we proved local application of EPO neutralizing antibody and short hairpin RNA (shRNA) against EPOR effectively inhibited the growth of EPO/EPOR overexpressed NSCLC cells and prolonged survivals of the mice. Finally, EPO/EPOR/Jak2/Stat5a/cyclinD1 signaling was found to be a mediator of hypoxia induced growth in EPO/EPOR overexpressed NSCLC. Our results illustrated a subgroup of NSCLC adapt to hypoxia through self-sustainable EPO/EPOR signaling and suggest local blockage of EPO/EPOR as potential therapeutic method in this distinct NSCLC population.