Oncotarget

Research Papers:

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

Lei He, Shouzhen Wu, Qiang Hao, Elhadji M. Dioum, Kuo Zhang, Cun Zhang, Weina Li, Wei Zhang, Yingqi Zhang, Jiming Zhou, Zhijun Pang, Lijuan Zhao, Xiaowen Ma, Meng Li and Qiuyang Zhang _

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Oncotarget. 2017; 8:82352-82365. https://doi.org/10.18632/oncotarget.19354

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Abstract

Lei He1,*, Shouzhen Wu2,*, Qiang Hao1,*, Elhadji M. Dioum3,4, Kuo Zhang1, Cun Zhang1, Weina Li1, Wei Zhang1, Yingqi Zhang1, Jiming Zhou1, Zhijun Pang1, Lijuan Zhao1, Xiaowen Ma1, Meng Li1 and Qiuyang Zhang3,5

1State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi’an, China

2Shaanxi Institute of Pediatric Diseases, Xi’an Children’s Hospital, Xi’an, China

3Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA

4Current/Present address: Diabetes Department, Nestle Institute of Health Science, EPFL Campus, Lausanne, Switzerland

5Current/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: [email protected]

Meng Li, email: [email protected]

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.


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