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.
Highlights
Erythropoietin (EPO), a glycoprotein produced in the fetal liver and the adult kidney, is the chief regulator of erythropoiesis [1]
We proved local application of EPO neutralizing antibody and short hairpin RNA against EPO receptor (EPOR) effectively inhibited the growth of EPO/EPOR overexpressed non-small cell lung cancer (NSCLC) cells and prolonged survivals of the mice
To explore the mechanism underlying the growthpromoting effects of EPO/EPOR in NSCLC cells, we examined the changes in cell cycles
Summary
Erythropoietin (EPO), a glycoprotein produced in the fetal liver and the adult kidney, is the chief regulator of erythropoiesis [1]. Over the last decade, growing evidences have shown the co-expression of EPO and EPOR are connected to cancer cell growth, migration, and invasiveness in various human malignancies [5,6,7,8,9]. A number of studies have demonstrated recombinant human EPO (rhEPO), known as erythropoiesis stimulating agents (ESAs) which have been widely used to relieve chemotherapy-induced anemia may enhance tumor progression or decrease patient survival www.impactjournals.com/oncotarget [10,11,12,13]. The negative impact of EPO in cancer patients is controversial or not straightforward [14, 15]. In a separate study EPO does not affect breast tumor cells but promote self-renewal of tumor-initiating cell [17]
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