Co-expression Of Erythropoietin And Its Receptor Promotes Self-sustainable Cell Cycle In Non-small Cell Lung Cancer

Erythropoietin,mainly produced by the fetal liver and adult kidney,is an important glycoprotein to promote erythropoiesis.EPO also has functions to promote tissue repair and regeneration and so on.EPO mainly play the biological role through its receptor EPOR.At present,erythropoiesis stimulating agents(ESAs)are widely used in the treatment of tumor chemotherapy-induced anemia.However,in recent years,more and more studies have shown that EPO / EPOR is co-expressed in various tumors and related to the growth,migration and invasion of tumor cells.There is also a great controversy about the use of ESAs.Some studies have shown that it can alleviate anemia symptoms,improve the life quality of patients,while other studies have shown it may promote tumor development and shorten the survival of patients.Lung cancer is a leading cause of worldwide cancer death.Non-small cell lung cancer accounts for more than 80% of the total number.NSCLC mainly treated with surgery and platinum-based chemotherapy.Although the various surgical regimens and chemotherapy have made great progress in the treatment of NSCLC,the overall prognosis of NSCLC patients is still discouraging.Further elucidation of its development mechanism is of great significance to the treatment.Similar to other tumors,chemotherapy-induced anemia is one of the common complications of NSCLC,and ESAs are also used extensively for the treatment of NSCLC-induced anemia.So whether EPO / EPOR expressed in non-small cell lung cancer? What is the role of rhEPO in the development of NSCLC and what's the molecular mechanism? Is there potential risks of ESAs in the treatment of NSCLC tumor chemotherapy-induced anemia? In order to clarify the above scientific problems,we carried out the following research : 1)Immunohistochemistry was used to detect the expression of EPO / EPOR in 60 cases of NSCLC clinical samples and 150 NSCLC tissue microarray.2)Real-time PCR and Western Blot were used to detect EPO/EPOR in 9 NSCLC cell lines.3)Edu proliferation assay kit,flow cytometry,transwell invasion assay detect the effect of rhEPO on the proliferation,apoptosis,migration and cell cycle of NSCLC cells;4)EPO / EPOR high expressed NSCLC cell line H1819 was selected to study the molecular mechanism of rhEPO promoting cell proliferation by real-time PCR,western Blot,small molecule inhibitor and si RNA transfection.Through the reaserch,we obtained the following conclusions: 1)EPOR positively expressed in 93.3% of 60 cases of NSCLC,EPO positively expressed in 60.3%.EPO expression level in stage ? and ? patients was significantly higher than that in stage ?,smoking patients higher than that of non-smoking patients;2)The expression level of EPO was correlated with the 5-year survival.EPO / EPOR were highly expressed in UT-7 and H1155,H1819,H1833 and H3122,while lowly expressed in NSCLC cell lines A549,HCC15,H44,H1993,H2073;4)rhEPO promoted cell proliferation not apoptosis or invasion;5)rhEPO up-regulated Cyclin D1 through EPOR / JAK2 / STAT5 pathway to promote cell cycle.We demonstrated that EPO / EPOR highly expressed in part of NSCLC patients and EPO/EPOR was negatively correlated with patient survival.RhEPO could promote the proliferation of highly EPO/EPOR expressed NSCLC cells by JAK2 / STAT5 / Cyclin D1 pathway.The results suggest that there may be EPO / EPOR autocrine pathway in NSCLC tumor tissue.For some patients with NSCLC,ESAs are detrimental to the treatment of tumor-induced anemia,and local blockage of EPO in tumor area may be helpful.