Abstract
Co-expression of erythropoietin (Epo) and erythropoietin receptor (EpoR) has been found in various non-hematopoietic cancers including hereditary and sporadic renal cell carcinomas (RCC), but the Epo/EpoR autocrine and paracrine mechanisms in tumor progression have not yet been identified. In this study, we used RNA interference method to down-regulate EpoR to investigate the function of Epo/EpoR pathway in human RCC cells. Epo and EpoR co-expressed in primary renal cancer cells and 6 human RCC cell lines. EpoR signaling was constitutionally phosphorylated in primary renal cancer cells, 786-0 and Caki-1 cells, and recombinant human Epo (rhEpo) stimulation had no significant effects on further phosphorylation of EpoR pathway, proliferation, and invasiveness of the cells. Down-regulation of EpoR expression in 786-0 cells by lentivirus-introduced siRNA resulted in inhibition of growth and invasiveness in vitro and in vivo, and promotion of cell apoptosis. In addition, rhEpo stimulation slightly antagonized the anti-tumor effect of Sunitinib on 786-0 cells. Sunitinib could induce more apoptotic cells in 786-0 cells with knockdown EpoR expression. Our results suggested that Epo/EpoR pathway was involved in cell growth, invasion, survival, and sensitivity to the multi-kinases inhibitor Sunitinib in RCC cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Apoptosis / genetics
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Carcinoma, Renal Cell / enzymology
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Carcinoma, Renal Cell / genetics
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Carcinoma, Renal Cell / metabolism*
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Carcinoma, Renal Cell / pathology*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Erythropoietin / metabolism*
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Erythropoietin / pharmacology
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Knockdown Techniques
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Humans
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Indoles / pharmacology
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Kidney Neoplasms / enzymology
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Kidney Neoplasms / genetics
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Kidney Neoplasms / metabolism*
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Kidney Neoplasms / pathology*
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Matrix Metalloproteinase 2 / metabolism
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Neoplasm Invasiveness
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Protein Kinase Inhibitors / pharmacology
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Pyrroles / pharmacology
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Receptors, Erythropoietin / genetics
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Receptors, Erythropoietin / metabolism*
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Recombinant Proteins / pharmacology
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Signal Transduction* / drug effects
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Signal Transduction* / genetics
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Sunitinib
Substances
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Indoles
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Protein Kinase Inhibitors
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Pyrroles
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Receptors, Erythropoietin
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Recombinant Proteins
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Erythropoietin
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MMP2 protein, human
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Matrix Metalloproteinase 2
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Sunitinib
Grants and funding
This work was supported by the National Natural Science Foundation of China (Grant Numbers: 30872560 and 81172418) (
http://www.nsfc.gov.cn/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.