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      Erythropoietin promoted the proliferation of hepatocellular carcinoma through hypoxia induced translocation of its specific receptor

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          Abstract

          Background

          Erythropoietin (EPO) is a hypoxia-inducible stimulator of erythropoiesis. Besides its traditional application in anemia therapy, it offers an effective treatment in the cancer patients, especially those who receive chemotherapy. Several reports indicated that it could promote the tumor cell proliferation through its specific receptor (EPOR). Unfortunately, the role of EPO/EPOR in hepatocellular carcinoma (HCC) progressing is still uncertain.

          Methods

          Protein in tumor tissue from HCC patients or H22 tumor-bearing mice was detected with immunohistochemistry. Cells were cultured under 1% oxygen to establish hypoxia. RT-PCR and western blotting were used to measure mRNA and protein of EPO/EPOR, respectively. MTT, flow cytometry and PCNA staining were used to detect cell proliferation. Immunofluorescence staining was applied to study the expression and location of cellular EPOR. The EPOR binding studies were performed with 125I-EPO radiolabeling assay.

          Results

          EPO and EPOR protein were up-regulated in HCC tissue of patients and H22-bearing mice. These were positively correlated with hypoxia-inducible factor -1 α and ki-67. Hypoxia up-regulated the expression of EPO and EPOR in HepG2 cells. It also induced the proliferation and increased the percentage of divided cells after 24, 48 and 72 h treatment. These were inhibited in cells pre-treated with 0.5 μg/mL soluble-EPOR. Immunofluorescence staining presented that EPOR was obviously translocated from nucleus to cytoplasm and membrane under hypoxia. EPOR binding activity was also increased after exposure to hypoxia. Recombinant human erythropoietin obviously elevated cell proliferation rate and the percentage of divided under hypoxia but not normoxia, which were also inhibited by soluble-EPOR.

          Conclusions

          Our result indicated for the first time that EPO promoted the proliferation of HCC cells through hypoxia induced translocation of it specific receptor.

          Trial registration TJC20141113, retrospectively registered

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          Most cited references48

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          Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver.

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            Hypoxia-inducible factor 1: master regulator of O2 homeostasis.

            Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that mediates essential homeostatic responses to reduced O2 availability in mammals. Recent studies have provided insights into the O2-dependent regulation of HIF-1 expression, target genes regulated by HIF-1, and the effects of HIF-1 deficiency on cellular physiology and embryonic development.
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              Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial.

              Anaemia is associated with poor cancer control, particularly in patients undergoing radiotherapy. We investigated whether anaemia correction with epoetin beta could improve outcome of curative radiotherapy among patients with head and neck cancer. We did a multicentre, double-blind, randomised, placebo-controlled trial in 351 patients (haemoglobin <120 g/L in women or <130 g/L in men) with carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. Patients received curative radiotherapy at 60 Gy for completely (R0) and histologically incomplete (R1) resected disease, or 70 Gy for macroscopically incompletely resected (R2) advanced disease (T3, T4, or nodal involvement) or for primary definitive treatment. All patients were assigned to subcutaneous placebo (n=171) or epoetin beta 300 IU/kg (n=180) three times weekly, from 10-14 days before and continuing throughout radiotherapy. The primary endpoint was locoregional progression-free survival. We assessed also time to locoregional progression and survival. Analysis was by intention to treat. 148 (82%) patients given epoetin beta achieved haemoglobin concentrations higher than 140 g/L (women) or 150 g/L (men) compared with 26 (15%) given placebo. However, locoregional progression-free survival was poorer with epoetin beta than with placebo (adjusted relative risk 1.62 [95% CI 1.22-2.14]; p=0.0008). For locoregional progression the relative risk was 1.69 (1.16-2.47, p=0.007) and for survival was 1.39 (1.05-1.84, p=0.02). Epoetin beta corrects anaemia but does not improve cancer control or survival. Disease control might even be impaired. Patients receiving curative cancer treatment and given erythropoietin should be studied in carefully controlled trials.
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                Author and article information

                Contributors
                shuomiaoshuomiao@163.com
                1157983786@qq.com
                402719092@qq.com
                m201675100@hust.edu.cn
                qingsong3333@163.com
                lg30003000@163.com
                hsqhaoren@aliyun.com
                chenxp@medmail.com.cn
                wpingwp@mails.tjmu.edu.cn
                Journal
                Cancer Cell Int
                Cancer Cell Int
                Cancer Cell International
                BioMed Central (London )
                1475-2867
                11 December 2017
                11 December 2017
                2017
                : 17
                : 119
                Affiliations
                [1 ]ISNI 0000 0004 0368 7223, GRID grid.33199.31, Department of Pathophysiology, , Tongji Medical College, Huazhong University of Science and Technology, ; Wuhan, 430030 China
                [2 ]ISNI 0000 0004 0368 7223, GRID grid.33199.31, Department of Surgery, Tongji Hospital, , Tongji Medical College, Huazhong University of Science and Technolgy, ; Wuhan, 430030 China
                [3 ]ISNI 0000 0004 0368 7223, GRID grid.33199.31, Department of Surgery, Liyuan Hospital, , Tongji Medical College, Huazhong University of Science and Technology, ; Wuhan, 430074 China
                [4 ]GRID grid.412594.f, Department of Hepatobiliary Surgery, , The First Affiliated Hospital of Guangxi Medical University, ; Nanning, 530021 China
                [5 ]ISNI 0000 0004 0368 7223, GRID grid.33199.31, Hepatic Surgery Center, Tongji Hospital, , Tongji Medical College, Huazhong University of Science and Technolgy, ; Wuhan, 430030 China
                Author information
                http://orcid.org/0000-0002-6870-3074
                Article
                494
                10.1186/s12935-017-0494-7
                5725980
                29238266
                79e07016-b40a-477b-b16c-f9200fc0fbe0
                © The Author(s) 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 24 August 2017
                : 4 December 2017
                Funding
                Funded by: National Natural Science Foundation of China
                Award ID: 81272313
                Award Recipient :
                Funded by: Project of Guangxi University Collaborative Innovation Center
                Funded by: 111 Project of China
                Award ID: No. D17011
                Award Recipient :
                Categories
                Primary Research
                Custom metadata
                © The Author(s) 2017

                Oncology & Radiotherapy
                erythropoietin,erythropoietin receptor,hepatocellular carcinoma,hypoxia,proliferation

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