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

Abstract

BackgroundErythropoietin (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.MethodsProtein 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.ResultsEPO 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.ConclusionsOur 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

Erythropoietin and its derivatives: from tissue protection to immune regulation

“…However, under hypoxia EPO significantly promoted cell proliferation 76,77 . One possible mechanism was that hypoxia not only induced the expression of EPOR, but also promoted translocation of EPOR from nucleus to cytoplasm and membrane, making it available to activate EPOR signaling 77 . In reality, the overgrowth of cancer cells frequently outstrips the supply of oxygen, leading to a hypoxia condition.…”

“…When EPOR signaling was blocked by EPOR knockdown or soluble EPOR against EPO, it inhibited tumor growth and invasion, and resulted in cell apoptosis 71,[75][76][77] . Interestingly, in most studies, EPO stimulation had no significant effects on tumor proliferation, survival or invasion under normoxia 69,[71][72][73][74]77,78 ; only in few cases, such as in melanoma, EPO was reported to stimulate tumor growth both in vivo and in vitro on eIF4Edependent pathway 79 . However, under hypoxia EPO significantly promoted cell proliferation 76,77 .…”

“…Interestingly, in most studies, EPO stimulation had no significant effects on tumor proliferation, survival or invasion under normoxia 69,[71][72][73][74]77,78 ; only in few cases, such as in melanoma, EPO was reported to stimulate tumor growth both in vivo and in vitro on eIF4Edependent pathway 79 . However, under hypoxia EPO significantly promoted cell proliferation 76,77 . One possible mechanism was that hypoxia not only induced the expression of EPOR, but also promoted translocation of EPOR from nucleus to cytoplasm and membrane, making it available to activate EPOR signaling 77 .…”

Correlations between P53 Mutation Status and Texture Features of CT Images for Hepatocellular Carcinoma

“…We minimized the influence of contrast and changes to the brightness, otherwise it would obscure the true image texture. 24,25 Two abdominal radiologists with 11 and 7 years of experience, respectively, performed the quantitative measurements in consensus.…”

“…Textural features have been shown to be beneficial when differentiating tumor types, predicting treatment response, and are also associated with prediction of microvascular invasion and prognosis. 1,3,[20][21][22][23][24][25][26][27] However, it is largely unknown what the biological correlates of textural features are. 20,21 To the best of our knowledge, there has been no study published regarding P53 mutation status and texture features of CT images for HCC.…”