Erythropoietin Signaling Promotes Invasiveness of Human Head and Neck Squamous Cell Carcinoma

Mohyeldin, Ahmed; Lu, Hongyang; Dalgard, Clifton L.; Lai, Stephen Y.; Cohen, Noam A.; Ács, Géza; Verma, Ajay

doi:10.1593/neo.04685

Cited by 98 publications

(83 citation statements)

References 35 publications

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“…Little is known about the role that EPOR may play in cancer cells. High expression of EPO/EPOR was found in preinvasive and invasive carcinoma of the breast, renal cancer, colorectal cancer, primary liver cancer and other tumors [8,[30][31][32][33][34][35]. Probably, the enhanced EPO binding to its receptor EPOR in cancer cells triggers JAK2 and then STAT5 cascade [36].…”

Section: Discussionmentioning

confidence: 99%

The relationships between hypoxia-dependent markers: HIF-1alpha, EPO and EPOR in colorectal cancer

Baltaziak

Wincewicz²,

Kańczuga‐Koda³

et al. 2014

Folia Histochem Cytobiol.

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Hypoxia triggers production of several cytoprotective proteins. Hypoxia-inducible factor 1alpha (HIF -1a) is a powerful stimulator of transcription of many genes, including erythropoietin (EPO) in hypoxia-affected cells. Recent data have also implicated signaling by EPO receptor (EPOR) as a new factor influencing tumor progression. The aim of the study was to detect by immunohistochemistry the presence of HIF-1a, EPO and EPOR in colorectal cancer (CRC) in reference to clinicopathological variables. We found the presence of the studied proteins in specimens of all 125 CRC patients which is suggestive of the occurrence of hypoxia in colorectal cancer tissues. The expression of HIF-1a correlated significantly with the presence of EPO and EPOR in all samples (P < 0.001, r = 0.549 and P < 0.001, r = 0.536, respectively). Significant correlations (from P < 0.024 to P < 0.001) were found in the analyses of CRC subgroups such as histopathological type tumor, tumor grade, tumor stage and patients with lymph nodes metastases. The same high significant correlations (P < 0.001) were observed in group of sex, age and tumor location. However, the values of the correlation coefficients (r) which usually ranged from 0.5 to 0.6 suggest the existence of independent or concurrent mechanism stimulating generation of these proteins in colorectal cancer.

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Section: Discussionmentioning

confidence: 99%

The relationships between hypoxia-dependent markers: HIF-1alpha, EPO and EPOR in colorectal cancer

Baltaziak

Wincewicz²,

Kańczuga‐Koda³

et al. 2014

Folia Histochem Cytobiol.

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“…However, further studies are needed with more specific antibodies and greater sample numbers to determine the prognostic significance of EpoR expression on tumors. The biological effects of Epo stimulation of tumor cells is still debated with reports of enhanced survival (8,11), proliferation (4,6,(38)(39)(40), resistance to treatment (38,41,42), tumor angiogenesis (43)(44)(45), chemotaxis (46), invasion (47)(48)(49)(50), and migration (40,46,51). Others have reported no discernible effects of Epo (52).…”

Section: Discussionmentioning

confidence: 99%

Erythropoietin-Induced Activation of the JAK2/STAT5, PI3K/Akt, and Ras/ERK Pathways Promotes Malignant Cell Behavior in a Modified Breast Cancer Cell Line

Shi

Hodges

Dunlop

et al. 2010

Molecular Cancer Research

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Erythropoietin (Epo), the major regulator of erythropoiesis, and its cognate receptor (EpoR) are also expressed in nonerythroid tissues, including tumors. Clinical studies have highlighted the potential adverse effects of erythropoiesis-stimulating agents when used to treat cancer-related anemia. We assessed the ability of EpoR to enhance tumor growth and invasiveness following Epo stimulation. A benign noninvasive rat mammary cell line, Rama 37, was used as a model system. Cell signaling and malignant cell behavior were compared between parental Rama 37 cells, which express few or no endogenous EpoRs, and a modified cell line stably transfected with human EpoR (Rama 37-28). The incubation of Rama 37-28 cells with pharmacologic levels of Epo led to the rapid and sustained increases in phosphorylation of signal transducers and activators of transcription 5, Akt, and extracellular signal-regulated kinase. The activation of these signaling pathways significantly increased invasion, migration, adhesion, and colony formation. The Epo-induced invasion capacity of Rama 37-28 cells was reduced by the small interfering RNA-mediated knockdown of EpoR mRNA levels and by inhibitors of the phosphoinositide 3-kinase/Akt and Ras/extracellular signal-regulated kinase signaling pathways with adhesion also reduced by Janus-activated kinase 2/signal transducers and activators of transcription 5 inhibition. These data show that Epo induces phenotypic changes in the behavior of breast cancer cell lines and establishes links between individual cell signaling pathways and the potential for cancer spread. Mol Cancer Res; 8(4); 615-26. ©2010 AACR.

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“…22 There are several reports of EpoR protein detection in human tumor tissues subjected to immunohistochemistry or Western blotting. 19,20,[23][24][25][26][27][28][29] In all of these studies, the C20 antibody raised against the 20 C-terminal amino acids of human EpoR was used for staining. In our immunohistochemical studies, C20 antibody, a monoclonal anti-human antibody MAB 307 and two polyclonal anti-murine antibodies (M20, 07-311) yielded staining of different cell compartments (membrane, cytosol, nucleus).…”

Section: Discussionmentioning

confidence: 99%

Lack of functional erythropoietin receptors of cancer cell lines

Laugsch¹,

Metzen²,

Svensson³

et al. 2007

Intl Journal of Cancer

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Erythropoietin (Epo) therapy reduces red cell transfusion requirements and improves the quality of life of anemic cancer patients receiving chemotherapy. However, there is concern that Epo may promote tumor growth. We investigated by real‐time RT‐PCR, immunofluorescence microscopy, Western blotting and cell growth analysis whether human cancer cell lines (SH‐SY5Y, MCF7, HepG2, U2‐OS, HeLa, HEK293T, RCC4, HCT116, 7860wt and SW480) possess functional Epo receptors (EpoR). We detected EpoR mRNA in all cell lines. Neither hypoxia nor Epo treatment altered the level of EpoR mRNA expression. Four commonly used commercial antibodies proved to be unsuitable for immunoblot procedures because they cross‐reacted with several proteins unrelated with EpoR. Depending on the antibody used, EpoR was localized to the plasma membrane, the cytoplasm or the nucleus. Experiments with small interfering RNA showed that EpoR protein was not expressed by the tumor cells except by UT7/Epo leukemia cells, which served as an EpoR positive control line, and by cells transfected with the human EpoR gene. Apart from UT7/Epo, none of the tumor cell lines responded to Epo treatment with phosphorylation of signaling molecules or with cell proliferation. © 2007 Wiley‐Liss, Inc.

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Erythropoietin Signaling Promotes Invasiveness of Human Head and Neck Squamous Cell Carcinoma

Cited by 98 publications

References 35 publications

The relationships between hypoxia-dependent markers: HIF-1alpha, EPO and EPOR in colorectal cancer

The relationships between hypoxia-dependent markers: HIF-1alpha, EPO and EPOR in colorectal cancer

Erythropoietin-Induced Activation of the JAK2/STAT5, PI3K/Akt, and Ras/ERK Pathways Promotes Malignant Cell Behavior in a Modified Breast Cancer Cell Line

Lack of functional erythropoietin receptors of cancer cell lines

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