2057

EPOR

erythropoietin receptor;EPOR;erythropoietin receptor

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19p13.3-p13.2

protein-coding

BACKGROUND: Erythropoietin (Epo), which is induced by hypoxia, controls erythropoiesis and protects neurons from hypoxic damage. Hypoxia in malignant disease is associated with invasion, metastasis, and resistance to therapy. The authors recently demonstrated hypoxia-stimulated expression of Epo and Epo receptor (EpoR) in human breast and cervical carcinomas, suggesting a role for autocrine Epo signaling in the hypoxic adaptations of carcinomas. METHODS: The authors characterized the expression of Epo, EpoR, hypoxia-inducible factor (HIF)-1alpha, estrogen receptor (ER), and progesterone receptor (PR) by immunohistochemical methods using endometrial carcinoma samples from 107 women and benign endometrial samples from 59 women in various phases of the menstrual cycle. They then analyzed potential correlations of Epo and EpoR immunostaining and clinicopathologic tumor features with outcome. RESULTS: In benign endometrial tissue samples, Epo and EpoR expression increased over the course of the cycle, with the highest levels observed in the late secretory phase. Epo expression in benign endometrial samples showed a negative correlation with ER and PR expression. The authors found Epo and EpoR expression in 95.3 % and 100% of endometrial carcinoma samples, respectively. Increased EpoR, but not Epo, expression in tumors was associated with advanced-stage disease, lymphovascular invasion, lymph node metastasis, and loss of ER expression. Increased Epo expression was observed in perinecrotic tumor regions in a pattern similar to the HIF-1alpha expression pattern. Increased Epo expression was significantly associated with adverse clinical outcome on both univariate and multivariate analysis. CONCLUSIONS: Hypoxia-inducible autocrine Epo signaling in endometrial carcinoma may contribute to tumor progression and increased aggressiveness. Increased Epo expression in endometrial carcinomas may be an independent prognostic and/or predictive factor.

Recombinant human erythropoietin (Epo) is used to prevent and treat tumor-related anemia and improve quality of life in cancer patients. Recent evidence suggested that Epo may adversely affect the survival of selected cancer patients by promoting tumor growth, inhibition of apoptosis, and induction of migration. Epo unfolds its effect on the Epo receptor (EpoR). We show--to the best of our knowledge for the first time--significantly increased EpoR expression in clinical melanoma metastases and primary melanomas in comparison with different sets of nevi by quantitative real-time reverse transcriptase-PCR, immunohistochemistry, and western blot analysis. When assessing the functionality of the EpoR-signaling pathway, recombinant human Epo led to the phosphorylation of JAK-2, signal transducers and activators of transcription 3 (STAT3), and ERK1/2 in several of the melanoma cell lines that were analyzed. Besides, Epo counteracted cisplatin-induced cell death in BLM and MV3 cells. Finally, Epo promoted cell migration of MV3 cells, whereas inhibition of the JAK/STAT and ERK1/2 pathways reduced Epo-mediated migration. In summary, we show the overexpression of functional EpoR expression in about half of the analyzed clinical melanoma metastasis specimens and show anti-apoptotic as well as pro-migratory effects of Epo, which is of importance for the treatment of anemia in advanced melanoma.