Estrogen-dependent Production of Erythropoietin in Uterus and Its Implication in Uterine Angiogenesis

Yasuda, Yoshiko; Masuda, Seiji; Chikuma, Mariko; Inoue, Kentaro; Nagao, Masaya; Sasaki, Ryuzo

doi:10.1074/jbc.273.39.25381

Cited by 250 publications

(198 citation statements)

References 45 publications

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“…23 The presence of EPO/Epo and EPOR/EpoR mRNA and protein in endometrial cells has been demonstrated previously, 9 and it has been suggested that Epo, acting in an autocrine/paracrine manner, may be involved in the cyclic proliferation of endometrial epithelial cells and in vascular proliferation. 8,9 Our results also support the role of Epo signaling in the endometrial changes that occur during the menstrual cycle. The observation of highly significant negative correlations between Epo and ER expression and between Epo and PR expression, together with data from the literature, 8,9 suggests that Epo expression in normal endometrial tissue is regulated by estrogen and progesterone.…”

Section: Discussionsupporting

confidence: 80%

“…8,9 Our results also support the role of Epo signaling in the endometrial changes that occur during the menstrual cycle. The observation of highly significant negative correlations between Epo and ER expression and between Epo and PR expression, together with data from the literature, 8,9 suggests that Epo expression in normal endometrial tissue is regulated by estrogen and progesterone. This hypothesis also is supported by the finding that the 5Ј-flanking region of the human EPO gene contains sequences that are highly homologous to the sequence responsible for ER binding.…”

Section: Discussionsupporting

confidence: 80%

“…However, recently, other sites of Epo production have been reported, including brain astrocytes, 4 breast epithelial cells, [5][6][7] and human female reproductive organs, including the uterus. 8,9 EpoR is expressed by a variety of cell types as well, including endothelial cells, 10 neurons, 11 mammary epithelial cells, [5][6][7] and human endometrial cells, 9 suggesting a wider biologic role for Epo signaling unrelated to erythropoiesis. Epo also stimulates proliferation and migration of human endothelial cells 10 and promotes angiogenesis.…”

mentioning

confidence: 99%

“…Epo also stimulates proliferation and migration of human endothelial cells 10 and promotes angiogenesis. 8 Because uterine Epo production is stimulated by estrogen, Epo signaling may play an important role in cyclic uterine angiogenesis. 8 Previous studies have shown that cultured human breast and cervical carcinoma cells, as well as other carcinoma cells, express high levels of EPO/Epo and EPOR/EpoR mRNA and protein.…”

mentioning

confidence: 99%

“…8 Because uterine Epo production is stimulated by estrogen, Epo signaling may play an important role in cyclic uterine angiogenesis. 8 Previous studies have shown that cultured human breast and cervical carcinoma cells, as well as other carcinoma cells, express high levels of EPO/Epo and EPOR/EpoR mRNA and protein. 5,12 Exposure of the tumor cells to recombinant human Epo (rHuEpo) stimulated tyrosine phosphorylation and DNA synthesis and proliferation, suggesting that Epo signaling is biologically active in malignant cells.…”

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confidence: 99%

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Prognostic significance of erythropoietin expression in human endometrial carcinoma

Ács

Chu

et al. 2004

Cancer

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Objective To study whether the Disease Activity Score (DAS) is a valid measure of disease activity in undifferentiated arthritis (UA). Methods Data from a randomized, double‐blind, placebo‐controlled trial of methotrexate (MTX) and placebo involving 110 patients with UA were used. Data included baseline and 3, 6, 9, and 12 months, as well as diagnosis at 18 months. Validity of the DAS was analyzed using factor analysis, correlations with disease activity variables, correlations with changes in disability and joint damage, differences in DAS between diagnoses, and detecting the difference between placebo and MTX. Results Three disease activity factors were retrieved from the disease activity variables: patient reported outcomes, tender and swollen joints, and acute phase reactants. The DAS had its highest correlations (r > 0.77) with tender joint counts, followed by swollen joint counts (r > 0.63) and patient reported outcomes (r > 0.30), but the DAS correlated less with C‐reactive protein levels (r = 0.32). Over time, the DAS was related to the Health Assessment Questionnaire response with an odds ratio of 4.1 (95% confidence interval 2.1–8.0), but not with change in joint damage. At 18 months, the mean DAS was 2.6 for rheumatoid arthritis patients, 2.2 for UA patients, and 1.9 for patients in remission (P = 0.001). The DAS discriminated better than all single variables between MTX and placebo, with a Guyatt's effect size of 0.89. Conclusion The DAS appears to be a reasonably valid measure of disease activity for use in UA clinical trials.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionsupporting

confidence: 80%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Prognostic significance of erythropoietin expression in human endometrial carcinoma

Ács

Chu

et al. 2004

Cancer

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A new biological strategy for high productivity of recombinant proteins in animal cells by the use of hypoxia-response enhancer

Masuda

Moon

Kambe

et al. 2000

Biotechnol. Bioeng.

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Oxygen supply is one of the major problems in the production of useful proteins by cultured animal cells and therefore it is of importance to devise a system by which a high productivity of human therapeutic recombinant proteins can be maintained or enhanced under low oxygen concentrations. A number of hypoxia‐inducible genes have been found in animal cells and the induction in most cases is due to hypoxic activation of the gene transcription. A consensus sequence (HRE = hypoxia‐response enhancer) responsible for the hypoxic activation exists in these genes and the binding of a protein, which is widely distributed in animal cells, to this sequence responding to hypoxia activates the promoter activity. The promoter of lactate dehydrogenase A gene is active in Chinese hamster ovary (CHO) cells and the vicinal HRE stimulates the promoter activity efficiently in hypoxia. We have prepared a number of permanent CHO cell lines producing recombinant human erythropoietin (Epo) under control of this promoter/HRE. Epo production was highly hypoxia‐inducible when the wild‐type of HRE was used but uninducible when the mutant HRE was used. There was little difference in the in vitro and in vivo activities, and glycosylation between Epo produced by the cells cultured in 21% and 2% oxygen. Furthermore, forced expression of hypoxia‐inducible factor‐1α (HIF‐1α) enhanced Epo production in all oxygen concentrations. These results indicate that a biological strategy based on the hypoxic induction of gene transcription provides a novel system which guarantees a high productivity even uner low oxygen concentrations. © 2000 John Wiley & Sons, Inc. Biotechnol Bioeng 67: 157–164, 2000.

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Immunohistochemical expression of erythropoietin and erythropoietin receptor in breast carcinoma

Ács

Zhang

Rebbeck

et al. 2002

Cancer

137

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BACKGROUNDErythropoietin (Epo), induced by hypoxia, controls the survival, proliferation, and differentiation of Epo receptor (EpoR)‐bearing erythroid progenitors and plays a role in the protection of neurons from hypoxic damage. Hypoxia in malignant disease is associated with invasion, metastasis, resistance to therapy, and selection for cells with diminished apoptotic potential. The authors recently demonstrated the basal and hypoxia‐stimulated expression of Epo and EpoR in human breast carcinoma cell lines and in breast carcinomas, suggesting a role for autocrine Epo signaling in the hypoxic adaptations of mammary neoplasms.METHODSThe authors characterized the expression of Epo and EpoR by immunohistochemistry in 184 invasive mammary carcinomas and 158 in situ mammary carcinomas and benign mammary epithelium. They analyzed the correlation of Epo and EpoR immunostaining with clinicopathologic tumor features and the patients' smoking history.RESULTSBenign mammary epithelial cells showed weak‐to‐moderate expression of Epo and EpoR. EpoR immunostaining was increased in carcinomas compared with benign epithelium both in nonsmokers and smokers, and Epo immunostaining was increased in carcinomas compared with benign epithelium in nonsmokers but not in smokers. Prominent Epo staining was seen in tumor cells adjacent to necrotic areas and at the infiltrating edge of tumors. EpoR staining, but not Epo staining, was significantly greater in tumors that showed high histologic grade, tumor necrosis, lymphovascular invasion, lymph node metastases, and loss of hormone receptor expression.CONCLUSIONSThe current findings suggest that increased EpoR expression may play an important role in breast carcinogenesis. The induction of autocrine or paracrine Epo signaling may represent a novel mechanism by which hypoxia can promote breast carcinoma. Cancer 2002;95:969–81. © 2002 American Cancer Society.DOI 10.1002/cncr.10787

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Estrogen-dependent Production of Erythropoietin in Uterus and Its Implication in Uterine Angiogenesis

Cited by 250 publications

References 45 publications

Prognostic significance of erythropoietin expression in human endometrial carcinoma

Prognostic significance of erythropoietin expression in human endometrial carcinoma

A new biological strategy for high productivity of recombinant proteins in animal cells by the use of hypoxia-response enhancer

Immunohistochemical expression of erythropoietin and erythropoietin receptor in breast carcinoma

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