Hypoxia differentially upregulates the expression of embryonic, fetal and adult hemoglobin in human glioblastoma cells

Emara,Marwan; Turner,A. Robert; Allalunis-Turner,Joan

doi:10.3892/ijo.2013.2239

2014-March Volume 44 Issue 3

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2014-March Volume 44 Issue 3

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Article

Hypoxia differentially upregulates the expression of embryonic, fetal and adult hemoglobin in human glioblastoma cells

Authors:
- Marwan Emara
- A. Robert Turner
- Joan Allalunis-Turner
View Affiliations / Copyright

Affiliations: Department of Oncology, University of Alberta and Alberta Health Services, Cross Cancer Institute, Edmonton, AΒ T6G 1Z2, Canada
Pages: 950-958
|
Published online on: December 31, 2013

https://doi.org/10.3892/ijo.2013.2239
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Abstract

Hemoglobin is produced mainly in erythroid cells. However, it has been reported in non-erythroid cells of human and rodents. We have shown previously that neuroglobin, cytoglobin and hemoglobin are expressed in human glioblastoma multiforme (GBM) cells. We sought to determine whether hemoglobin expression is upregulated by hypoxia, and whether its expression is restricted to the cancer stem cell populations in different GBM cell lines or GBM brain tumor initiating cells (BTICs). Flow cytometry, magnetic cell sorting and qRT-PCR were used to examine the hypoxic upregulation of hemoglobins as well as erythropoietin (EPO) and erythropoietin receptor (EPOR) in GBM cell lines (M006x, M059J, M059K, U87R and U87T) and GBM-BTICs. The data showed significantly increased expression in globins (α, β, γ, δ, ζ and ε), EPO and EPOR mRNA levels under hypoxia. Globin expression is not limited to the stem cell populations or GBM-BTICs but is a property of the entire GBM population. We assumed that the total expression of mRNA of different normalized globins (α, β, γ, δ, ζ and ε) at different time‑points for the same cell line is 100%. Under aerobic conditions, ε globin was predominantly expressed, and then decreased gradually with increasing time in hypoxia. This was coupled to a concomitant increase in α and γ globins. Our findings suggest that hypoxic upregulation of hemoglobin expression in GBM cells may be a part of a repertoire of active defence and adaptation mechanisms enabling these cells to acquire resistance to aggressive multimodality treatments of chemotherapy and radiotherapy. New therapeutic strategies to interfere with hemoglobin expression or function in GBM cells are required.

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Hypoxia differentially upregulates the expression of embryonic, fetal and adult hemoglobin in human glioblastoma cells

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