Hypoxic regulation of cytoglobin and neuroglobin expression in human normal and tumor tissues

Joan Allalunis-Turner,Marwan Emara,A Robert Turner

doi:10.1186/1475-2867-10-33

Joan Allalunis-Turner, Marwan Emara + Show 1 more

Open Access

https://doi.org/10.1186/1475-2867-10-33

Copy DOI

Journal: Cancer Cell International	Publication Date: Sep 9, 2010
Citations: 123	License type: cc-by

Affiliation: University of Alberta

Abstract

BackgroundCytoglobin (Cygb) and neuroglobin (Ngb) are recently identified globin molecules that are expressed in vertebrate tissues. Upregulation of Cygb and Ngb under hypoxic and/or ischemic conditions in vitro and in vivo increases cell survival, suggesting possible protective roles through prevention of oxidative damage. We have previously shown that Ngb is expressed in human glioblastoma multiforme (GBM) cell lines, and that expression of its transcript and protein can be significantly increased after exposure to physiologically relevant levels of hypoxia. In this study, we extended this work to determine whether Cygb is also expressed in GBM cells, and whether its expression is enhanced under hypoxic conditions. We also compared Cygb and Ngb expression in human primary tumor specimens, including brain tumors, as well as in human normal tissues. Immunoreactivity of carbonic anhydrase IX (CA IX), a hypoxia-inducible metalloenzyme that catalyzes the hydration of CO2 to bicarbonate, was used as an endogenous marker of hypoxia.ResultsCygb transcript and protein were expressed in human GBM cells, and this expression was significantly increased in most cells following 48 h incubation under hypoxia. We also showed that Cygb and Ngb are expressed in both normal tissues and human primary cancers, including GBM. Among normal tissues, Cygb and Ngb expression was restricted to distinct cell types and was especially prominent in ductal cells. Additionally, certain normal organs (e.g. stomach fundus, small bowel) showed distinct regional co-localization of Ngb, Cygb and CA IX. In most tumors, Ngb immunoreactivity was significantly greater than that of Cygb. In keeping with previous in vitro results, tumor regions that were positively stained for CA IX were also positive for Ngb and Cygb, suggesting that hypoxic upregulation of Ngb and Cygb also occurs in vivo.ConclusionsOur finding of hypoxic up-regulation of Cygb/Ngb in GBM cell lines and human tumor tissues suggests that these globin molecules may be part of the repertoire of defense mechanisms that allow cancer cells to survive in hypoxic microenvironments.

Highlights

Cytoglobin (Cygb) and neuroglobin (Ngb) are recently identified globin molecules that are expressed in vertebrate tissues
A third member of the vertebrate globin family, neuroglobin (Ngb), was discovered in 2000 and so-named because it is primarily expressed in neuronal tissue, including retina [1]
Some studies have reported that Ngb is expressed exclusively in neurons but not in glia [35,36], others have reported Ngb expression in astrocytes cultured from newborn mouse brain [37], and we have shown that Ngb is expressed and upregulated by hypoxia in human glioblastoma multiforme (GBM) cell lines [38]

Summary

Introduction

Cytoglobin (Cygb) and neuroglobin (Ngb) are recently identified globin molecules that are expressed in vertebrate tissues. A third member of the vertebrate globin family, neuroglobin (Ngb), was discovered in 2000 and so-named because it is primarily expressed in neuronal tissue, including retina [1]. The lower O2 affinity of Ngb (P50 of 7.5 torr under physiological conditions of pH and temperature) [8] compared to that of Mb (P50 of 2-3 torr) [7] does not support an O2 storage function for Ngb in neuronal tissue, including retina, as only a small fraction of Ngb (~ 12%) will be O2 saturated under normal conditions [5,8,9,10]

Methods

Results

Conclusion