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

Cygb 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.Our 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.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]. Shortly thereafter, a fourth vertebrate globin--cytoglobin (Cygb), was described independently by three groups [2-4]. Cygb is expressed ubiquitously in human tissue [2], however, low cellular levels of Cygb and Ngb (μM range) may have impeded their earlier discovery [5]. The amino acid sequences of Cygb and Ngb show little similarity to that of hemoglobin (Hb) or myoglobin (Mb) (< 30% and <25% identity for Cygb and Ngb, respectively). However, amino acids that confer Hb and Mb function are conserved together with all features of the globin fold [2,4,6]. Unlike Hb and Mb, the physiological roles of Ngb and Cygb are incompletely understood and several functions are conceivable. Ngb and Cygb may function as a Mb-type molecule to store O2