Abstract
Glioblastoma multiforme (GBM) is the most aggressive human brain cancer. Little is known regarding how these cells adapt to the harsh tumor microenvironment, and consequently survive and resist various treatments. Myoglobin (MB), the oxygen‑binding hemoprotein, has been shown to be ectopically expressed in different human cancers and cell lines, and its expression is hypothesized to be an adaptation mechanism to hypoxia. The aim of the present study was to determine whether cancer‑related and hypoxia‑responsive MB mRNA splice variants are expressed in human GBM cells and glioblastoma tumor xenografts, and whether their expression is induced by hypoxia and correlated with hypoxia markers [lactate dehydrogenase A (LDHA), glucose transporter 1 (GLUT1), vascular endothelial growth factor (VEGF) and carbonic anhydrase IX (CAIX)]. Conventional reverse transcription (RT)‑PCR, DNA sequencing, RT‑quantitative PCR and immunohistochemistry were conducted to investigate MB expression in hypoxia‑sensitive (M010b, M059J) and ‑tolerant (M059K, M006xLo) GBM cell lines that also exhibit differential response towards radiation, rendering them a valuable translational GBM model. It was revealed that cancer‑related MB variants 9, 10, 11 and 13 were expressed in GBM cells under normoxia, and following hypoxia, their expression exhibited modest‑to‑significant upregulation that correlated with hypoxia markers. It was also demonstrated that MB was upregulated in hypoxic microregions of glioblastoma tumor xenografts that were stained in matched tumor regions of serial tumor sections with the hypoxia markers, pimonidazole, CAIX, VEGF and LDHA. The present study identified myoglobin as a potential contributor to the hypoxia adaptation and survival strategies of glioblastoma, and may explain the aggressiveness and frequent recurrence rates associated with GBM.