Identifying G6PC3 as a potential key molecule in hypoxic glucose metabolism of glioblastoma derived from the depiction of 18F-fluoromisonidazole and 18F-fluorodeoxyglucose positron emission tomography

Abstract

Abstract Background: Glioblastoma is the most offensive primary brain tumour, defined by its distinctive intratumoral hypoxia. Sequential preoperative evaluations using 18F-fluoromisonidazole (FMISO) and 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) could determine the degree of glucose metabolism with the hypoxic condition. However, the molecular mechanism of glucose metabolism under hypoxia in glioblastoma remains unclear. The goal of this research was to determine the key molecules of hypoxic glucose metabolism. Results: Using surgically derived specimens, gene expressions linked to glucose metabolism were evaluated in patients with glioblastoma (n = 33) who had preoperative FMISO and FDG PET to determine affected molecules according to hypoxic conditions. Tumour in vivo metabolic activities was semiquantitatively assessed by lesion normal tissue-ratio (LNR). Among the genes involving the glucose metabolic pathway, mRNA expression of glucose-6-phosphatase 3 (G6PC3) correlated with FDG LNR (P = 0.03). Furthermore, G6PC3 mRNA expression in FMISO high-accumulated glioblastomas was considerably higher than that in FMISO low-accumulated glioblastomas (P < 0.01). Protein expression of G6PC3 conformed with mRNA expression, which was determined by immunofluorescence analysis. These outcomes implied that the G6PC3 expression might be influenced by the hypoxic condition in glioblastomas. We then assessed the clinical relevance of G6PC3 regarding prognosis. The connection between gene expression and overall survival was investigated in another independent non-overlapping clinical cohort, and confirmed by the cancer genome atlas (TCGA) database. Among the glioblastoma patients who received gross total resection, mRNA expressions of G6PC3 in the patients with low prognosis (less than 1-year survival) were considerably higher than that in the patients who survive more than 3 years. Furthermore, high mRNA expression of G6PC3 was linked to poor overall survival in glioblastoma, as determined by the TCGA database. Conclusion: G6PC3 was significantly demonstrated in glioblastoma tissues with coincidentally high FDG and FMISO accumulation. Furthermore, it might function as a prognostic biomarker of glioblastoma. Therefore, G6PC3 is a potential key molecule of glucose metabolism under hypoxia in glioblastoma.