■胶质母细胞瘤是侵袭性最强的原发性脑肿瘤,以其独特的瘤内缺氧为特征。使用氟-18-氟咪唑(18F-FMISO)和氟-18-氟脱氧葡萄糖(18F-FDG)正电子发射断层扫描(PET)的序贯术前检查可以描述缺氧条件下的葡萄糖代谢程度。然而,胶质母细胞瘤缺氧条件下葡萄糖代谢的分子机制尚不清楚。本研究的目的是确定低氧葡萄糖代谢的关键分子。
■使用手术获得的标本,我们分析了术前接受18F-FMISO和18F-FDGPET的胶质母细胞瘤患者(n=33)中与葡萄糖代谢相关的基因表达,以根据缺氧情况鉴定受影响的分子.通过病变-正常组织比(LNR)半定量评估肿瘤体内代谢活性。通过免疫荧光染色确认蛋白质表达。为了评估预后价值,在另一个独立的非重叠临床队列(n=17)中研究了基因表达与总生存期之间的关系,并通过癌症基因组图谱(TCGA)数据库(n=167)进行了验证.
■在涉及葡萄糖代谢途径的基因中,葡萄糖-6-磷酸酶3(G6PC3)的mRNA表达与18F-FDGLNR相关(P=0.03)。此外,18F-FMISO高积累胶质母细胞瘤的G6PC3mRNA表达显著高于18F-FMISO低积累胶质母细胞瘤(P<0.01)。G6PC3蛋白表达与mRNA表达一致,免疫荧光分析证实了这一点。这些发现表明,胶质母细胞瘤中的缺氧条件可能会促进G6PC3的表达。接下来,我们调查了G6PC3在预后方面的临床意义.在接受全切除的胶质母细胞瘤患者中,G6PC3mRNA在预后不良(生存期小于1年)患者中的表达明显高于生存期大于3年的患者。此外,G6PC3mRNA的高表达与胶质母细胞瘤的总体生存率低相关,经TCGA数据库验证。
■G6PC3在胶质母细胞瘤组织中丰富表达,同时具有较高的18F-FDG和18F-FMISO积累。Further,它可能作为胶质母细胞瘤的预后生物标志物。因此,G6PC3是胶质母细胞瘤缺氧条件下葡萄糖代谢的潜在关键分子。
UNASSIGNED: Glioblastoma is the most aggressive primary brain tumor, characterized by its distinctive intratumoral hypoxia. Sequential preoperative examinations using fluorine-18-fluoromisonidazole (18F-FMISO) and fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) could depict the degree of glucose metabolism with hypoxic condition. However, molecular mechanism of glucose metabolism under hypoxia in glioblastoma has been unclear. The aim of this study was to identify the key molecules of hypoxic glucose metabolism.
UNASSIGNED: Using surgically obtained specimens, gene expressions associated with glucose metabolism were analyzed in patients with glioblastoma (n = 33) who underwent preoperative 18F-FMISO and 18F-FDG PET to identify affected molecules according to hypoxic condition. Tumor in vivo metabolic activities were semiquantitatively evaluated by lesion-normal tissue ratio (LNR). Protein expression was confirmed by immunofluorescence staining. To evaluate prognostic value, relationship between gene expression and overall survival was explored in another independent nonoverlapping clinical cohort (n = 17) and validated by The Cancer Genome Atlas (TCGA) database (n = 167).
UNASSIGNED: Among the genes involving glucose metabolic pathway, mRNA expression of glucose-6-phosphatase 3 (G6PC3) correlated with 18F-FDG LNR (P = 0.03). In addition, G6PC3 mRNA expression in 18F-FMISO high-accumulated glioblastomas was significantly higher than that in 18F-FMISO low-accumulated glioblastomas (P < 0.01). Protein expression of G6PC3 was consistent with mRNA expression, which was confirmed by immunofluorescence analysis. These findings indicated that the G6PC3 expression might be facilitated by hypoxic condition in glioblastomas. Next, we investigated the clinical relevance of G6PC3 in terms of prognosis. Among the glioblastoma patients who received gross total resection, mRNA expressions of G6PC3 in the patients with poor prognosis (less than 1-year survival) were significantly higher than that in the patients who survive more than 3 years. Moreover, high mRNA expression of G6PC3 was associated with poor overall survival in glioblastoma, as validated by TCGA database.
UNASSIGNED: G6PC3 was affluently expressed in glioblastoma tissues with coincidentally high 18F-FDG and 18F-FMISO accumulation. Further, it might work as a prognostic biomarker of glioblastoma. Therefore, G6PC3 is a potential key molecule of glucose metabolism under hypoxia in glioblastoma.