Abstract
Simple SummaryGlioblastoma multiforme (GBM) is the most aggressive type of glioma and exhibits extensive heterogeneity and poor prognosis with a high recurrence rate. Among the genetic alterations in GBM with different phenotypic states, a mesenchymal subtype has been associated with a worse outcome in patients with GBM. The mechanisms for the gain of the mesenchymal subtype in GBM remain unclear. Our aim was to investigate whether NOX2-induced high glycolytic activity could contribute to the gain of the mesenchymal phenotype in GBM. We revealed that NOX2-induced high glycolytic activity can induce the gain of the COL5A1-mediated mesenchymal phenotype in GBM. Our findings will provide the molecular mechanism by which NOX2 contributes to the gain of mesenchymal phenotype in GBM.The alteration of the cellular metabolism is a hallmark of glioma. The high glycolytic phenotype is a critical factor in the pathogenesis of high-grade glioma, including glioblastoma multiforme (GBM). GBM has been stratified into three subtypes as the proneural, mesenchymal, and classical subtypes. High glycolytic activity was found in mesenchymal GBM relative to proneural GBM. NADPH oxidase 2 (NOX2) has been linked to cellular metabolism and epithelial-mesenchymal transition (EMT) in tumors. The role of NOX2 in the regulation of the high glycolytic phenotype and the gain of the mesenchymal subtype in glioma remain unclear. Here, our results show that the levels of NOX2 were elevated in patients with GBM. NOX2 induces hexokinase 2 (HK2)-dependent high glycolytic activity in U87MG glioma cells. High levels of NOX2 are correlated with high levels of HK2 and glucose uptake in patients with GBM relative to benign glioma. Moreover, NOX2 increases the expression of mesenchymal-subtype-related genes, including COL5A1 and FN1 in U87MG glioma cells. High levels of NOX2 are correlated with high levels of COL5A1 and the accumulation of extracellular matrix (ECM) in patients with GBM relative to benign glioma. Furthermore, high levels of HK2 are correlated with high levels of COL5A1 in patients with GBM relative to benign glioma. Our results suggest that NOX2-induced high glycolytic activity contributes to the gain of the COL5A1-mediated mesenchymal phenotype in GBM.
Highlights
Glioma is a malignant brain tumor with the highest incidence among central nervous system (CNS) tumors [1,2]
Our results suggest that NADPH oxidase 2 (NOX2) induces hexokinase 2 (HK2)-dependent high glycolytic activity in glioblastoma multiforme (GBM)
Our findings provide a molecular mechanism by which NOX2-dependent glycolytic activity contributes to the elevation of the mesenchymal phenotype in GBM
Summary
Glioma is a malignant brain tumor with the highest incidence among central nervous system (CNS) tumors [1,2]. According to the 2016 WHO brain tumor classification criteria, glioma is divided into biologically benign (grade 1) and diffusely infiltrating features (grade 2, grade 3, and grade 4) based on histological pathologic evaluation and genetic molecular patterns [1,3]. GBM has been stratified into four subtypes, including the proneural, neuronal, mesenchymal, and classical subtypes, according to different criteria and gene expression signature [5]. In glioma tissues of GBM, mesenchymal subtype cells have the high expression of mesenchymal subtype signature genes, including chitinase 3 like 1 (CHI3L1), collagen type V alpha 1 chain (COL5A1), fibronectin 1 (FN1), cyclin B1 (CCNB1), and maternal embryonic leucine zipper kinase (MELK) [6,7]. Among the mesenchymal subtype signature genes, COL5A1 is a representative gene of mesenchymal subtype cell markers in glioma [8,9,10]
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