MicroRNA Regulation of Glycolytic Metabolism in Glioblastoma

Abstract

Glioblastoma (GBM) is the most aggressive and common malignant brain tumour in adults. A well-known hallmark of GMB and many other tumours is aerobic glycolysis. MicroRNAs (miRNAs) are a class of short nonprotein coding sequences that exert posttranscriptional controls on gene expression and represent critical regulators of aerobic glycolysis in GBM. In GBM, miRNAs regulate the expression of glycolytic genes directly and via the regulation of metabolism-associated tumour suppressors and oncogenic signalling pathways. This review aims to establish links between miRNAs expression levels, the expression of GBM glycolytic regulatory genes, and the malignant progression and prognosis of GBM. In this review, the involvement of 25 miRNAs in the regulation of glycolytic metabolism of GBM is discussed. Seven of these miRNAs have been shown to regulate glycolytic metabolism in other tumour types. Further eight miRNAs, which are differentially expressed in GBM, have also been reported to regulate glycolytic metabolism in other cancer types. Thus, these miRNAs could serve as potential glycolytic regulators in GBM but will require functional validation. As such, the characterisation of these molecular and metabolic signatures in GBM can facilitate a better understanding of the molecular pathogenesis of this disease.

Figure 1

Clinical classifications and glycolytic phenotype of GBMs. H6PD: glucose-1-dehydrogenase, ENO1: enolase 1, LDHA/B: lactate dehydrogenase isoform A/B, ALDOC: fructose-bisphosphate C, and PDH: pyruvate dehydrogenase.

Figure 2

miRNA regulation of glycolytic transporters and enzymes in GBM. Red ovals represent downregulated miRNAs and blunt ends designate negative regulation. c-Myc (downstream effector of RTKs signalling pathways) upregulates glycolysis by negatively regulating let-7a which targets PKM2: pyruvate kinase type M2. Dashed black lines indicate that several steps have been omitted. Mitochondria represent entry into the citric acid cycle. P: phosphate. P-: phospho-.

Figure 3

miRNA regulation of glycolytic regulatory signalling pathways in GBM. Arrowheads designate positive regulation. Blunt ends designate negative regulation. Dashed lines indicate indirect effects. Green and red ovals indicate upregulated and downregulated miRNAs. c-Myc regulates miRNAs and is regulated by the glycolytic enzymes PKM2: pyruvate kinase type M2.

Figure 4

Differentially expressed miRNAs in GBM which are involved in the regulation of glycolytic metabolism in other tumours. Downregulated miRNAs are shown in red ovals. Blunt ends designate negative regulation. Double lines represent cell membrane. Dashed red lines denote indirect regulation. Dashed black lines indicate that several steps have been omitted.