MicroRNAs and glioblastoma: roles in core signalling pathways and potential clinical implications

Abstract

MicroRNAs (miRNAs) are endogenously expressed small non-coding RNAs that act as post-transcriptional regulators of gene expression. Dysregulation of these molecules has been indicated in the development of many cancers. Altered expression levels of several miRNAs were identified also in glioblastoma. It was repeatedly found that miRNAs are involved in important signalling pathways, which play roles in crucial cellular processes, such as proliferation, apoptosis, cell cycle regulation, invasion, angiogenesis and stem cell behaviour. Therefore, miRNAs represent promising therapeutic targets in glioblastoma. In this review, we summarize the current knowledge about miRNAs significance in glioblastoma, with special focus on their involvement in core signalling pathways, their roles in drug resistance and potential clinical implications.

Fig 1

MiRNAs involved in EGFR and PI3K/AKT signalling pathways. EGFR: epidermal growth factor receptor; AKT: serine/threonine protein kinase Akt; PTEN: phosphatase and tensin homologue; Bmi-1: polycomb ring finger oncogene; Raf: raf kinase, effector of Ras; IRS1/2: insulin receptor substrate 1/2; PI3K: Phosphotidylinositol 3 kinase; MMP9/2: matrix metallopeptidase 9/2; p27: cyclin-dependent kinase inhibitor 1B (p27, Kip1); p21: cyclin-dependent kinase inhibitor 1A (p21, Cip1); Bcl-2: B-cell CLL/lymphoma 2; Grb2: growth factor receptor-bound protein 2; SOS: son of sevenless homologue 1; MEK: mitogen-activated protein kinase kinase 1; ERK: extracellular signal-regulated kinase. Dashed lines indicated indirect regulation, solid lines indicate direct regulation.

Fig 2

MiRNAs involved in TGF-β and IFN-α/IFN-β signalling pathways. TGFBR2/3: transforming growth factor β receptor 2/3; TGFB1/2: transforming growth factor β 1/2; DAXX: death-domain associated protein; SMAD3/4: SMAD family member 3/4; APAF: apoptotic peptidase activating factor; CASP3/7/9: caspase 3/7/9; p53: tumour protein p53; p21: cyclin-dependent kinase inhibitor 1A (p21, Cip1); p63: tumour protein p63; CDK2/4: cyclin-dependent kinase 2/4; JMY: junction mediating and regulatory protein, p53 cofactor; TOPORS: topoisomerase I binding, arginine/serine-rich, E3 ubiquitin protein ligase; HNRNPK: heterogeneous nuclear ribonucleoprotein K; TP53BP2: tumour protein p53 binding protein, 2; IFN: interferon; STAT1/2/3: signal transducer and activator of transcription 1/2/3; JAK: Janus kinase. Dashed lines indicated indirect regulation, solid lines indicate direct regulation. EGFR: epidermal growth factor receptor.

Fig 3

MiRNAs involved in notch and NF-κB signalling pathways. IKK-α/β/γ: inhibitor of κB kinase α/β/γ; NF-κB: nuclear factor of κB; IκB: inhibitor I κB; LRRFIP1: leucine rich repeat (in FLII) interacting protein 1; CDK6: cyclin-dependent kinase 6; c-MET: met proto-oncogene (hepatocyte growth factor receptor); PKM2: pyruvate kinase, muscle. Dashed lines indicated indirect regulation, solid lines indicate direct regulation. EGFR: epidermal growth factor receptor.