No abstract

Glioblastoma (GBM) mesenchymal (MES) transition can be regulated by long non-coding RNAs (lncRNAs) via modulation of various factors (Epithelial-to-Mesenchymal (EMT) markers, biological signalling, and the extracellular matrix (ECM)). However, understanding of these mechanisms in terms of lncRNAs is largely sparse. This review systematically analysed the mechanisms by which lncRNAs influence MES transition in GBM from a systematic search of the literature (using PRISMA) performed in five databases (PubMed, MEDLINE, EMBASE, Scopus, and Web of Science). We identified a total of 62 lncRNAs affiliated with GBM MES transition, of which 52 were upregulated and 10 were downregulated in GBM cells, where 55 lncRNAs were identified to regulate classical EMT markers in GBM (E-cadherin, N-cadherin, and vimentin) and 25 lncRNAs were reported to regulate EMT transcription factors (ZEB1, Snai1, Slug, Twist, and Notch); a total of 16 lncRNAs were found to regulate the associated signalling pathways (Wnt/β-catenin, PI3k/Akt/mTOR, TGFβ, and NF-κB) and 14 lncRNAs were reported to regulate ECM components (MMP2/9, fibronectin, CD44, and integrin-β1). A total of 25 lncRNAs were found dysregulated in clinical samples (TCGA vs. GTEx), of which 17 were upregulated and 8 were downregulated. Gene set enrichment analysis predicted the functions of HOXAS3, H19, HOTTIP, MEG3, DGCR5, and XIST at the transcriptional and translational levels based on their interacting target proteins. Our analysis observed that the MES transition is regulated by complex interplays between the signalling pathways and EMT factors. Nevertheless, further empirical studies are required to elucidate the complexity in this process between these EMT factors and the signalling involved in the GBM MES transition.

Glioblastoma (GBM) is the deadliest type of primary brain tumours with a high mortality rate, attributing to high post-surgical tumour recurrence. This unfavourable prognosis is due to the highly invasive phenotype observed in GBM cells, especially within the mesenchymal (MES) subtype of GBM. In recent years, the involvement of non-coding RNA (ncRNA) such as long non-coding RNA (lncRNA) and microRNA (miRNA) have been extensively deliberated in cancers and GBM. They were reported to be involved in the regulation of multiple biological pathways and cellular processes, which leads to increased cell invasion observed in tumours. This review focuses on two cellular processes; angiogenesis and MES transition, which can stimulate the invasive nature of GBM cells. Additionally, the extracellular matrix (ECM) and the hypoxic environment of GBM microenvironment which are central factors regulating both cellular processes will be discussed. Both cellular processes affiliated with cell invasion are downstream of signalling pathways such as PI3K/Akt or Wnt/β-catenin signalling, which will also be elaborated. Finally, recent studies characterising novel lncRNAs in the regulation of cell-invasion in GBM, specifically via the biological processes and signalling pathways discussed previously will be compiled and reviewed.

Long non-coding RNA (lncRNA) has been identified in the regulation of cell-invasion via various cellular processes. Research on lncRNAs is however lacking in the context of Glioblastoma (GBM), which held-up identification of GBM-related lncRNAs via bioinformatic databases. This study intends to identify potential lncRNA candidates in the regulation of GBM cell-invasion based on target miRNA and mRNA/proteins. Microarray was carried out to identify upregulated lncRNA in GBM and astrocytoma cells, followed by bioinformatics-based prediction analysis to identify lncRNAs involved in cellular processes related to GBM cell-invasion. A total of 372 and 806 upregulated lncRNA were identified in GBM and astrocytoma cells. From these lncRNAs, 8 lncRNAs were predicted based on functions of target proteins; LINC00221 associated with EMT, LINC01564 and LINC00265 with angiogenesis, and LOC100240735 with cell-migration. Network analysis of lncRNA based on function of target miRNAs predicted LINC00999, ALOX12-AS1, CHKB-AS1, and LINC01588 as regulators of angiogenesis, with LINC00482, LINC00239, and LINC01003 for regulation of EMT. Based on the network analysis, three novel lncRNA-miRNA-mRNA interacting axis from NEAT1, CRNDE, and SNHG1 were predicted to regulate GBM invasion. These findings have allowed prediction of lncRNA as regulators of GBM cell-invasion which can be considered as potential candidates for experimental studies as a GBM prognostic biomarkers.