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.

Background: The multiple drug-resistant phenomenon has long since plagued the effectiveness of various chemotherapies used in the treatment of patients with glioblastoma (GBM), which is still incurable to this day. ATP-binding cassette (ABC) transporters function as drug transporters and have been touted to be the main culprits in developing resistance to xenobiotic drugs in GBM. Methods: This review systematically analyzed the efficacy of ABC transporters against various anticancer drugs from 16 studies identified from five databases (PubMed, Medline, Embase, Scopus, and ScienceDirect). Results: Inhibition of ABC transporters, especially ABCB1, improved drug efficacies. Staple GBM phenotypes, such as GBM stem cells and increased activation of the PI3K/Akt/NF-κB pathway, have been implicated in the expression of several ABC transporters. Using the datasets in The Cancer Genome Atlas and Gene Expression Omnibus, we found upregulated ABC transporters that either negatively impacted survival in univariate analyses (ABCA1, ABCA13, ABCB9, ABCD4) or were independent negative prognosis factors for patients with GBM (ABCA13, ABCB9). Our multivariate analysis further demonstrated three ABC transporters, ABCA13 (Hazard Ratio (HR) = 1.31, p = 0.017), ABCB9 (HR = 1.26, p = 0.03), and ABCB5 (HR = 0.77, p = 0.016), with the administration of alkylating agents (HR = 0.41, p < 0.001), were independent negative prognosis factors for patients with GBM. Conclusions: These findings reinforce the important role played by ABC transporters, particularly by ABCA13, ABCB9, and ABCB1, which could be potential targets that warrant further evaluations for alternate strategies to augment the effects of existing alkylating agents and xenobiotic drugs.

Glioblastoma (GBM), a highly lethal form of adult malignant gliomas with little clinical advancement, raises the need for alternative therapeutic approaches. Lipid-soluble vitamins have gained attention in malignant brain tumors owing to their pleiotropic properties and their anti-cancer potential have been reported in a number of human GBM cell lines. The aim of this paper is to systematically review and describe the roles of various biomarkers regulated by lipid-soluble vitamins, such as vitamins A, D, E, and K, in the pathophysiology of GBM. Briefly, research articles published between 2005 and 2021 were systematically searched and selected from five databases (Scopus, PubMed, Ovid MEDLINE, EMBASE via Ovid, and Web of Science) based on the study’s inclusion and exclusion criteria. In addition, a number of hand-searched research articles identified from Google Scholar were also included for the analysis. A total of 40 differentially expressed biomarkers were identified from the 19 eligible studies. The results from the analysis suggest that retinoids activate cell differentiation and suppress the biomarkers responsible for stemness in human GBM cells. Vitamin D appears to preferentially modulate several cell cycle biomarkers, while vitamin E derivatives seem to predominantly modulate biomarkers related to apoptosis. However, vitamin K1 did not appear to induce any significant changes to the Raf/MEK/ERK signaling or apoptotic pathways in human GBM cell lines. From the systematic analysis, 12 biomarkers were identified that may be of interest for further studies, as these were modulated by one or two of these lipid-soluble vitamins.

A paradigm shift in preclinical evaluations of new anticancer GBM drugs should occur in favour of 3D cultures. This study leveraged the vast genomic data banks to investigate the suitability of 3D cultures as cell-based models for GBM. We hypothesised that correlating genes that are highly upregulated in 3D GBM models will have an impact in GBM patients, which will support 3D cultures as more reliable preclinical models for GBM. Using clinical samples of brain tissue from healthy individuals and GBM patients from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), Chinese Glioma Genome Atlas (CGGA), and Genotype-Tissue Expression (GTEx) databases, several genes related to pathways such as epithelial-to-mesenchymal transition (EMT)-related genes (CD44, TWIST1, SNAI1, CDH2, FN1, VIM), angiogenesis/migration-related genes (MMP1, MMP2, MMP9, VEGFA), hypoxia-related genes (HIF1A, PLAT), stemness-related genes (SOX2, PROM1, NES, FOS), and genes involved in the Wnt signalling pathway (DKK1, FZD7) were found to be upregulated in brain samples from GBM patients, and the expression of these genes were also enhanced in 3D GBM cells. Additionally, EMT-related genes were upregulated in GBM archetypes (wild-type IDH1^R132 ) that historically have poorer treatment responses, with said genes being significant predictors of poorer survival in the TCGA cohort. These findings reinforced the hypothesis that 3D GBM cultures can be used as reliable models to study increased epithelial-to-mesenchymal transitions in clinical GBM samples.