• brain tumours
• cell‐of‐origin
• epigenetics
• glioblastoma
• interpatient heterogeneity

• Humans
• Glioblastoma/genetics
• Glioblastoma/pathology
• Epigenesis, Genetic
• DNA Methylation/genetics
• Brain Neoplasms/genetics
• Brain Neoplasms/pathology
• MicroRNAs/genetics
• MicroRNAs/metabolism
• RNA, Long Noncoding/genetics
• RNA, Long Noncoding/metabolism
• Gene Expression Regulation, Neoplastic
• Animals
• Chromatin Assembly and Disassembly/genetics

• Brain Tumour Research
• MGU0447 Barts Charity
• C23985/A29199 Cancer Research UK
• Brain Tumour Research
• Barts Charity
• Cancer Research UK

• Glioblastoma
• Glioma
• RNA
• mRNA
• miRNA
• microRNA

• And circRNAs
• Glioblastoma
• LncRNAs
• MiRNAs
• Multidrug resistance

• Humans
• RNA, Long Noncoding/genetics
• RNA, Long Noncoding/metabolism
• Glioblastoma/drug therapy
• Glioblastoma/genetics
• Glioblastoma/pathology
• RNA, Untranslated/genetics
• RNA, Untranslated/metabolism
• MicroRNAs/genetics
• Drug Resistance, Multiple

• cancer treatment
• cellular pathways
• malignant melanoma
• melanoma initiation
• melanoma progression
• microRNAs
• polyphenols
• signaling

IDH (isocitrate dehydrogenase) mutation, hypoxia, and neo-angiogenesis, three hallmarks of diffuse gliomas, modulate the expression of small non-coding RNAs (miRNA). In this paper, we tested whether pro-angiogenic and/or pro-hypoxic miRNAs could be used to monitor patients with glioma. The miRNAs were extracted from tumoral surgical specimens embedded in the paraffin of 97 patients with diffuse gliomas and, for 7 patients, from a blood sample too. The expression of 10 pro-angiogenic and/or pro-hypoxic miRNAs was assayed by qRT-PCR and normalized to the miRNA expression of non-tumoral brain tissues. We confirmed in vitro that IDH in hypoxia (1% O₂, 24 h) alters pro-angiogenic and/or pro-hypoxic miRNA expression in HBT-14 (U-87 MG) cells. Then, we reported that the expression of these miRNAs is (i) strongly affected in patients with glioma compared to that in a non-tumoral brain; (ii) correlated with the histology/grade of glioma according to the 2016 WHO classification; and (iii) predicts the overall and/or progression-free survival of patients with glioma in univariate but not in a multivariate analysis after adjusting for sex, age at diagnosis, and WHO classification. Finally, the expression of miRNAs was found to be the same between the plasma and glial tumor of the same patient. This study highlights a panel of seven pro-angiogenic and/or pro-hypoxic miRNAs as a potential tool for monitoring patients with glioma.

• angiogenesis
• glioma
• hypoxia
• miRNA

Glioblastoma (GBM), a grade IV brain tumor, is known for its heterogenicity and its resistance to the current treatment regimen. Over the last few decades, a significant amount of new molecular and genetic findings has been reported regarding factors contributing to GBM’s development into a lethal phenotype and its overall poor prognosis. MicroRNA (miRNAs) are small non-coding sequences of RNA that regulate and influence the expression of multiple genes. Many research findings have highlighted the importance of miRNAs in facilitating and controlling normal biological functions, including cell differentiation, proliferation, and apoptosis. Furthermore, miRNAs’ ability to initiate and promote cancer development, directly or indirectly, has been shown in many types of cancer. There is a clear association between alteration in miRNAs expression in GBM’s ability to escape apoptosis, proliferation, and resistance to treatment. Further, miRNAs regulate the already altered pathways in GBM, including P53, RB, and PI3K-AKT pathways. Furthermore, miRNAs also contribute to autophagy at multiple stages. In this review, we summarize the functions of miRNAs in GBM pathways linked to dysregulation of cell cycle control, apoptosis and resistance to treatment, and the possible use of miRNAs in clinical settings as treatment and prediction biomarkers.

• EGFR
• MGMT
• P53
• PI3K
• RB
• TMZ
• apoptosis
• autophagy
• exosomal miRNAs

The regulatory roles of long non-coding RNA (lncRNA) CRNDE in temozolomide (TMZ) chemoresistance to glioblastoma multiforme (GBM) are still poorly understood. Therefore, the function, characteristics, and possible mechanism of CRNDE in TMZ-induced chemoresistance to GBM were explored.

Firstly, the expression level of CRNDE in 58 cases of glioma tissue specimens and 30 cases of normal brain tissues were tested by qRT-PCR. Meanwhile, the correlation between CRNDE expression level, the clinicopathological characteristics, and survival time of patients with glioma were analyzed. Then, the CRNDE expression in various glioma cell lines was detected, and CRNDE knockdown cell models were constructed. Subsequently, to explore the effect of CRNDE on chemosensitivity to TMZ, cell viability was detected by the CCK-8 assay and IC₅₀ values, and cell proliferation was detected by cell clone assay and EdU assay, as well as cell survival was detected by apoptosis with flow cytometry under TMZ treatment. Further, the expression of drug-resistance protein ABCG2, autophagy related proteins, and PI3K/Akt/mTOR pathway were measured by western blot or qRT-PCR in TMZ-treated glioma cells. Finally, the mouse tumor xenograft model was established and the tumor volume and weight were measured, and ABCG2 expression was conducted by immunohistochemistry assay.

The integrated results demonstrated lncRNA CRNDE was a poor prognosis factor for GBM patient, which was upregulated in patients who were resistant to TMZ, and closely associated with chemotherapeutic response status to TMZ treatment. Further, functional assays revealed that knockdown of CRNDE could notably reduce glioma cell viability and proliferation, and elevate cell apoptosis to enhance the chemosensitivity to TMZ in vitro and in vivo. Mechanistically, the depression of CRNDE could diminish the expression of LC3 II/I, Beclin1 and Atg5 and increase the p62 expression level to inhibit autophagy due to the activation of PI3K/Akt/mTOR pathway as well as highly correlated with ABCG2 expression.

Overall, the study provided that lncRNA CRNDE is a reliable clinical predictor of outcome and prognosis and a potential biomarker for predicting TMZ treatment response in GBM by modulating the autophagy through PI3K/Akt/mTOR pathway and ABCG2 expression which may be a novel therapeutic target for regulating TMZ sensitivity to GBM.

The online version contains supplementary material available at 10.1186/s12935-021-02153-x.

• Autophagy
• CRNDE
• Chemosensitivity
• Glioblastoma multiforme
• PI3K/Akt/mTOR
• Temozolomide

• apoptosis
• brain tumors
• cell death
• human neural stem cell
• human neural/neural crest cancer stem cell
• melanoma
• miRNA
• neurodegeneration
• stemness
• therapeutic target

• Animals
• Apoptosis
• Cell Differentiation
• Humans
• MicroRNAs/genetics
• Neoplasms/genetics
• Neoplasms/pathology
• Neoplastic Stem Cells/metabolism
• Neoplastic Stem Cells/pathology
• Neural Stem Cells/metabolism
• Neural Stem Cells/pathology

• NA Fondo Integrativo per la Ricerca (FIR), University of Cagliari (Italy)

Germinomas (IG) account for up to 50% of all intracranial germ cell tumours. These tumours are reputed to be more prevalent in Oriental populations in comparison to Western cohorts. Biological characteristics of IG in other ethnic groups are unknown. Singapore is a multi-ethnic country with diverse cultures. Owing to inter-racial heterogeneity, the authors hypothesize there are molecular differences between paediatric IG patients in our local population. The aims of this study are exploratory: firstly, to identify molecular characteristics in this tumour type and circulating CSF unique to different racial cohorts; and next, to corroborate our findings with published literature.

This is a single-institution, retrospective study of prospectively collected data. Inclusion criteria encompass all paediatric patients with histologically confirmed IG. Excess CSF and brain tumour tissues are collected for molecular analysis. Tumour tissues are subjected to a next generation sequencing (NGS) targeted panel for KIT and PDGRA. All CSF samples are profiled via a high-throughput miRNA multiplexed workflow. Results are then corroborated with existing literature and public databases.

In our cohort of 14 patients, there are KIT exon variants in the tumour tissues and CSF miRNAs corroborative with published studies. Separately, there are also KIT exon variants and miRNAs not previously highlighted in IG. A subgroup analysis demonstrates differential CSF miRNAs between Chinese and Malay IG patients.

This is the first in-depth molecular study of a mixed ethnic population of paediatric IGs from a Southeast Asian cohort. Validation studies are required to assess the relevance of novel findings in our study.

The online version contains supplementary material available at 10.1186/s12883-020-01981-0.

• Intracranial germinomas
• KIT
• miRNA

• Adipocyte differentiation-associated long noncoding RNA (ADNCR)
• long noncoding RNAs (lncRNAs)
• miR-204-5p
• transcription factor 3 (TCF3)

• RNA
• children
• glioblastoma multiforme
• glioma
• high grade glioma
• miRNA
• pediatric population

• CR-42-24
• GLUT1
• TUBB4
• fasentin
• homology modeling

MicroRNAs (miRNAs/miRs) are a novel class of gene regulators that may be involved in tumor chemoresistance. Recently, specific miRNA expression profiles have been identified in adult glioblastoma (aGBM), but there are only limited data available on the role of miRNAs in pediatric GBM (pGBM). In the present study, the expression profile of miRNAs was examined in seven pGBMs and three human GBM cell lines (U87MG, A172 and T98G), compared with a non-tumoral pool of pediatric cerebral cortex samples by microarray analysis. A set of differentially expressed miRNAs was identified, including miR-490, miR-876-3p, miR-876-5p, miR-448 and miR-137 (downregulated), as well as miR-501-3p (upregulated). Through bioinformatics analysis, a series of target genes was predicted. In addition, similar gene expression patterns in pGBMs and cell lines was confirmed. Of note, drug resistant T98G cells had upregulated nuclear casein kinase and cyclin-dependent kinase substrate 1 (NUCKS1) expression, a protein overexpressed in many tumors that serves an important role in cell proliferation and progression. On the basis of the present preliminary report, it could be intriguing to further investigate the relationship between each of the identified differentially expressed miRNAs and NUCKS1, in order to clarify their involvement in the multi-drug resistance mechanism of pGBMs.

• gene
• glioblastoma multiforme
• high-grade glioma
• microRNAs
• pediatric brain tumor

Glioblastomas are characterized by amplification of EGFR. Approximately half of tumors with EGFR over-expression also express a constitutively active ligand independent EGFR variant III (EGFRvIII). While current treatments emphasize surgery followed by radiation and chemotherapy with Temozolomide (TMZ), acquired chemoresistance is a universal feature of recurrent GBMs. To mimic the GBM resistant state, we generated an in vitro TMZ resistant model and demonstrated that dichloroacetate (DCA), a metabolic inhibitor of pyruvate dehydrogenase kinase 1 (PDK1), reverses the Warburg effect. Microarray analysis conducted on the TMZ resistant cells with their subsequent treatment with DCA revealed PDK1 as its sole target. DCA treatment also induced mitochondrial membrane potential change and apoptosis as evidenced by JC-1 staining and electron microscopic studies. Computational homology modeling and docking studies confirmed DCA binding to EGFR, EGFRvIII and PDK1 with high affinity. In addition, expression of EGFRvIII was comparable to PDK1 when compared to EGFR in GBM surgical specimens supporting our in silico prediction data. Collectively our current study provides the first in vitro proof of concept that DCA reverses the Warburg effect in the setting of EGFRvIII positivity and TMZ resistance leading to GBM cytotoxicity, implicating cellular tyrosine kinase signaling in cancer cell metabolism.

• DCA
• EGFR
• EGFRvIII
• glioblastoma
• homology modeling

MicroRNAs (miRNA) are believed to play an important role in glioblastoma multiforme (GBM)chemotherapy. Our study aims to investigate potential miRNA biomarkers in GBM. Sixty GBM patients, which were given temozolomide (TMZ) chemotherapy and recurrent radiotherapy, were recruited. miRNA array was performed in cancerous and in paired normal tissues. Microarray results were further validated by a quantitative real-time PCR in selected tissues and GBM cell lines. TMZ resistance cells were developed and cell proliferation along with colony formation assays was determined. Our study employed H2AX formation and flow cytometry to analyse the role of miRNA in DNA damage and apoptosis. Our study illustrated 16 miRNA in which 9 were up-regulated and 7 down-regulated. and their differential expression were demonstrated in a recurrent GBM tissue. Among them, miRNA-370-3p demonstrated the highest level of down- regulation in tissues and in TMZ resistance cells. miRNA-370-3p mimic increased its expression and sensitivity of GBM cells to TMZ by suppressing the self-reparative ability of tumour cell DNA. O⁶-methylguanine-DNA methyltransferase (MGMT) was identified as the direct target gene of miR-370-3p, and it was found to be inversely correlated with miR-370-3p expression in tissue samples obtained. Thus, our study demonstrated a critical clinical role of an up-regulated miR-370-3p expression in glioblastoma multiforme chemotherapy sensitivity.

This overview seeked to bring together the microRNA (miRNA) researches on biogenesis and bio-function in these areas of clinical diagnosis and therapy for malignant glioma.

Using the keyword terms “glioma” and “miRNA,” we performed the literature search in PubMed, Ovid, and web.metstr.com databases from their inception to October 2014.

In screening out the quality of the articles, factors such as clinical setting of the study, the size of clinical samples were taken into consideration. Animal studied for verification and reviews article were also included in our data collection.

Despite many advance in miRNA for malignant glioma, further studies were still required to focus on the following aspects: (i) Improving the understanding about biogenesis of miRNA and up-down regulation; (ii) utilizing high-throughput miRNA expression analysis to screen out the core miRNA for glioma; (iii) Focusing related miRNAs on the signal transduction pathways that regulate the proliferation and growth of glioma.

We discussed the most promising miRNA, correlative signaling pathway and their relation with gliomas in the way of prompting miRNA target into being a clinical therapeutic strategy.

Glioblastoma multiforme (GBM), designated as World Health Organization (WHO) grade IV astrocytoma, is a lethal and therapy-resistant brain cancer comprised of several tumor cell subpopulations, including GBM stem cells (GSCs) which are believed to contribute to tumor recurrence following initial response to therapies. Emerging evidence demonstrates that GBM tumors are initiated from GSCs. The development and use of novel therapies including small molecule inhibitors of specific proteins in signaling pathways that regulate stemness, proliferation and migration of GSCs, immunotherapy, and non-coding microRNAs may provide better means of treating GBM. Identification and characterization of GSC-specific signaling pathways would be necessary to identify specific therapeutic targets which may lead to the development of more efficient therapies selectively targeting GSCs. Several signaling pathways including mTOR, AKT, maternal embryonic leucine zipper kinase (MELK), NOTCH1 and Wnt/β-catenin as well as expression of cancer stem cell markers CD133, CD44, Oct4, Sox2, Nanog, and ALDH1A1 maintain GSC properties. Moreover, the data published in the Cancer Genome Atlas (TCGA) specifically demonstrated the activated PI3K/AKT/mTOR pathway in GBM tumorigenesis. Studying such pathways may help to understand GSC biology and lead to the development of potential therapeutic interventions to render them more sensitive to chemotherapy and radiation therapy. Furthemore, recent demonstration of dedifferentiation of GBM cell lines into CSC-like cells prove that any successful therapeutic agent or combination of drugs for GBM therapy must eliminate not only GSCs, but the differentiated GBM cells and the entire bulk of tumor cells.

• ALDH1A1
• CD133
• CD44
• SOX2
• dedifferentiation
• glioblastoma multiforme
• stem cells

• Astrocytomas
• Grades
• MiR-128
• TROVE2
• mRNA

• Cancer stem cells
• Dedifferentiation
• Epigenetic
• GBM plasticity
• GBM stem cells
• Glioblastoma
• Stemness

• R01 CA138798 NCI NIH HHS

• Brain tumor
• Glioma
• Medulloblastoma
• Neural stem cell
• Progenitor
• Reprogramming
• miRNA

• Animals
• Cell Differentiation/physiology
• Cell Lineage
• Cell Transformation, Neoplastic/genetics
• Humans
• Neural Stem Cells/cytology
• Signal Transduction/physiology
• Stem Cells/cytology

• U54 CA163155 NCI NIH HHS
• U54CA163155-01 NCI NIH HHS
• K08 NS063456 NINDS NIH HHS
• K08NS063456 NINDS NIH HHS
• R01 NS081117 NINDS NIH HHS
• 1R01 NS081117-01 NINDS NIH HHS

• Glioblastoma
• Mesenchymal stem cells
• Neural stem cells
• Therapy

•

miR-34a was decreased in both glioma and glioma stem cell-lines as compared to normal brain tissues.

MiRNA-34a is considered as a potential prognostic marker for glioma, as studies suggest that its expression negatively correlates with patient survival in grade III and IV glial tumors. Here, we show that expression of miR-34a was decreased in a graded manner in glioma and glioma stem cell-lines as compared to normal brain tissues. Ectopic expression of miR-34a in glioma stem cell-lines HNGC-2 and NSG-K16 decreased the proliferative and migratory potential of these cells, induced cell cycle arrest and caused apoptosis. Notably, the miR-34a glioma cells formed significantly smaller xenografts in immuno-deficient mice as compared with control glioma stem cell-lines. Here, using a bioinformatics approach and various biological assays, we identify Rictor, as a novel target for miR-34a in glioma stem cells. Rictor, a defining component of mTORC2 complex, is involved in cell survival signaling. mTORC2 lays downstream of Akt, and thus is a direct activator of Akt. Our earlier studies have elaborated on role of Rictor in glioma invasion (Das et al., 2011). Here, we demonstrate that miR34a over-expression in glioma stem cells profoundly decreased levels of p-AKT (Ser473), increased GSK-3β levels and targeted for degradation β-catenin, an important mediator of Wnt signaling pathway. This led to diminished levels of the Wnt effectors cyclin D1 and c-myc. Collectively, we show that the tumor suppressive function of miR-34a in glioblastoma is mediated via Rictor, which through its effects on AKT/mTOR pathway and Wnt signaling causes pronounced effects on glioma malignancy.

• Beta-catenin
• CNS, central nervous system
• EGF, epidermal growth factor
• EMT, epithelial–mesenchymal transition
• EV, empty vector
• GBM, glioblastoma multiforme
• GIC, glioma initiating cell
• GSC, glioma stem cell
• GSK-3β, glycogen synthase kinase 3β
• Glioblastoma
• Heterogeneity
• Mesenchymal
• NOD/SCID, nonobese diabetic/severe combined immunodeficiency
• PARP, poly ADP-ribose polymerases
• PDGFRA, platelet-derived growth factor receptor-α
• Rictor
• TCGA, the cancer genome atlas database
• bFGF, basic fibroblast growth factor
• qRT-PCR, quantitative real time PCR

Glioblastoma Multiforme (GBM) is a grade IV astrocytoma, with a median survival of 14.6 mo. Within GBM, stem-like cells, namely glioblastoma stem cells (GSCs), have the ability to self-renew, differentiate into distinct lineages within the tumor and initiate tumor xenografts in immunocompromised animal models. More importantly, GSCs utilize cell-autonomous and tumor microenvironment-mediated mechanisms to overcome current therapeutic approaches. They are, therefore, very important therapeutic targets. Although the functional criteria defining GSCs are well defined, their molecular characteristics, the mechanisms whereby they establish the cellular hierarchy within tumors, and their contribution to tumor heterogeneity are not well understood. This review is aimed at summarizing current findings about GSCs and their therapeutic importance from a molecular and cellular point of view. A better characterization of GSCs is crucial for designing effective GSC-targeted therapies.

• Glioblastoma
• Glioblastoma stem cells
• Self-renewal
• Differentiation
• Molecular markers
• Therapy resistance

• P30 CA016087 NCI NIH HHS
• R21 NS087241 NINDS NIH HHS
• T32 GM007308 NIGMS NIH HHS
• UL1 TR000038 NCATS NIH HHS

• Apoptosis/genetics
• Blotting, Western
• Brain Neoplasms/genetics
• Brain Neoplasms/pathology
• Cell Differentiation/genetics
• Cell Movement/genetics
• Cell Proliferation
• Cell Transformation, Neoplastic/genetics
• Cell Transformation, Neoplastic/pathology
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Gene Regulatory Networks
• Genetic Predisposition to Disease/genetics
• Genome-Wide Association Study
• Glioblastoma/genetics
• Glioblastoma/pathology
• Humans
• MicroRNAs/genetics
• Models, Genetic
• Neoplasm Proteins/genetics
• Neoplasm Proteins/metabolism
• Neurogenesis/genetics
• Neurons/metabolism
• Neurons/pathology
• Oligonucleotide Array Sequence Analysis
• Reverse Transcriptase Polymerase Chain Reaction

• R01 HG006015 NHGRI NIH HHS
• KL2 TR001118 NCATS NIH HHS
• HHSN261200800001C NCI NIH HHS
• Intramural NIH HHS
• P30 CA016058 NCI NIH HHS
• UL1 TR001120 NCATS NIH HHS
• HHSN261200800001E NCI NIH HHS
• HG006015 NHGRI NIH HHS
• UL1 TR000149 NCATS NIH HHS

• Chemoresistance
• Gliomas
• MicroRNA
• Temozolomide

• Epigenetics
• Glioma stem cells
• Hypoxia
• Microenvironment
• Therapeutic resistance

• Brain Neoplasms/diagnosis
• Brain Neoplasms/metabolism
• Brain Neoplasms/therapy
• Glioma/diagnosis
• Glioma/genetics
• Glioma/therapy
• Humans
• MicroRNAs/genetics
• MicroRNAs/metabolism

• Animals
• Brain Neoplasms/drug therapy
• Brain Neoplasms/genetics
• Brain Neoplasms/radiotherapy
• Brain Neoplasms/therapy
• Cell Line, Tumor
• Drug Resistance, Neoplasm/genetics
• Gene Expression Regulation, Neoplastic/drug effects
• Gene Expression Regulation, Neoplastic/radiation effects
• Humans
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Molecular Targeted Therapy/methods
• Radiation Tolerance/genetics