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microRNAs (miRNAs) play an important role in the pathology of glioblastoma (GBM), which is the most malignant and most common primary malignant brain tumor. miRNAs can target multiple genes simultaneously and are considered as potential therapeutic agents or targets. This study aimed to determine the role of miR-3174 in the pathobiology of GBM using both in vitro and in vivo approaches. This is the first study deciphering the role of miR-3174 in GBM. We studied the expression of miR-3174 and found it to be downregulated in a panel of GBM cell lines, GSCs and tissues relative to astrocytes and normal brain tissue. This finding led us to hypothesize that miR-3174 has a tumor-suppressive role in GBM. Exogenous expression of miR-3174 inhibited GBM cell growth and invasion, and hampered the neurosphere formation ability of GSCs. miR-3174 downregulated the expression of multiple tumor-promoting genes including CD44, MDM2, RHOA, PLAU and CDK6. Further, overexpression of miR-3174 reduced tumor volume in nude mice with intracranial xenografts. Immuno-histochemical study of brain sections with intracranial tumor xenografts revealed the pro-apoptotic and anti-proliferative activity of miR-3174. In conclusion, we demonstrated that miR-3174 has a tumor-suppressive role in GBM and could be exploited for therapeutic purposes. [ABSTRACT FROM AUTHOR]

Transcribed ultraconserved regions are putative lncRNA molecules that are transcribed from DNA that is 100% conserved in human, mouse, and rat genomes. This is notable, as lncRNAs are typically poorly conserved. TUCRs remain very understudied in many diseases, including cancer. In this review, we summarize the current literature on TUCRs in cancer with respect to expression deregulation, functional roles, mechanisms of action, and clinical perspectives. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most frequent and lethal primary malignant brain tumor. Despite decades of research, therapeutic advances that significantly prolong life are non-existent. In recent years, microRNAs (miRNAs) have been a focus of study in the pathobiology of cancer because of their ability to simultaneously regulate multiple genes. The aim of this study was to determine the functional and mechanistic effects of miR-3928 in GBM both in vitro and in vivo. To the best of our knowledge, this is the first article investigating the role of miR-3928 in GBM. We measured endogenous miR-3928 expression levels in a panel of patient-derived GBM tissue samples and cell lines. We found that GBM tissue samples and cell lines express lower levels of miR-3928 than normal brain cortex and astrocytes, respectively. Therefore, we hypothesized that miR-3928 is a tumor suppressive microRNA. We verified this hypothesis by showing that exogenous expression of miR-3928 has a strong inhibitory effect on both cell growth and invasiveness of GBM cells. Stable ex vivo overexpression of miR-3928 in GBM cells led to a reduction in tumor size in nude mice xenografts. We identified many targets (MDM2, CD44, DDX3X, HMGA2, CCND1, BRAF, ATOH8, and BMI1) of miR-3928. Interestingly, inhibition of the oncogene MDM2 also led to an upregulation of wild-type p53 expression and phosphorylation. In conclusion, we find that miR-3928, through the downregulation of several oncogenes and upregulation and activation of wild-type p53, is a strong tumor suppressor in GBM. Furthermore, the fact that miR-3928 can target many important dysregulated proteins in GBM suggests it might be a "master" regulatory microRNA that could be therapeutically exploited. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is a lethal brain tumor with dismal prognosis. Current therapeutic options, consisting of surgery, chemotherapy and radiation, have only served to marginally increase patient survival. Receptor tyrosine kinases (RTKs) are dysregulated in approximately 90% of GBM; attributed to this, research has focused on inhibiting RTKs as a novel and effective therapy for GBM. Overexpression of RTK mesenchymal epithelial transition (MET), and its ligand, hepatocyte growth factor (HGF), in GBM highlights a promising new therapeutic target. This review will discuss the role of MET in cell cycle regulation, cell proliferation, evasion of apoptosis, cell migration and invasion, angiogenesis and therapeutic resistance in GBM. It will also discuss the modes of deregulation of HGF/MET and their regulation by microRNAs. As the HGF/MET pathway is a vital regulator of multiple pro-survival pathways, efforts and strategies for its exploitation for GBM therapy are also described. [ABSTRACT FROM AUTHOR]

Simple Summary: Ependymomas are the second most common paediatric brain tumour, and the 5-year survival rate remains no higher than 50%. Identifying new prognostic markers and targets for therapy in ependymoma is an important area of research. In this study, we demonstrate that brain lipid binding protein (BLBP, FABP7) is expressed in a sub-population of cells in ependymoma patient samples, consistent with it being a cancer stem cell marker. BLBP expression was associated with both significantly reduced event free survival and overall survival. BLBP can be functionally inhibited by PPAR antagonists, and we demonstrated that these antagonists can reduce ependymoma cell migration, invasion and chemo-resistance. The BLBP ligand docosohexanoic acid also attenuated these three hallmark characteristics of ependymomas, leading us to conclude that BLBP is not just a prognostic marker for poor ependymoma survival, but that it represents a druggable target in ependymoma therapy. Paediatric ependymomas are aggressive, treatment-resistant tumours with a tendency towards relapse, consistent with a sub-population of therapy-resistant cancer stem cells. These cells are believed to derive from brain lipid binding protein (BLBP)-expressing radial glia, hence we proposed that BLBP may be a marker for ependymoma therapy resistance. BLBP protein expression correlated with reduced overall survival (OS) in patients from two trials (CNS9204, a chemotherapy-led infant trial—5 y OS 45% vs. 80%, p = 0.011—and CNS9904, a radiotherapy-led trial—OS 38% vs. 85%, p = 0.002). All ependymoma cell lines examined by qRT-PCR expressed BLBP, with expression elevated in stem cell-enriched neurospheres. Modulation of BLBP function in 2D and 3D assays, using either peroxisome proliferator activated receptor (PPAR) antagonists or BLBP's fatty acid substrate docosahexaneoic acid (DHA), potentiated chemotherapy response and reduced cell migration and invasion in ependymoma cell lines. BLBP is therefore an independent predictor of poor survival in paediatric ependymoma, and treatment with PPAR antagonists or DHA may represent effective novel therapies, preventing chemotherapy resistance and invasion in paediatric ependymoma patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Since the completion of the Human Genome Project, noncoding RNAs (ncRNAs) have emerged as an important class of genetic regulators. Several classes of ncRNAs, which include microRNAs (miRNAs), long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), and piwi-interacting RNAs (piRNAs), have been shown to play important roles in controlling developmental and disease processes. In this article, we discuss the potential roles of ncRNAs in regulating glioblastoma (GBM) formation and progression as well as potential strategies to exploit the diagnostic and therapeutic potential of ncRNAs in GBM. Noncoding RNAs (ncRNAs) have emerged as a novel class of genomic regulators, ushering in a new era in molecular biology. With the advent of advanced genetic sequencing technology, several different classes of ncRNAs have been uncovered, including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), and piwi-interacting RNAs (piRNAs), which have been linked to many important developmental and disease processes and are being pursued as clinical and therapeutic targets. Molecular phenotyping studies of glioblastoma (GBM), the most common and lethal cancer of the adult brain, revealed that several ncRNAs are frequently dysregulated in its pathogenesis. Additionally, ncRNAs regulate many important aspects of glioma biology including tumour cell proliferation, migration, invasion, apoptosis, angiogenesis, and self-renewal. Here, we present an overview of the biogenesis of the different classes of ncRNAs, discuss their biological roles, as well as their relevance to gliomagenesis. We conclude by discussing potential approaches to therapeutically target the ncRNAs in clinic. [ABSTRACT FROM AUTHOR]

Hepatocyte growth factor (HGF) ligand and its receptor tyrosine kinase (RTK) mesenchymal-epithelial transition factor (MET) are important regulators of cellular processes such as proliferation, motility, angiogenesis, and tissue regeneration. In healthy adult somatic cells, this ligand and receptor pair is expressed at low levels and has little activity except when tissue injuries arise. In cancer cells, HGF/MET are often overexpressed, and this overexpression is found to correlate with tumorigenesis, metastasis, and poorer overall prognosis. This review focuses on the signaling of these molecules in the context of malignant brain tumors. RTK signaling pathways are among the most common and universally dysregulated pathways in gliomas. We focus on the role of HGF/MET in the following primary malignant brain tumors: astrocytomas, glioblastomas, oligodendrogliomas, ependymomas, and embryonal central nervous system tumors (including medulloblastomas and others). Brain metastasis, as well as current advances in targeted therapies, are also discussed. [ABSTRACT FROM AUTHOR]

The tumor suppressor and transcription factor p53 plays critical roles in tumor prevention by orchestrating a wide variety of cellular responses, including damaged cell apoptosis, maintenance of genomic stability, inhibition of angiogenesis, and regulation of cell metabolism and tumor microenvironment. TP53 is one of the most commonly deregulated genes in cancer. The p53-ARF-MDM2 pathway is deregulated in 84% of glioblastoma (GBM) patients and 94% of GBM cell lines. Deregulated p53 pathway components have been implicated in GBM cell invasion, migration, proliferation, evasion of apoptosis, and cancer cell stemness. These pathway components are also regulated by various microRNAs and long non-coding RNAs. TP53 mutations in GBM are mostly point mutations that lead to a high expression of a gain of function (GOF) oncogenic variants of the p53 protein. These relatively understudied GOF p53 mutants promote GBM malignancy, possibly by acting as transcription factors on a set of genes other than those regulated by wild type p53. Their expression correlates with worse prognosis, highlighting their potential importance as markers and targets for GBM therapy. Understanding mutant p53 functions led to the development of novel approaches to restore p53 activity or promote mutant p53 degradation for future GBM therapies. [ABSTRACT FROM AUTHOR]