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The Plentiful Roles of RNA in Glioblastoma

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 May 2020) | Viewed by 30510

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Special Issue Editors

Dr. Silvia Anna Ciafrè

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Guest Editor

Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier, 1, 00133 Rome, Italy
Interests: glioblastoma; prostate carcinoma; microRNAs; lncRNAs; RNA-binding proteins; splicing; post-transcriptional regulation

Dr. Silvia Galardi

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Co-Guest Editor

Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy
Interests: glioblastoma; prostate carcinoma; microRNAs; lncRNAs; RNA-binding proteins; splicing; post-transcriptional regulation

Dr. Alessandro Michienzi

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Co-Guest Editor

Dept. of Biomedicine and Prevention University of Rome Tor Vergata, Rome, Italy
Interests: RNA editing; transposable elements; post-transcriptional regulation; HIV-infection; RNA modifications

Special Issue Information

Dear Colleagues,

The scientific community working on cancer is sadly aware that glioblastoma is one of the most lethal human cancers and the deadliest among brain tumors, leading to patient death in less than 15 months from diagnosis, on average. There is a huge ongoing effort to unravel the deadly complexity of this neoplasm, in order to find a rationale for therapeutic approaches that differ from the present standard of care, which comprises surgical resection followed by radiotherapy and chemotherapy with temozolomide, and has been unsuccessful in curing patients.

One of the main scientific achievements in the last two decades is recognition of the extraordinarily wide role of noncoding RNAs in the regulation of gene expression and, as a consequence, as possible targets or tools for therapy. The aim of this Special Issue is to gather studies in which RNA (both coding and noncoding), in its many diverse functions, is recognized as a key factor in the development of glioblastoma. Thus, this Special Issue welcomes studies describing coding and noncoding RNA molecules which can impact glioblastoma if mutated or aberrantly expressed, with a particular interest in studies describing the mechanisms underlying the observations. Moreover, studies about processing and post-transcriptional modifications of RNAs, including alternative splicing and polyadenylation, or editing and methylation, and the RNA-binding proteins involved in these processes are of particular interest.

Dr. Silvia Anna Ciafrè
Dr. Silvia Galardi
Dr. Alessandro Michienzi
Guest Editor

Manuscript Submission Information

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Keywords

glioblastoma
glioblastoma stem cells
microRNAs
long noncoding RNAs
RNA processing
splicing
polyadenylation
RNA-binding proteins
RNA editing
RNA methylation
post-transcriptional regulation

Published Papers (7 papers)

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Research

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22 pages, 2953 KiB

Open AccessArticle

Analysis of miR-9-5p, miR-124-3p, miR-21-5p, miR-138-5p, and miR-1-3p in Glioblastoma Cell Lines and Extracellular Vesicles

by Alja Zottel, Neja Šamec, Ana Kump, Lucija Raspor Raspor Dall’Olio, Pia Pužar Dominkuš, Rok Romih, Samo Hudoklin, Jernej Mlakar, Daniil Nikitin, Maxim Sorokin, Anton Buzdin, Ivana Jovčevska and Radovan Komel

Int. J. Mol. Sci. 2020, 21(22), 8491; https://doi.org/10.3390/ijms21228491 - 11 Nov 2020

Cited by 27 | Viewed by 3548

Abstract

Glioblastoma (GBM), the most common primary brain tumor, is a complex and extremely aggressive disease. Despite recent advances in molecular biology, there is a lack of biomarkers, which would improve GBM’s diagnosis, prognosis, and therapy. Here, we analyzed by qPCR the expression levels of a set of miRNAs in GBM and lower-grade glioma human tissue samples and performed a survival analysis in silico. We then determined the expression of same miRNAs and their selected target mRNAs in small extracellular vesicles (sEVs) of GBM cell lines. We showed that the expression of miR-21-5p was significantly increased in GBM tissue compared to lower-grade glioma and reference brain tissue, while miR-124-3p and miR-138-5p were overexpressed in reference brain tissue compared to GBM. We also demonstrated that miR-9-5p and miR-124-3p were overexpressed in the sEVs of GBM stem cell lines (NCH421k or NCH644, respectively) compared to the sEVs of all other GBM cell lines and astrocytes. VIM mRNA, a target of miR-124-3p and miR-138-5p, was overexpressed in the sEVs of U251 and U87 GBM cell lines compared to the sEVs of GBM stem cell line and also astrocytes. Our results suggest VIM mRNA, miR-9-5p miRNA, and miR-124-3p miRNA could serve as biomarkers of the sEVs of GBM cells. Full article

(This article belongs to the Special Issue The Plentiful Roles of RNA in Glioblastoma)

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22 pages, 4941 KiB

Open AccessArticle

Deep Sequencing of Small RNAs from Neurosurgical Extracellular Vesicles Substantiates miR-486-3p as a Circulating Biomarker that Distinguishes Glioblastoma from Lower-Grade Astrocytoma Patients

by Susannah Hallal, Saeideh Ebrahim Khani, Heng Wei, Maggie Yuk Ting Lee, Hao-Wen Sim, Joanne Sy, Brindha Shivalingam, Michael E. Buckland and Kimberley L. Alexander-Kaufman

Int. J. Mol. Sci. 2020, 21(14), 4954; https://doi.org/10.3390/ijms21144954 - 13 Jul 2020

Cited by 27 | Viewed by 3151

Abstract

Extracellular vesicles (EVs) play key roles in glioblastoma (GBM; astrocytoma grade IV) biology and are novel sources of biomarkers. EVs released from GBM tumors can cross the blood-brain-barrier into the periphery carrying GBM molecules, including small non-coding RNA (sncRNA). Biomarkers cargoed in circulating EVs have shown great promise for assessing the molecular state of brain tumors in situ. Neurosurgical aspirate fluids captured during tumor resections are a rich source of GBM-EVs isolated directly from tumor microenvironments. Using density gradient ultracentrifugation, EVs were purified from cavitron ultrasonic surgical aspirate (CUSA) washings from GBM (n = 12) and astrocytoma II-III (GII-III, n = 5) surgeries. The sncRNA contents of surgically captured EVs were profiled using the Illumina^® NextSeq^TM 500 NGS System. Differential expression analysis identified 27 miRNA and 10 piRNA species in GBM relative to GII-III CUSA-EVs. Resolved CUSA-EV sncRNAs could discriminate serum-EV sncRNA profiles from GBM and GII-III patients and healthy controls and 14 miRNAs (including miR-486-3p and miR-106b-3p) and cancer-associated piRNAs (piR_016658, _016659, _020829 and _204090) were also significantly expressed in serum-EVs. Circulating EV markers that correlate with histological, neuroradiographic and clinical parameters will provide objective measures of tumor activity and improve the accuracy of GBM tumor surveillance. Full article

(This article belongs to the Special Issue The Plentiful Roles of RNA in Glioblastoma)

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21 pages, 2137 KiB

Open AccessArticle

Mir-370-3p Impairs Glioblastoma Stem-Like Cell Malignancy Regulating a Complex Interplay between HMGA2/HIF1A and the Oncogenic Long Non-Coding RNA (lncRNA) NEAT1

by Valentina Lulli, Mariachiara Buccarelli, Ramona Ilari, Giorgia Castellani, Chiara De Dominicis, Alessandra Di Giamberardino, Quintino Giorgio D′Alessandris, Stefano Giannetti, Maurizio Martini, Vittorio Stumpo, Alessandra Boe, Gabriele De Luca, Mauro Biffoni, Giovanna Marziali, Roberto Pallini and Lucia Ricci-Vitiani

Int. J. Mol. Sci. 2020, 21(10), 3610; https://doi.org/10.3390/ijms21103610 - 20 May 2020

Cited by 28 | Viewed by 3287

Abstract

Glioblastoma (GBM) is the most aggressive and prevalent form of a human brain tumor in adults. Several data have demonstrated the implication of microRNAs (miRNAs) in tumorigenicity of GBM stem-like cells (GSCs). The regulatory functions of miRNAs in GSCs have emerged as potential therapeutic candidates for glioma treatment. The current study aimed at investigating the function of miR-370-3p in glioma progression, as aberrant expression of miR-370-3p, is involved in various human cancers, including glioma. Analyzing our collection of GBM samples and patient-derived GSC lines, we found the expression of miR-370-3p significantly downregulated compared to normal brain tissues and normal neural stem cells. Restoration of miR-370-3p expression in GSCs significantly decreased proliferation, migration, and clonogenic abilities of GSCs, in vitro, and tumor growth in vivo. Gene expression analysis performed on miR-370-3p transduced GSCs, identified several transcripts involved in Epithelial to Mesenchymal Transition (EMT), and Hypoxia signaling pathways. Among the genes downregulated by the restored expression of miR-370-3p, we found the EMT-inducer high-mobility group AT-hook 2 (HMGA2), the master transcriptional regulator of the adaptive response to hypoxia, Hypoxia-inducible factor (HIF)1A, and the long non-coding RNAs (lncRNAs) Nuclear Enriched Abundant Transcript (NEAT)1. NEAT1 acts as an oncogene in a series of human cancers including gliomas, where it is regulated by the Epidermal Growth Factor Receptor (EGFR) pathways, and contributes to tumor growth and invasion. Noteworthy, the expression levels of miR-370-3p and NEAT1 were inversely related in both GBM tumor specimens and GSCs, and a dual-luciferase reporter assay proved the direct binding between miR-370-3p and the lncRNAs NEAT1. Our results identify a critical role of miR-370-3p in the regulation of GBM development, indicating that miR-370-3p acts as a tumor-suppressor factor inhibiting glioma cell growth, migration and invasion by targeting the lncRNAs NEAT1, HMGA2, and HIF1A, thus, providing a potential candidate for GBM patient treatment. Full article

(This article belongs to the Special Issue The Plentiful Roles of RNA in Glioblastoma)

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Review

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29 pages, 1043 KiB

Open AccessReview

Recent Trends of microRNA Significance in Pediatric Population Glioblastoma and Current Knowledge of Micro RNA Function in Glioblastoma Multiforme

by Marek Mazurek, Cezary Grochowski, Jakub Litak, Ida Osuchowska, Ryszard Maciejewski and Piotr Kamieniak

Int. J. Mol. Sci. 2020, 21(9), 3046; https://doi.org/10.3390/ijms21093046 - 27 Apr 2020

Cited by 17 | Viewed by 3864

Abstract

Central nervous system tumors are a significant problem for modern medicine because of their location. The explanation of the importance of microRNA (miRNA) in the development of cancerous changes plays an important role in this respect. The first papers describing the presence of miRNA were published in the 1990s. The role of miRNA has been pointed out in many medical conditions such as kidney disease, diabetes, neurodegenerative disorder, arthritis and cancer. There are several miRNAs responsible for invasiveness, apoptosis, resistance to treatment, angiogenesis, proliferation and immunology, and many others. The research conducted in recent years analyzing this group of tumors has shown the important role of miRNA in the course of gliomagenesis. These particles seem to participate in many stages of the development of cancer processes, such as proliferation, angiogenesis, regulation of apoptosis or cell resistance to cytostatics. Full article

(This article belongs to the Special Issue The Plentiful Roles of RNA in Glioblastoma)

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16 pages, 313 KiB

Open AccessReview

Insights into the Regulatory Role of m⁶A Epitranscriptome in Glioblastoma

by Silvia Galardi, Alessandro Michienzi and Silvia Anna Ciafrè

Int. J. Mol. Sci. 2020, 21(8), 2816; https://doi.org/10.3390/ijms21082816 - 17 Apr 2020

Cited by 31 | Viewed by 5209

Abstract

N⁶-methyladenosine (m⁶A) is one of the most widespread and abundant internal messenger RNA modifications found in eukaryotes. Emerging evidence suggests that this modification is strongly linked to the activation and inhibition of cancer pathways and is associated with prognostically significant tumour subtypes. The present review describes the dynamic nature of m⁶A regulator enzymes, as methyltransferases, demethylases and m⁶A binding proteins, and points out thevalue of the balance among these proteins in regulating gene expression, cell metabolism and cancer development. The main focus of this review is on the roles of m⁶A modification in glioblastoma, the most aggressive and invariably lethal brain tumour. Although the study of m⁶A in glioblastoma is a young one, and papers in this field can yield divergent conclusions, the results collected so far clearly demonstrate that modulation of mRNA m⁶A levels impacts multiple aspects of this tumour, including growth, glioma stem cells self-renewal, and tumorigenesis, suggesting that mRNA m⁶A modification may serve as a promising target for glioblastoma therapy. We also present recent data about another type of epitranscriptomic modification, the methylation of cytosine at a specific site of 28S rRNA, as it was recently shown to affect the biology of glioma cells, with high potential of clinical implications. Full article

(This article belongs to the Special Issue The Plentiful Roles of RNA in Glioblastoma)

27 pages, 762 KiB

Open AccessReview

Emerging Roles and Potential Applications of Non-Coding RNAs in Glioblastoma

by Carlos DeOcesano-Pereira, Raquel A. C. Machado, Ana Marisa Chudzinski-Tavassi and Mari Cleide Sogayar

Int. J. Mol. Sci. 2020, 21(7), 2611; https://doi.org/10.3390/ijms21072611 - 9 Apr 2020

Cited by 16 | Viewed by 3873

Abstract

Non-coding RNAs (ncRNAs) comprise a diversity of RNA species, which do not have the potential to encode proteins. Non-coding RNAs include two classes of RNAs, namely: short regulatory ncRNAs and long non-coding RNAs (lncRNAs). The short regulatory RNAs, containing up to 200 nucleotides, include small RNAs, such as microRNAs (miRNA), short interfering RNAs (siRNAs), piwi-interacting RNAs (piRNAs), and small nucleolar RNAs (snoRNAs). The lncRNAs include long antisense RNAs and long intergenic RNAs (lincRNAs). Non-coding RNAs have been implicated as master regulators of several biological processes, their expression being strictly regulated under physiological conditions. In recent years, particularly in the last decade, substantial effort has been made to investigate the function of ncRNAs in several human diseases, including cancer. Glioblastoma is the most common and aggressive type of brain cancer in adults, with deregulated expression of small and long ncRNAs having been implicated in onset, progression, invasiveness, and recurrence of this tumor. The aim of this review is to guide the reader through important aspects of miRNA and lncRNA biology, focusing on the molecular mechanism associated with the progression of this highly malignant cancer type. Full article

(This article belongs to the Special Issue The Plentiful Roles of RNA in Glioblastoma)

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35 pages, 4239 KiB

Open AccessReview

The Roles of miRNA in Glioblastoma Tumor Cell Communication: Diplomatic and Aggressive Negotiations

by Andrei Buruiană, Ștefan Ioan Florian, Alexandru Ioan Florian, Teodora-Larisa Timiș, Carmen Mihaela Mihu, Maria Miclăuș, Sergiu Oșan, Iona Hrapșa, Radu Constantin Cataniciu, Marius Farcaș and Sergiu Șușman

Int. J. Mol. Sci. 2020, 21(6), 1950; https://doi.org/10.3390/ijms21061950 - 12 Mar 2020

Cited by 71 | Viewed by 7145

Abstract

Glioblastoma (GBM) consists of a heterogeneous collection of competing cellular clones which communicate with each other and with the tumor microenvironment (TME). MicroRNAs (miRNAs) present various exchange mechanisms: free miRNA, extracellular vesicles (EVs), or gap junctions (GJs). GBM cells transfer miR-4519 and miR-5096 to astrocytes through GJs. Oligodendrocytes located in the invasion front present high levels of miR-219-5p, miR-219-2-3p, and miR-338-3p, all related to their differentiation. There is a reciprocal exchange between GBM cells and endothelial cells (ECs) as miR-5096 promotes angiogenesis after being transferred into ECs, whereas miR-145-5p acts as a tumor suppressor. In glioma stem cells (GSCs), miR-1587 and miR-3620-5p increase the proliferation and miR-1587 inhibits the hormone receptor co-repressor-1 (NCOR1) after EVs transfers. GBM-derived EVs carry miR-21 and miR-451 that are up-taken by microglia and monocytes/macrophages, promoting their proliferation. Macrophages release EVs enriched in miR-21 that are transferred to glioma cells. This bidirectional miR-21 exchange increases STAT3 activity in GBM cells and macrophages, promoting invasion, proliferation, angiogenesis, and resistance to treatment. miR-1238 is upregulated in resistant GBM clones and their EVs, conferring resistance to adjacent cells via the CAV1/EGFR signaling pathway. Decrypting these mechanisms could lead to a better patient stratification and the development of novel target therapies. Full article

(This article belongs to the Special Issue The Plentiful Roles of RNA in Glioblastoma)

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