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      Exosomal noncoding RNAs in Glioma: biological functions and potential clinical applications

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          Abstract

          Gliomas are complex and heterogeneous brain tumors with poor prognosis. Glioma cells can communicate with their surroundings to create a tumor-permissive microenvironment. Exosomes represent a new means of intercellular communication by delivering various bioactive molecules, including proteins, lipids and nucleic acids, and participate in tumor initiation and progression. Noncoding RNAs (ncRNAs) including microRNA, long-noncoding RNA, and circular RNA, account for a large portion of human transcriptome and play important roles in various pathophysiological processes, especially in cancers. In addition, ncRNAs can be selectively packaged, secreted and transferred between cells in exosomes and modulate numerous hallmarks of glioma, such as proliferation, invasion, angiogenesis, immune-escape, and treatment resistance. Hence, the strategies of specifically targeting exosomal ncRNAs could be attractive therapeutic options. Exosomes are able to cross the blood brain barrier (BBB), and are readily accessible in nearly all types of human biofluids, which make them the promising biomarkers for gliomas. Additionally, given the biocompatibility of exosomes, they can be engineered to deliver therapeutic factors, such as RNA, proteins and drugs, to target cells for therapeutic applications. Here, we reviewed current research on the roles of exosomal ncRNAs in glioma progression. We also discussed their potential clinical applications as novel biomarkers and therapeutics.

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          Most cited references68

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          miRBase: from microRNA sequences to function

          Abstract miRBase catalogs, names and distributes microRNA gene sequences. The latest release of miRBase (v22) contains microRNA sequences from 271 organisms: 38 589 hairpin precursors and 48 860 mature microRNAs. We describe improvements to the database and website to provide more information about the quality of microRNA gene annotations, and the cellular functions of their products. We have collected 1493 small RNA deep sequencing datasets and mapped a total of 5.5 billion reads to microRNA sequences. The read mapping patterns provide strong support for the validity of between 20% and 65% of microRNA annotations in different well-studied animal genomes, and evidence for the removal of >200 sequences from the database. To improve the availability of microRNA functional information, we are disseminating Gene Ontology terms annotated against miRBase sequences. We have also used a text-mining approach to search for microRNA gene names in the full-text of open access articles. Over 500 000 sentences from 18 542 papers contain microRNA names. We score these sentences for functional information and link them with 12 519 microRNA entries. The sentences themselves, and word clouds built from them, provide effective summaries of the functional information about specific microRNAs. miRBase is publicly and freely available at http://mirbase.org/.
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            MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells.

            MicroRNAs (miRNAs) are small noncoding RNA molecules that regulate protein expression by targeting the mRNA of protein-coding genes for either cleavage or repression of translation. The roles of miRNAs in lineage determination and proliferation as well as the location of several miRNA genes at sites of translocation breakpoints or deletions has led to the speculation that miRNAs could be important factors in the development or maintenance of the neoplastic state. Here we show that the highly malignant human brain tumor, glioblastoma, strongly over-expresses a specific miRNA, miR-21. Our studies show markedly elevated miR-21 levels in human glioblastoma tumor tissues, early-passage glioblastoma cultures, and in six established glioblastoma cell lines (A172, U87, U373, LN229, LN428, and LN308) compared with nonneoplastic fetal and adult brain tissues and compared with cultured nonneoplastic glial cells. Knockdown of miR-21 in cultured glioblastoma cells triggers activation of caspases and leads to increased apoptotic cell death. Our data suggest that aberrantly expressed miR-21 may contribute to the malignant phenotype by blocking expression of critical apoptosis-related genes.
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              Dynamic biodistribution of extracellular vesicles in vivo using a multimodal imaging reporter.

              Extracellular vesicles (EVs) are nanosized vesicles released by normal and diseased cells as a novel form of intercellular communication and can serve as an effective therapeutic vehicle for genes and drugs. Yet, much remains unknown about the in vivo properties of EVs such as tissue distribution, blood levels, and urine clearance, important parameters that will define their therapeutic effectiveness and potential toxicity. Here we combined Gaussia luciferase and metabolic biotinylation to create a sensitive EV reporter (EV-GlucB) for multimodal imaging in vivo, as well as monitoring of EV levels in the organs and biofluids ex vivo after administration of EVs. Bioluminescence and fluorescence-mediated tomography imaging on mice displayed a predominant localization of intravenously administered EVs in the spleen followed by the liver. Monitoring EV signal in the organs, blood, and urine further revealed that the EVs first undergo a rapid distribution phase followed by a longer elimination phase via hepatic and renal routes within six hours, which are both faster than previously reported using dye-labeled EVs. Moreover, we demonstrate systemically injected EVs can be delivered to tumor sites within an hour following injection. Altogether, we show the EVs are dynamically processed in vivo with accurate spatiotemporal resolution and target a number of normal organs as well as tumors with implications for disease pathology and therapeutic design.
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                Author and article information

                Contributors
                drchengjian@163.com
                docmeng891203@163.com
                lei_zhu@scu.edu.cn
                yongpeng@scu.edu.cn
                Journal
                Mol Cancer
                Mol. Cancer
                Molecular Cancer
                BioMed Central (London )
                1476-4598
                25 March 2020
                25 March 2020
                2020
                : 19
                : 66
                Affiliations
                [1 ]GRID grid.13291.38, ISNI 0000 0001 0807 1581, Laboratory of Molecular Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, , Sichuan University, ; Chengdu, 610041 China
                [2 ]GRID grid.13291.38, ISNI 0000 0001 0807 1581, Department of Neurosurgery, West China Hospital, , Sichuan University, ; Chengdu, China
                [3 ]Department of Radiology, Hospital of Chengdu Office of People’s Government of Tibetan Autonomous Region (Hospital C.T.), Chengdu, China
                Article
                1189
                10.1186/s12943-020-01189-3
                7098115
                32213181
                5f8704a3-4eb2-410d-82ea-78014e8389a4
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 12 February 2020
                : 19 March 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100012226, Fundamental Research Funds for the Central Universities;
                Award ID: 2018SCUH0018
                Award Recipient :
                Funded by: Department of Sichuan Science & Technology Program
                Award ID: 2019JDTD0013
                Award Recipient :
                Funded by: The 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University
                Award ID: ZYJC18030
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100010031, Postdoctoral Research Foundation of China;
                Award ID: 2019M663514
                Award Recipient :
                Funded by: Post-Doctor Research Project, West China Hospital, Sichuan University
                Award ID: 2019HXBH084
                Award Recipient :
                Categories
                Review
                Custom metadata
                © The Author(s) 2020

                Oncology & Radiotherapy
                exosome,extracellular vesicles,noncoding rna,glioma,cancer diagnosis,cancer therapy

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