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      Roles and clinical application of exosomal circRNAs in the diagnosis and treatment of malignant tumors

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          Abstract

          Exosomes are microvesicles secreted by cells. They contain a variety of bioactive substances with important roles in intercellular communication. Circular RNA (circRNA), a type of nucleic acid molecule found in exosomes, forms a covalently bonded closed loop without 5′ caps or 3′ poly(A) tails. It is structurally stable, widely distributed, and tissue specific. CircRNAs mainly act as microRNA sponges and have important regulatory roles in gene expression; they are superior to other non-coding RNAs as molecular diagnostic markers and drug treatment targets. Exosomal-derived circRNAs in the body fluids of tumor patients can modulate tumor proliferation, invasion, metastasis, and drug resistance. They can be used as effective biomarkers for early non-invasive diagnosis and prognostic evaluation of tumors, and also represent ideal targets for early precision therapeutic intervention. This review provides a theoretical basis for exploring the applications of exosomal circRNAs in malignant tumor diagnosis and treatment. We describe the biological functions of exosomal circRNAs in the occurrence and development of malignant tumors, their potential utility in diagnosis and treatment, and possible mechanisms.

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          The biology, function, and biomedical applications of exosomes

          The study of extracellular vesicles (EVs) has the potential to identify unknown cellular and molecular mechanisms in intercellular communication and in organ homeostasis and disease. Exosomes, with an average diameter of ~100 nanometers, are a subset of EVs. The biogenesis of exosomes involves their origin in endosomes, and subsequent interactions with other intracellular vesicles and organelles generate the final content of the exosomes. Their diverse constituents include nucleic acids, proteins, lipids, amino acids, and metabolites, which can reflect their cell of origin. In various diseases, exosomes offer a window into altered cellular or tissue states, and their detection in biological fluids potentially offers a multicomponent diagnostic readout. The efficient exchange of cellular components through exosomes can inform their applied use in designing exosome-based therapeutics.
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            Circular RNAs are abundant, conserved, and associated with ALU repeats.

            Circular RNAs composed of exonic sequence have been described in a small number of genes. Thought to result from splicing errors, circular RNA species possess no known function. To delineate the universe of endogenous circular RNAs, we performed high-throughput sequencing (RNA-seq) of libraries prepared from ribosome-depleted RNA with or without digestion with the RNA exonuclease, RNase R. We identified >25,000 distinct RNA species in human fibroblasts that contained non-colinear exons (a "backsplice") and were reproducibly enriched by exonuclease degradation of linear RNA. These RNAs were validated as circular RNA (ecircRNA), rather than linear RNA, and were more stable than associated linear mRNAs in vivo. In some cases, the abundance of circular molecules exceeded that of associated linear mRNA by >10-fold. By conservative estimate, we identified ecircRNAs from 14.4% of actively transcribed genes in human fibroblasts. Application of this method to murine testis RNA identified 69 ecircRNAs in precisely orthologous locations to human circular RNAs. Of note, paralogous kinases HIPK2 and HIPK3 produce abundant ecircRNA from their second exon in both humans and mice. Though HIPK3 circular RNAs contain an AUG translation start, it and other ecircRNAs were not bound to ribosomes. Circular RNAs could be degraded by siRNAs and, therefore, may act as competing endogenous RNAs. Bioinformatic analysis revealed shared features of circularized exons, including long bordering introns that contained complementary ALU repeats. These data show that ecircRNAs are abundant, stable, conserved and nonrandom products of RNA splicing that could be involved in control of gene expression.
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              Circular RNA is enriched and stable in exosomes: a promising biomarker for cancer diagnosis.

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                Author and article information

                Contributors
                yedong518@sina.com
                szs7216@sina.com
                Journal
                J Transl Med
                J Transl Med
                Journal of Translational Medicine
                BioMed Central (London )
                1479-5876
                5 April 2022
                5 April 2022
                2022
                : 20
                : 161
                Affiliations
                [1 ]GRID grid.203507.3, ISNI 0000 0000 8950 5267, Department of Otorhinolaryngology-Head and Neck Surgery, , Lihuili Hospital of Ningbo University, ; Ningbo, 315040 Zhejiang China
                [2 ]GRID grid.460077.2, ISNI 0000 0004 1808 3393, Department of Thoracic Surgery, , Affiliated Hospital of Ningbo University, ; Ningbo, 315020 Zhejiang China
                Author information
                http://orcid.org/0000-0003-2055-0256
                Article
                3367
                10.1186/s12967-022-03367-x
                8981684
                35382838
                f5363812-7b26-42be-9413-bff3e90b466c
                © The Author(s) 2022

                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
                : 9 December 2021
                : 26 March 2022
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100004731, Natural Science Foundation of Zhejiang Province;
                Award ID: LY19H160014
                Award ID: LY20H130001
                Award ID: LQ21H130001
                Award Recipient :
                Funded by: Medical and Health Research Project of Zhejiang Province
                Award ID: 2019ZD018
                Award ID: 2021KY307)
                Award Recipient :
                Funded by: Ningbo Health Branding Subject Fund
                Award ID: PPXK2018-02
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100007834, Natural Science Foundation of Ningbo;
                Award ID: 2018A610361
                Award ID: 2019A610319
                Award ID: 202003N4239
                Award Recipient :
                Funded by: the Key Project of Teaching and Research of Ningbo University
                Award ID: JYXMXZD2021033
                Award Recipient :
                Categories
                Review
                Custom metadata
                © The Author(s) 2022

                Medicine
                exosome,circrnas,malignant tumors,function,application
                Medicine
                exosome, circrnas, malignant tumors, function, application

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