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      Circular RNAs: new biomarkers of chemoresistance in cancer

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          Abstract

          Chemotherapeutics are validated conventional treatments for patients with advanced cancer. However, with continual application of chemotherapeutics, chemoresistance, which is often predictive of poor prognosis, has gradually become a concern in recent years. Circular RNAs (circRNAs), a class of endogenous noncoding RNAs (ncRNAs) with a closed-loop structure, have been reported to be notable targets and markers for the prognosis, diagnosis, and treatment of many diseases, particularly cancer. Although dozens of studies have shown that circRNAs play major roles in drug-resistance activity in tumors, the mechanisms by which circRNAs affect chemoresistance have yet to be explored. In this review, we describe the detailed mechanisms of circRNAs and chemotherapeutics in various cancers and summarize potential therapeutic targets for drug-resistant tumors.

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          MicroRNA therapeutics: towards a new era for the management of cancer and other diseases

          Rajesha Rupaimoole, Frank J Slack (2017)
          MicroRNAs (miRNAs) are small non-coding RNAs that can modulate mRNA expression. Insights into the roles of miRNAs in development and disease have led to the development of new therapeutic approaches that are based on miRNA mimics or agents that inhibit their functions (antimiRs), and the first such approaches have entered the clinic. This Review discusses the role of different miRNAs in cancer and other diseases, and provides an overview of current miRNA therapeutics in the clinic.
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            Circular RNAs are abundant, conserved, and associated with ALU repeats.

            W. R. Jeck, J A Sorrentino, K. Wang … (2013)
            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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              circRNA biogenesis competes with pre-mRNA splicing.

              Reut Ashwal-Fluss, Markus Meyer, Nagarjuna Reddy Pamudurti … (2014)
              Circular RNAs (circRNAs) are widely expressed noncoding RNAs. However, their biogenesis and possible functions are poorly understood. Here, by studying circRNAs that we identified in neuronal tissues, we provide evidence that animal circRNAs are generated cotranscriptionally and that their production rate is mainly determined by intronic sequences. We demonstrate that circularization and splicing compete against each other. These mechanisms are tissue specific and conserved in animals. Interestingly, we observed that the second exon of the splicing factor muscleblind (MBL/MBNL1) is circularized in flies and humans. This circRNA (circMbl) and its flanking introns contain conserved muscleblind binding sites, which are strongly and specifically bound by MBL. Modulation of MBL levels strongly affects circMbl biosynthesis, and this effect is dependent on the MBL binding sites. Together, our data suggest that circRNAs can function in gene regulation by competing with linear splicing. Furthermore, we identified muscleblind as a factor involved in circRNA biogenesis. Copyright © 2014 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cancer Biol Med
                Journal ID (iso-abbrev): Cancer Biol Med
                Journal ID (publisher-id): CBM
                Title: Cancer Biology & Medicine
                Publisher: Compuscript (Ireland )
                ISSN (Print): 2095-3941
                Publication date (Print): 15 May 2021
                Publication date (Electronic): 15 June 2021
                Volume: 18
                Issue: 2
                Pages: 421-436
                Affiliations
                [1 ]Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, China
                [2 ]Institute of Digestive Diseases of Xuzhou Medical University, Xuzhou 221002, China
                Author notes
                Correspondence to: Jun Song, E-mail: songjun@ 123456xzhmu.edu.cn
                Author information
                https://orcid.org/0000-0002-6350-2695
                Article
                Publisher ID: j.issn.2095-3941.2020.0312
                DOI: 10.20892/j.issn.2095-3941.2020.0312
                PMC ID: 8185855
                PubMed ID: 33738995
                SO-VID: fc6411e8-714d-4160-b2b6-2dd800c3ad96
                Copyright © Copyright: © 2021, Cancer Biology & Medicine
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY) 4.0, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 29 June 2020
                Date accepted : 27 November 2020
                Page count
                Figures: 3, Tables: 2, References: 134, Pages: 16
                Categories
                Subject: Review

                Keywords: circular rna,chemoresistance,drug resistance,cancer
                Data availability:
                Keywords: circular rna, chemoresistance, drug resistance, cancer

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