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      Targeting non-coding RNAs to overcome cancer therapy resistance

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          Abstract

          It is now well known that non-coding RNAs (ncRNAs), rather than protein-coding transcripts, are the preponderant RNA transcripts. NcRNAs, particularly microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are widely appreciated as pervasive regulators of multiple cancer hallmarks such as proliferation, apoptosis, invasion, metastasis, and genomic instability. Despite recent discoveries in cancer therapy, resistance to chemotherapy, radiotherapy, targeted therapy, and immunotherapy continue to be a major setback. Recent studies have shown that ncRNAs also play a major role in resistance to different cancer therapies by rewiring essential signaling pathways. In this review, we present the intricate mechanisms through which dysregulated ncRNAs control resistance to the four major types of cancer therapies. We will focus on the current clinical implications of ncRNAs as biomarkers to predict treatment response (intrinsic resistance) and to detect resistance to therapy after the start of treatment (acquired resistance). Furthermore, we will present the potential of targeting ncRNA to overcome cancer treatment resistance, and we will discuss the challenges of ncRNA-targeted therapy—especially the development of delivery systems.

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          Most cited references178

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          Circular RNAs are a large class of animal RNAs with regulatory potency.

          Circular RNAs (circRNAs) in animals are an enigmatic class of RNA with unknown function. To explore circRNAs systematically, we sequenced and computationally analysed human, mouse and nematode RNA. We detected thousands of well-expressed, stable circRNAs, often showing tissue/developmental-stage-specific expression. Sequence analysis indicated important regulatory functions for circRNAs. We found that a human circRNA, antisense to the cerebellar degeneration-related protein 1 transcript (CDR1as), is densely bound by microRNA (miRNA) effector complexes and harbours 63 conserved binding sites for the ancient miRNA miR-7. Further analyses indicated that CDR1as functions to bind miR-7 in neuronal tissues. Human CDR1as expression in zebrafish impaired midbrain development, similar to knocking down miR-7, suggesting that CDR1as is a miRNA antagonist with a miRNA-binding capacity ten times higher than any other known transcript. Together, our data provide evidence that circRNAs form a large class of post-transcriptional regulators. Numerous circRNAs form by head-to-tail splicing of exons, suggesting previously unrecognized regulatory potential of coding sequences.
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            Natural RNA circles function as efficient microRNA sponges.

            MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression that act by direct base pairing to target sites within untranslated regions of messenger RNAs. Recently, miRNA activity has been shown to be affected by the presence of miRNA sponge transcripts, the so-called competing endogenous RNA in humans and target mimicry in plants. We previously identified a highly expressed circular RNA (circRNA) in human and mouse brain. Here we show that this circRNA acts as a miR-7 sponge; we term this circular transcript ciRS-7 (circular RNA sponge for miR-7). ciRS-7 contains more than 70 selectively conserved miRNA target sites, and it is highly and widely associated with Argonaute (AGO) proteins in a miR-7-dependent manner. Although the circRNA is completely resistant to miRNA-mediated target destabilization, it strongly suppresses miR-7 activity, resulting in increased levels of miR-7 targets. In the mouse brain, we observe overlapping co-expression of ciRS-7 and miR-7, particularly in neocortical and hippocampal neurons, suggesting a high degree of endogenous interaction. We further show that the testis-specific circRNA, sex-determining region Y (Sry), serves as a miR-138 sponge, suggesting that miRNA sponge effects achieved by circRNA formation are a general phenomenon. This study serves as the first, to our knowledge, functional analysis of a naturally expressed circRNA.
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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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                Author and article information

                Contributors
                chenbq@sysucc.org.cn
                mihnea.dragomir@charite.de
                gcalin@mdanderson.org
                Journal
                Signal Transduct Target Ther
                Signal Transduct Target Ther
                Signal Transduction and Targeted Therapy
                Nature Publishing Group UK (London )
                2095-9907
                2059-3635
                13 April 2022
                13 April 2022
                2022
                : 7
                : 121
                Affiliations
                [1 ]GRID grid.488530.2, ISNI 0000 0004 1803 6191, Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, , Sun Yat-sen University Cancer Center, Guangzhou, ; Guangdong, 510060 China
                [2 ]GRID grid.484013.a, ISNI 0000 0004 6879 971X, Institute of Pathology, Charité-Universitätsmedizin Berlin, , corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, ; Berlin, 10117 Germany
                [3 ]GRID grid.484013.a, ISNI 0000 0004 6879 971X, Berlin Institute of Health, , Anna-Louisa-Karsch-Straße 2, ; 10178 Berlin, Germany
                [4 ]GRID grid.7497.d, ISNI 0000 0004 0492 0584, German Cancer Consortium (DKTK), , Partner Site Berlin, German Cancer Research Center (DKFZ), ; 69210 Heidelberg, Germany
                [5 ]GRID grid.240145.6, ISNI 0000 0001 2291 4776, Department of Translational Molecular Pathology, , The University of Texas MD Anderson Cancer Center, ; Houston, TX 77030 USA
                [6 ]GRID grid.240145.6, ISNI 0000 0001 2291 4776, Center for RNA Interference and Non-Coding RNAs, , The University of Texas MD Anderson Cancer Center, ; Houston, TX 77030 USA
                Author information
                http://orcid.org/0000-0002-7427-0578
                Article
                975
                10.1038/s41392-022-00975-3
                9008121
                35418578
                d4f45653-b043-4d77-a68e-e7402cf45628
                © The Author(s) 2022

                Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 30 September 2021
                : 7 March 2022
                : 7 March 2022
                Funding
                Funded by: FundRef https://doi.org/10.13039/100006108, U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences (NCATS);
                Award ID: UH3TR00943-01
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100000054, U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI);
                Award ID: 1R01 CA182905-01
                Award ID: 1R01CA222007-01A1
                Award Recipient :
                Funded by: U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
                Funded by: FundRef https://doi.org/10.13039/100000057, U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS);
                Award ID: 1R01GM122775-01
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100000005, U.S. Department of Defense (United States Department of Defense);
                Award ID: CA160445P1
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);
                Award ID: 81902462
                Award Recipient :
                Categories
                Review Article
                Custom metadata
                © The Author(s) 2022

                tumour biomarkers,cancer genetics
                tumour biomarkers, cancer genetics

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