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      Circular RNAs’ cap-independent translation protein and its roles in carcinomas

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          Abstract

          Circular RNAs a kind of covalently closed RNA and widely expressed in eukaryotes. CircRNAs are involved in a variety of physiological and pathological processes, but their regulatory mechanisms are not fully understood. Given the development of the RNA deep-sequencing technology and the improvement of algorithms, some CircRNAs are discovered to encode proteins through the cap-independent mechanism and participate in the important process of tumorigenesis and development. Based on an overview of CircRNAs, this paper summarizes its translation mechanism and research methods, and reviews the research progress of CircRNAs translation in the field of oncology in recent years. Moreover, this paper aims to provide new ideas for tumor diagnosis and treatment through CircRNAs translation.

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

          Sebastian Memczak, Marvin Jens, Antigoni Elefsinioti … (2013)
          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.
          Article 0 comments Cited 2174 times – based on 0 reviews     Review now
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            Natural RNA circles function as efficient microRNA sponges.

            Thomas B. Hansen, Trine I. Jensen, Bettina H. Clausen … (2014)
            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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              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.
              Article 0 comments Cited 1226 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Xiaoyan Wang: 726343819@qq.com
                Yu Fan: yuf36@sina.com
                Journal
                Journal ID (nlm-ta): Mol Cancer
                Journal ID (iso-abbrev): Mol Cancer
                Title: Molecular Cancer
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1476-4598
                Publication date (Electronic): 15 September 2021
                Publication date PMC-release: 15 September 2021
                Publication date Collection: 2021
                Volume: 20
                Electronic Location Identifier: 119
                Affiliations
                [1 ]GRID grid.452247.2, Cancer Institue, Affiliated People’s Hospital of Jiangsu University, ; No 8, Dianli Road, Zhenjiang, Jiangsu Province 212002 People’s Republic of China
                [2 ]GRID grid.89957.3a, ISNI 0000 0000 9255 8984, Department of Gastroenterology, , Affiliated Suqian First People’s Hospital of Nanjing Medical University, ; No 120, Suzhi Road, Suqian, Jiangsu Province 223812 People’s Republic of China
                Article
                Publisher ID: 1417
                DOI: 10.1186/s12943-021-01417-4
                PMC ID: 8442428
                PubMed ID: 34526007
                SO-VID: 50e4f031-44c0-4417-8640-427c5bbfaa94
                Copyright © © The Author(s) 2021
                License:

                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
                Date received : 13 June 2021
                Date accepted : 31 August 2021
                Funding
                Funded by: jiangsu innovative team leading talent fund
                Award ID: CXTDC2016006, QNRC2016446
                Award Recipient :
                Funded by: jiangsu 333 talent fund
                Award ID: BRA2020016
                Award Recipient :
                Funded by: jiangsu provincial key research and development special fund
                Award ID: BE2015666
                Award Recipient :
                Funded by: jiangsu six high peak talent fund
                Award ID: WSW-205,WSW236
                Award Recipient :
                Funded by: suqian science and technology support project fund
                Award ID: K201907
                Award Recipient :
                Categories
                Subject: Review
                Custom metadata
                issue-copyright-statement © The Author(s) 2021

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: carcinoma,circular rna,translation,circrna-derived protein
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: carcinoma, circular rna, translation, circrna-derived protein

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