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      Newly discovered mechanisms that mediate tumorigenesis and tumour progression: circRNA‐encoded proteins

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          Abstract

          Proteins produced by cap‐independent translation mediated by an internal ribosome entry site (IRES) in circular RNAs (circRNAs) play important roles in tumour progression. To date, numerous studies have been performed on circRNAs and the proteins they encode. In this review, we summarize the biogenesis of circRNAs and the mechanisms regulating circRNA‐encoded proteins expression. We also describe relevant research methods and their applications to biological processes such as tumour cell proliferation, metastasis, epithelial‐mesenchymal transition (EMT), apoptosis, autophagy and chemoresistance. This paper offers deeper insights into the roles that circRNA‐encoded proteins play in tumours. It also provides a theoretical basis for the use of circRNA‐encoded proteins as biomarkers of tumorigenesis and for the development of new targets for tumour therapy.

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          Most cited references78

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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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              The biogenesis, biology and characterization of circular RNAs

              Circular RNAs (circRNAs) are covalently closed, endogenous biomolecules in eukaryotes with tissue-specific and cell-specific expression patterns, whose biogenesis is regulated by specific cis-acting elements and trans-acting factors. Some circRNAs are abundant and evolutionarily conserved, and many circRNAs exert important biological functions by acting as microRNA or protein inhibitors ('sponges'), by regulating protein function or by being translated themselves. Furthermore, circRNAs have been implicated in diseases such as diabetes mellitus, neurological disorders, cardiovascular diseases and cancer. Although the circular nature of these transcripts makes their detection, quantification and functional characterization challenging, recent advances in high-throughput RNA sequencing and circRNA-specific computational tools have driven the development of state-of-the-art approaches for their identification, and novel approaches to functional characterization are emerging.
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                Author and article information

                Contributors
                xiaoxuhuang1984@163.com
                Journal
                J Cell Mol Med
                J Cell Mol Med
                10.1111/(ISSN)1582-4934
                JCMM
                Journal of Cellular and Molecular Medicine
                John Wiley and Sons Inc. (Hoboken )
                1582-1838
                1582-4934
                18 April 2023
                June 2023
                : 27
                : 12 ( doiID: 10.1111/jcmm.v27.12 )
                : 1609-1620
                Affiliations
                [ 1 ] Department of Gastrointestinal Surgery The First Affiliated Yijishan Hospital of Wannan Medical College Wuhu China
                [ 2 ] Key Laboratory of Non‐coding RNA Transformation Research of Anhui Higher Education Institution Wannan Medical College Wuhu China
                [ 3 ] Department of Thoracic Surgery The First Affiliated Yijishan Hospital of Wannan Medical College Wuhu China
                [ 4 ] The Second Affiliated Hospital of Wannan Medical College Wuhu China
                Author notes
                [*] [* ] Correspondence

                Xiaoxu Huang, Department of Gastrointestinal Surgery, The First Affiliated Yijishan Hospital of Wannan Medical College, Wuhu, No.2, Zheshan West Road, Anhui 241001, China.

                Email: xiaoxuhuang1984@ 123456163.com

                Author information
                https://orcid.org/0000-0001-8308-987X
                Article
                JCMM17751 JCMM-01-2023-134.R1
                10.1111/jcmm.17751
                10273065
                37070530
                25a46fdf-cb44-4b6d-8c2c-019367f1baf4
                © 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 18 March 2023
                : 31 January 2023
                : 08 April 2023
                Page count
                Figures: 4, Tables: 1, Pages: 12, Words: 7007
                Funding
                Funded by: National Natural Science Foundation of China , doi 10.13039/501100001809;
                Award ID: 81902515
                Funded by: Natural Science Research Project of Higher Education in Anhui Province
                Award ID: KJ2021A0857
                Categories
                Review
                Reviews
                Custom metadata
                2.0
                June 2023
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.2.9 mode:remove_FC converted:16.06.2023

                Molecular medicine
                circrna,circrna‐encoded protein,research methods,translational medicine,tumour malignancy progression

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