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      The emerging roles and functions of circular RNAs and their generation

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          Abstract

          Circular RNAs (circRNAs) are closed long non-coding RNAs, in which the 5’ and 3’ termini are covalently linked by back-splicing of exons from a single pre-mRNA. Emerging evidence indicates that circRNAs are broadly expressed in mammalian cells and show cell type- or tissue-specific expression patterns. Importantly, circRNAs have been shown to participate in regulating various biological processes. Functionally, circRNAs can influence cellular physiology through various molecular mechanisms, such as serving as a decoy for microRNAs or RNA-binding proteins to modulate gene expression or translation of regulatory proteins. The biogenesis of circRNAs is known to be tightly regulated by cis- (intronic complementary sequences) and/or trans-factors (splicing factors) that constitute a cell- and context-dependent regulatory layer in the control of gene expression. However, our understanding of the regulation and function of circRNAs is still limited. In this review, we summarize the current progress in elucidating the functional roles, mechanisms and biogenesis of circRNAs. We also discuss the relationship between regulation and formation of circRNAs.

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          Genome-wide analysis of drosophila circular RNAs reveals their structural and sequence properties and age-dependent neural accumulation.

          Circularization was recently recognized to broadly expand transcriptome complexity. Here, we exploit massive Drosophila total RNA-sequencing data, >5 billion paired-end reads from >100 libraries covering diverse developmental stages, tissues, and cultured cells, to rigorously annotate >2,500 fruit fly circular RNAs. These mostly derive from back-splicing of protein-coding genes and lack poly(A) tails, and the circularization of hundreds of genes is conserved across multiple Drosophila species. We elucidate structural and sequence properties of Drosophila circular RNAs, which exhibit commonalities and distinctions from mammalian circles. Notably, Drosophila circular RNAs harbor >1,000 well-conserved canonical miRNA seed matches, especially within coding regions, and coding conserved miRNA sites reside preferentially within circularized exons. Finally, we analyze the developmental and tissue specificity of circular RNAs and note their preferred derivation from neural genes and enhanced accumulation in neural tissues. Interestingly, circular isoforms increase substantially relative to linear isoforms during CNS aging and constitute an aging biomarker. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
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            CircHIPK3 promotes colorectal cancer growth and metastasis by sponging miR-7

            Mounting evidences indicate that circular RNAs (circRNAs) have a vital role in human diseases, especially cancers. More recently, circHIPK3, a particularly abundant circRNA, was proposed to be involved in tumorigenesis. However, its role in colorectal cancer (CRC) has not been explored. In this study, we found circHIPK3 was significantly upregulated in CRC tissues and cell lines, at least in part, due to c-Myb overexpression and positively correlated with metastasis and advanced clinical stage. Moreover, Cox multivariate survival analysis showed that high-level expression of circHIPK3 was an independent prognostic factor of poor overall survival (OS) in CRC (hazard ratio [HR] = 2.75, 95% confidence interval [CI] 1.74–6.51, p = 0.009). Functionally, knockdown of circHIPK3 markedly inhibited CRC cells proliferation, migration, invasion, and induced apoptosis in vitro and suppressed CRC growth and metastasis in vivo. Mechanistically, by using biotinylated-circHIPK3 probe to perform RNA pull-down assay in CRC cells, we identified miR-7 was the only one microRNA that was abundantly pulled down by circHIPK3 in both HCT116 and HT29 cells and these interactions were also confirmed by biotinylated miR-7 pull-down and dual-luciferase reporter assays. Overexpression of miR-7 mimicked the effect of circHIPK3 knockdown on CRC cells proliferation, migration, invasion, and apoptosis. Furthermore, ectopic expression of circHIPK3 effectively reversed miR-7-induced attenuation of malignant phenotypes of CRC cells by increasing the expression levels of miR-7 targeting proto-oncogenes (FAK, IGF1R, EGFR, YY1). Remarkably, the combination of circHIPK3 silencing and miR-7 overexpression gave a better effect on tumor suppression both in vitro and in vivo than did circHIPK3 knockdown or miR-7 overexpression alone. Taken together, our data indicate that circHIPK3 may have considerable potential as a prognostic biomarker in CRC, and support the notion that therapeutic targeting of the c-Myb/circHIPK3/miR-7 axis may be a promising treatment approach for CRC patients.
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              Foxo3 circular RNA promotes cardiac senescence by modulating multiple factors associated with stress and senescence responses

              Circular RNAs are a subclass of non-coding RNAs detected within mammalian cells. This study was designed to test the roles of a circular RNA circ-Foxo3 in senescence using in vitro and in vivo approaches.
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                Author and article information

                Contributors
                +886 2 27899580 , kuohuch@gate.sinica.edu.tw
                Journal
                J Biomed Sci
                J. Biomed. Sci
                Journal of Biomedical Science
                BioMed Central (London )
                1021-7770
                1423-0127
                25 April 2019
                25 April 2019
                2019
                : 26
                : 29
                Affiliations
                [1 ]ISNI 0000 0001 2287 1366, GRID grid.28665.3f, Institute of Cellular and Organismic Biology, , Academia Sinica, ; No. 128, Sec. 2, Academia Road, Nankang, Taipei, 11529 Taiwan
                [2 ]ISNI 0000 0004 0532 3650, GRID grid.412047.4, Department of Biomedical Sciences, , National Chung Cheng University, ; Chiayi, Taiwan
                [3 ]ISNI 0000 0004 0546 0241, GRID grid.19188.39, Graduate Institute of Medical Genomics and Proteomics, College of Medicine, , National Taiwan University, ; Taipei, Taiwan
                Author information
                http://orcid.org/0000-0002-7320-7876
                Article
                523
                10.1186/s12929-019-0523-z
                6485060
                31027496
                f57654d5-94f8-4239-88cb-f3cb00bf9fe9
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 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.

                History
                : 15 January 2019
                : 16 April 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100004663, Ministry of Science and Technology, Taiwan;
                Award ID: MOST 104-0210-01-09-02
                Award ID: MOST 105-0210-01-13-01
                Award ID: MOST106-0210-01-15-02
                Award ID: MOST-106-2321-B-194-001-MY3
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001869, Academia Sinica;
                Award ID: AS-104-TP-B09
                Award ID: AS-103-TP-B10
                Award Recipient :
                Categories
                Review
                Custom metadata
                © The Author(s) 2019

                Molecular medicine
                circular rnas (circrnas),splicing factor,micro rnas (mirnas),long non-coding rnas (lncrnas)

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