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      The RNA-binding protein RBM3 promotes cell proliferation in hepatocellular carcinoma by regulating circular RNA SCD-circRNA 2 production

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          Abstract

          Background

          With the development of RNA-seq technology, tens of thousands of circular RNAs (circRNAs), a novel class of RNAs, have been identified. However, little is known about circRNA formation and biogenesis in hepatocellular carcinoma (HCC).

          Methods

          We performed ribosomal-depleted RNA-seq profiling of HCC and para-carcinoma tissues and analyzed the expression of a hotspot circRNA derived from the 3’UTR of the stearoyl-CoA desaturase (SCD) gene, termed SCD-circRNA 2.

          Findings

          It was significantly upregulated in HCC and correlated with poor patient prognosis. Moreover, we observed that the production of SCD-circRNA 2 was dynamically regulated by RNA-binding protein 3 (RBM3). RBM3 overexpression was indicative of a short recurrence-free survival and poor overall survival for HCC patients. Furthermore, by modulating the RBM3 or SCD-circRNA 2 levels, we found that RBM3 promoted the HCC cell proliferation in a SCD-circRNA 2 dependent manner.

          Interpretation

          Herein, we report that RBM3 is crucial for the SCD-circRNA 2 formation in HCC cells, which not only provides mechanistic insights into cancer-related circRNA dysregulation but also establishes RBM3 as an oncogene with both therapeutic potential and prognostic value.

          Fund

          This work was supported by the National Key Research and Development Program of China (2016YFC1302303), the National Natural Science Foundation of China (Grant No. 81672345 and 81,402,269). The funders did not have any roles in study design, data collection, data analysis, interpretation, writing of the report.

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          Most cited references30

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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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            The Biogenesis of Nascent Circular RNAs.

            Steady-state circular RNAs (circRNAs) have been mapped to thousands of genomic loci in mammals. We studied circRNA processing using metabolic tagging of nascent RNAs with 4-thiouridine (4sU). Strikingly, the efficiency of circRNA processing from pre-mRNA is extremely low endogenously. Additional studies revealed that back-splicing outcomes correlate with fast RNA Polymerase II elongation rate and are tightly controlled by cis-elements in vivo. Additionally, prolonged 4sU labeling in cells shows that circRNAs are largely processed post-transcriptionally and that circRNAs are stable. Circular RNAs that are abundant at a steady-state level tend to accumulate. This is particularly true in cells, such as neurons, that have slow division rates. This study uncovers features of circRNA biogenesis by investigating the link between nascent circRNA processing and transcription.
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              Systematic identification and analysis of exonic splicing silencers.

              Exonic splicing silencers (ESSs) are cis-regulatory elements that inhibit the use of adjacent splice sites, often contributing to alternative splicing (AS). To systematically identify ESSs, an in vivo splicing reporter system was developed to screen a library of random decanucleotides. The screen yielded 141 ESS decamers, 133 of which were unique. The silencer activity of over a dozen of these sequences was also confirmed in a heterologous exon/intron context and in a second cell type. Of the unique ESS decamers, most could be clustered into groups to yield seven putative ESS motifs, some resembling known motifs bound by hnRNPs H and A1. Potential roles of ESSs in constitutive splicing were explored using an algorithm, ExonScan, which simulates splicing based on known or putative splicing-related motifs. ExonScan and related bioinformatic analyses suggest that these ESS motifs play important roles in suppression of pseudoexons, in splice site definition, and in AS.
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                Author and article information

                Contributors
                Journal
                EBioMedicine
                EBioMedicine
                EBioMedicine
                Elsevier
                2352-3964
                22 June 2019
                July 2019
                22 June 2019
                : 45
                : 155-167
                Affiliations
                [a ]The Department of Medical Genetics, Second Military Medical University, 800 Xiangyin Road, Shanghai, China
                [b ]The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai, China
                [c ]International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, 225 Changhai Road, Shanghai, China
                [d ]Shanghai Key Laboratory of Cell Engineering (14DZ2272300), Second Military Medical University, 800 Xiangyin Road, Shanghai, China
                Author notes
                [* ]Correspondence to: F. Yang, the Department of Medical Genetics, Second Military Medical University, 800 Xiangyin Road, Shanghai, China. yangfusq1997@ 123456smmu.edu.cn
                [** ]Correspondence to: H. Liu, The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, 200438 Shanghai, China. liuhuigg@ 123456hotmail.com
                [*** ]Correspondence to: J. Ding, International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China. dingjin1103@ 123456163.com
                [1]

                Contributed equally (shared first-author)

                [2]

                Contributed equally (shared last-author)

                Article
                S2352-3964(19)30411-6
                10.1016/j.ebiom.2019.06.030
                6642271
                31235426
                c109aabc-ce9a-418e-bfc3-78eea2d2bc5a
                © 2019 The Authors. Published by Elsevier B.V.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 27 February 2019
                : 16 June 2019
                : 17 June 2019
                Categories
                Research paper

                circular rna,hepatocellular carcinoma,oncogene,rbm3,stearoyl-coa desaturase,circrna, circular rna,hcc, hepatocelluar carcinoma,rbm3, rna-binding protein 3,rfs, recurrence-free survival,os, overall survival,scd, stearoyl-coa desaturase,rip, rna immunoprecipitation

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