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      Circular RNA cTFRC acts as the sponge of MicroRNA-107 to promote bladder carcinoma progression

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          Abstract

          Background

          Circular RNA (circRNA) represents a broad and diverse endogenous RNAs that can regulate gene expression in cancer. However, the regulation and function of bladder cancer (BC) circRNAs remain largely unknown.

          Methods

          Here we generated circRNA microarray data from three BC tissues and paired non-cancerous matched tissues, and detected circular RNA-cTFRC up-regulated and correlated with tumor grade and poor survival rate of BC patients. We subsequently performed functional analyses in cell lines and an animal model to support clinical findings. Mechanistically, we demonstrated that cTFRC could directly bind to miR-107 and relieve suppression for target TFRC expression.

          Results

          We detected circular RNA-cTFRC up-regulated and correlated with tumor grade and poor survival rate of BC patients. Knock down of cTFRC inhibited invasion and proliferation of BC cell lines in vitro and tumor growth in vivo. Furthermore, the expression of cTFRC correlated with TFRC and negatively correlated with miR-107 both in BC cell lines and BC clinical samples. In addition, up-regulation of cTFRC promoted TFRC expression and contributed to an epithelial to mesenchymal transition phenotype in BC cells. Finally, we found that cTFRC acts as a competing endogenous RNA (ceRNA) for miR-107 to regulate TFRC expression.

          Conclusions

          cTFRC may exert regulatory functions in BC and may be a potential marker of BC diagnosis or progression.

          Electronic supplementary material

          The online version of this article (10.1186/s12943-019-0951-0) contains supplementary material, which is available to authorized users.

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          Most cited references12

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          Coding-independent regulation of the tumor suppressor PTEN by competing endogenous mRNAs.

          Here, we demonstrate that protein-coding RNA transcripts can crosstalk by competing for common microRNAs, with microRNA response elements as the foundation of this interaction. We have termed such RNA transcripts as competing endogenous RNAs (ceRNAs). We tested this hypothesis in the context of PTEN, a key tumor suppressor whose abundance determines critical outcomes in tumorigenesis. By a combined computational and experimental approach, we identified and validated endogenous protein-coding transcripts that regulate PTEN, antagonize PI3K/AKT signaling, and possess growth- and tumor-suppressive properties. Notably, we also show that these genes display concordant expression patterns with PTEN and copy number loss in cancers. Our study presents a road map for the prediction and validation of ceRNA activity and networks and thus imparts a trans-regulatory function to protein-coding mRNAs. Copyright © 2011 Elsevier Inc. All rights reserved.
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            MicroRNA Targets in Drosophila

            Additional data files Additional data file 1, 2, 3 and 4. Supplementary Material Additional data file 1 Additional data file 1 Click here for additional data file Additional data file 2 Additional data file 2 Click here for additional data file Additional data file 3 Additional data file 3 Click here for additional data file Additional data file 4 Additional data file 4 Click here for additional data file
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              In vivo identification of tumor- suppressive PTEN ceRNAs in an oncogenic BRAF-induced mouse model of melanoma.

              We recently proposed that competitive endogenous RNAs (ceRNAs) sequester microRNAs to regulate mRNA transcripts containing common microRNA recognition elements (MREs). However, the functional role of ceRNAs in cancer remains unknown. Loss of PTEN, a tumor suppressor regulated by ceRNA activity, frequently occurs in melanoma. Here, we report the discovery of significant enrichment of putative PTEN ceRNAs among genes whose loss accelerates tumorigenesis following Sleeping Beauty insertional mutagenesis in a mouse model of melanoma. We validated several putative PTEN ceRNAs and further characterized one, the ZEB2 transcript. We show that ZEB2 modulates PTEN protein levels in a microRNA-dependent, protein coding-independent manner. Attenuation of ZEB2 expression activates the PI3K/AKT pathway, enhances cell transformation, and commonly occurs in human melanomas and other cancers expressing low PTEN levels. Our study genetically identifies multiple putative microRNA decoys for PTEN, validates ZEB2 mRNA as a bona fide PTEN ceRNA, and demonstrates that abrogated ZEB2 expression cooperates with BRAF(V600E) to promote melanomagenesis. Copyright © 2011 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                86-0755-25650005 , wusong@szu.edu.cn
                86-10-64887989 , lichong@moon.ibp.ac.cn
                Journal
                Mol Cancer
                Mol. Cancer
                Molecular Cancer
                BioMed Central (London )
                1476-4598
                19 February 2019
                19 February 2019
                2019
                : 18
                : 27
                Affiliations
                [1 ]GRID grid.410578.f, Department of urology, Affiliated Traditional Chinese Medicine Hospital, , Southwest Medical University, ; Luzhou, 646699 China
                [2 ]ISNI 0000 0004 1792 5640, GRID grid.418856.6, Core Facility for Protein Research, Institute of Biophysics, Chinese Academy of Sciences, ; Beijing, 100101 China
                [3 ]ISNI 0000 0001 0472 9649, GRID grid.263488.3, Department of Urology, The Affiliated Luohu Hospital of Shenzhen University, Shenzhen University, ; Shenzhen, 518000 China
                [4 ]ISNI 0000 0000 9931 8406, GRID grid.48166.3d, College of Life Science and Technology, Beijing University of Chemical Technology, ; Beijing, China
                [5 ]Beijing Jianlan Institute of Medicine, Beijing, 100190 China
                [6 ]ISNI 0000 0001 2150 1785, GRID grid.17088.36, Michigan State University, ; 426 Auditorium Rd, East Lansing, MI 48824 USA
                [7 ]ISNI 0000 0001 0472 9649, GRID grid.263488.3, Department of Urology, Urology Institute of Shenzhen University, The Third Affiliated Hospital of Shenzhen University, Shenzhen University, ; Shenzhen, 518000 China
                [8 ]ISNI 0000 0001 0477 188X, GRID grid.440648.a, Department of Clinical Medicine, School of Medicine, Anhui University of Science and Technology, ; Huainan, 232001 China
                [9 ]GRID grid.470124.4, Department of Urology, Minimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical University, ; Guangzhou, 510000 China
                [10 ]Beijing Zhongke Jianlan Biotechnology Co., Ltd., Beijing, 101400 China
                Article
                951
                10.1186/s12943-019-0951-0
                6379985
                30782157
                7bba0d19-68dd-4f85-b647-055f11862205
                © 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
                : 8 November 2018
                : 4 February 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81472413
                Award ID: 81602644
                Award ID: 81672956
                Award Recipient :
                Funded by: National Key Research and Development Program
                Award ID: 2017YFA0105900
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2019

                Oncology & Radiotherapy
                bladder cancer,ctfrc,mir-107,tfrc,circular rna
                Oncology & Radiotherapy
                bladder cancer, ctfrc, mir-107, tfrc, circular rna

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