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      Long Non-Coding RNA GAPLINC Promotes Tumor-Like Biologic Behaviors of Fibroblast-Like Synoviocytes as MicroRNA Sponging in Rheumatoid Arthritis Patients

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          Rapidly accumulating evidence has now suggested that the long non-coding RNAs (LncRNAs), a large and diverse class of non-coding transcribed RNA molecules with diverse functional roles and mechanisms, play a major role in the pathogenesis of many human inflammatory diseases. Although some LncRNAs are overexpressed in plasma, T cell, and synovial tissues of patients with rheumatoid arthritis (RA), there is a dearth of knowledge in what role these transcripts play in fibroblast-like synoviocytes (FLSs) of these patients. Here, our studies showed that GAPLINC, a newly identified functional LncRNA in oncology, displayed a greater degree of expression in FLSs from RA than in patients with traumatic injury. GAPLINC suppression in RA-FLS cells revealed significant alterations in cell proliferation, invasion, migration, and proinflammatory cytokines production. Additionally, we performed a preliminary bioinformatics analysis of GAPLINC gene sequence in order to find its target molecules, using miRanda, PITA, RNAhybrid algorithms, Kyoto encyclopedia of genes and genomes, and gene ontology analysis. Since the results predicted that some of microRNAs and mRNA may interact with GAPLINC, we simulated a gene co-action network model based on a competitive endogenous RNA theory. Further verification of this model demonstrated that silencing of GAPLINC increased miR-382-5p and miR-575 expression. The results of this study suggest that GAPLINC may function as a novel microRNAs sponging agent affecting the biological characteristics of RA-FLSs. Additionally, GAPLINC may also promote RA-FLS tumor-like behaviors in a miR-382-5p-dependent and miR-575-dependent manner. Based upon these findings, LncRNA GAPLINC may provide a novel valuable therapeutic target for RA patients.

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          Most cited references 40

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          Rheumatoid arthritis.

          Rheumatoid arthritis is a chronic inflammatory joint disease, which can cause cartilage and bone damage as well as disability. Early diagnosis is key to optimal therapeutic success, particularly in patients with well-characterised risk factors for poor outcomes such as high disease activity, presence of autoantibodies, and early joint damage. Treatment algorithms involve measuring disease activity with composite indices, applying a treatment-to-target strategy, and use of conventional, biological, and newz non-biological disease-modifying antirheumatic drugs. After the treatment target of stringent remission (or at least low disease activity) is maintained, dose reduction should be attempted. Although the prospects for most patients are now favourable, many still do not respond to current therapies. Accordingly, new therapies are urgently required. In this Seminar, we describe current insights into genetics and aetiology, pathophysiology, epidemiology, assessment, therapeutic agents, and treatment strategies together with unmet needs of patients with rheumatoid arthritis.
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            Endogenous microRNA sponges: evidence and controversy.

            The competitive endogenous RNA (ceRNA) hypothesis proposes that transcripts with shared microRNA (miRNA) binding sites compete for post-transcriptional control. This hypothesis has gained substantial attention as a unifying function for long non-coding RNAs, pseudogene transcripts and circular RNAs, as well as an alternative function for messenger RNAs. Empirical evidence supporting the hypothesis is accumulating but not without attracting scepticism. Recent studies that model transcriptome-wide binding-site abundance suggest that physiological changes in expression of most individual transcripts will not compromise miRNA activity. In this Review, we critically evaluate the evidence for and against the ceRNA hypothesis to assess the impact of endogenous miRNA-sponge interactions.
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              LncRNA: a link between RNA and cancer.

              Unraveling the gene expression networks governing cancer initiation and development is essential while remains largely uncompleted. With the innovations in RNA-seq technologies and computational biology, long noncoding RNAs (lncRNAs) are being identified and characterized at a rapid pace. Recent findings reveal that lncRNAs are implicated in serial steps of cancer development. These lncRNAs interact with DNA, RNA, protein molecules and/or their combinations, acting as an essential regulator in chromatin organization, and transcriptional and post-transcriptional regulation. Their misexpression confers the cancer cell capacities for tumor initiation, growth, and metastasis. The review here will emphasize their aberrant expression and function in cancer, and the roles in cancer diagnosis and therapy will be also discussed.

                Author and article information

                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                10 April 2018
                : 9
                1Department of Internal Medicine, Division of Rheumatology, The Third Affiliated Hospital of Sun Yat-sen University , Guangzhou, China
                2Department of Internal Medicine, Division of Rheumatology, The Affiliated Hospital of Shenzhen University , Shenzhen, China
                3Center for Clinic Immunology, The Third Affiliated Hospital of Sun Yat-sen University , Guangzhou, China
                4Department of Medicine, Division of Rheumatology, Hershey Medical Center at Penn State University , Hershey, PA, United States
                5Department of Pediatrics and Microbiology-Immunology, Georgetown University Medical Center , Washington, DC, United States
                Author notes

                Edited by: Jixin Zhong, Case Western Reserve University, United States

                Reviewed by: Zhanguo Li, Peking University People’s Hospital, China; Cao Feng Lin, First Affiliated Hospital of Harbin Medical University, China; Liwu Li, Virginia Tech, United States

                *Correspondence: Song Guo Zheng, szheng1@ ; Yun Feng Pan, p-yunfeng@

                These authors have contributed equally to this work.

                Specialty section: This article was submitted to Inflammation, a section of the journal Frontiers in Immunology

                Copyright © 2018 Mo, Guo, Yang, Liu, Bi, Liu, Fang, Luo, Wang, Bellanti, Pan and Zheng.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 6, Tables: 0, Equations: 0, References: 40, Pages: 11, Words: 6639
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Award ID: 81671611
                Original Research


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