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      miR-34a as hub of T cell regulation networks

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          Abstract

          Background

          Micro(mi)RNAs are increasingly recognized as central regulators of immune cell function. While it has been predicted that miRNAs have multiple targets, the majority of these predictions still await experimental confirmation. Here, miR-34a, a well-known tumor suppressor, is analyzed for targeting genes involved in immune system processes of leucocytes.

          Methods

          Using an in-silico approach, we combined miRNA target prediction with GeneTrail2, a web tool for Multi-omics enrichment analysis, to identify miR-34a target genes, which are involved in the immune system process subcategory of Gene Ontology.

          Results

          Out of the 193 predicted target genes in this subcategory we experimentally tested 22 target genes and confirmed binding of miR-34a to 14 target genes including VAMP2, IKBKE, MYH9, MARCH8, KLRK1, CD11A, TRAFD1, CCR1, PYDC1, PRF1, PIK3R2, PIK3CD, AP1B1, and ADAM10 by dual luciferase assays. By transfecting Jurkat, primary CD4 + and CD8 + T cells with miR-34a, we demonstrated that ectopic expression of miR-34a leads to reduced levels of endogenous VAMP2 and CD11A, which are central to the analyzed subcategories. Functional downstream analysis of miR-34a over-expression in activated CD8 + T cells exhibits a distinct decrease of PRF1 secretion.

          Conclusions

          By simultaneous targeting of 14 mRNAs miR-34a acts as major hub of T cell regulatory networks suggesting to utilize miR-34a as target of intervention towards a modulation of the immune responsiveness of T-cells in a broad tumor context.

          Electronic supplementary material

          The online version of this article (10.1186/s40425-019-0670-5) contains supplementary material, which is available to authorized users.

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          Most cited references38

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          Perforin-mediated target-cell death and immune homeostasis.

          The granule exocytosis pathway of cytotoxic lymphocytes is crucial for immune surveillance and homeostasis. The trafficking of granule components, including the membrane-disruptive protein perforin, to the immunological synapse leads to the delivery of granule proteases (granzymes) into the target cell and its destruction through apoptosis. Several independent molecular abnormalities associated with defects of either granule trafficking or perforin function can cause cytotoxic lymphocyte dysfunction. In humans, inherited perforin mutations result in severe immune dysregulation that manifests as familial haemophagocytic lymphohistiocytosis. This Review describes recent progress in defining the structure, function, biochemistry and cell biology of perforin.
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            Toward the blood-borne miRNome of human diseases.

            In a multicenter study, we determined the expression profiles of 863 microRNAs by array analysis of 454 blood samples from human individuals with different cancers or noncancer diseases, and validated this 'miRNome' by quantitative real-time PCR. We detected consistently deregulated profiles for all tested diseases; pathway analysis confirmed disease association of the respective microRNAs. We observed significant correlations (P = 0.004) between the genomic location of disease-associated genetic variants and deregulated microRNAs.
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              Principles and effects of microRNA-mediated post-transcriptional gene regulation.

              MicroRNAs (miRNAs) are abundant regulatory RNAs involved in the regulation of many key biological processes. Recent advances in understanding the mechanism of RNA interference and miRNA-mediated mechanisms shed light on major principals of the formation of the regulatory complex and provide models to explain how these small regulatory RNA species interfere with gene expression and how they influence the translational status of the transcriptome.
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                Author and article information

                Contributors
                +49 (0) 6841-1626074 , martin.hart@uks.eu
                Barbara.Walch@uks.eu
                lena.krammes@uni-saarland.de
                tkehl@bioinf.uni-sb.de
                stefanie.rheinheimer@uks.eu
                Tanja.Taenzer@uks.eu
                Birgit.Glombitza@uks.eu
                Martina.Sester@uks.eu
                len@bioinf.uni-sb.de
                andreas.keller@ccb.uni-saarland.de
                eckart.meese@uks.eu
                Journal
                J Immunother Cancer
                J Immunother Cancer
                Journal for Immunotherapy of Cancer
                BioMed Central (London )
                2051-1426
                16 July 2019
                16 July 2019
                2019
                : 7
                : 187
                Affiliations
                [1 ]ISNI 0000 0001 2167 7588, GRID grid.11749.3a, Institute of Human Genetics, Saarland University, ; Building 60, 66421 Homburg, Germany
                [2 ]ISNI 0000 0001 2167 7588, GRID grid.11749.3a, Institute of Virology and Center of Human and Molecular Biology, , Saarland University, ; 66421 Homburg, Germany
                [3 ]ISNI 0000 0001 2167 7588, GRID grid.11749.3a, Center for Bioinformatics, , Saarland University, ; 66123 Saarbrücken, Germany
                [4 ]ISNI 0000 0001 2167 7588, GRID grid.11749.3a, Department of Transplant and Infection Immunology, , Saarland University, ; 66421 Homburg, Germany
                [5 ]ISNI 0000 0001 2167 7588, GRID grid.11749.3a, Chair for Clinical Bioinformatics, , Saarland University, ; 66123 Saarbrücken, Germany
                Author information
                http://orcid.org/0000-0001-9361-8106
                Article
                670
                10.1186/s40425-019-0670-5
                6636054
                31311583
                617540a6-3544-4c75-9dcd-845047940f1e
                © 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
                : 5 March 2019
                : 8 July 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100011102, Seventh Framework Programme;
                Award ID: 600841
                Funded by: FundRef http://dx.doi.org/10.13039/100000864, Michael J. Fox Foundation for Parkinson's Research;
                Award ID: 14446
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2019

                mir-34a,immune system process, cd11a,vamp2,cd4 + & cd8+ t cells

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