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      Activation of STAT3 signaling is mediated by TFF1 silencing in gastric neoplasia

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          Abstract

          TFF1, a secreted protein, plays an essential role in keeping the integrity of gastric mucosa and its barrier function. Loss of TFF1 expression in the TFF1-knockout (KO) mouse leads to a pro-inflammatory phenotype with a cascade of gastric lesions that include low-grade dysplasia, high-grade dysplasia, and adenocarcinomas. In this study, we demonstrate nuclear localization of p-STAT Y705, with significant overexpression of several STAT3 target genes in gastric glands from the TFF1 -KO mice. We also show frequent loss of TFF1 with nuclear localization of STAT3 in human gastric cancers. The reconstitution of TFF1 protein in human gastric cancer cells and 3D gastric glands organoids from TFF1-KO mice abrogates IL6-induced nuclear p-STAT3 Y705 expression. Reconstitution of TFF1 inhibits IL6-induced STAT3 transcription activity, suppressing expression of its target genes. TFF1 blocks IL6Rα-GP130 complex formation through interfering with binding of IL6 to its receptor IL6Rα. These findings demonstrate a functional role of TFF1 in suppressing gastric tumorigenesis by impeding the IL6-STAT3 pro-inflammatory signaling axis.

          Abstract

          Trefoil factor 1 (TFF1) is a protein secreted by the gastric mucosa that protects against gastric tumourigenesis. Here, the authors show that TFF1 inhibits the oncogenic inflammatory response and IL-6-mediated STAT3 activation by interfering with the binding of IL6 to its receptor IL6Rα.

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          Most cited references 33

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          Hexameric structure and assembly of the interleukin-6/IL-6 alpha-receptor/gp130 complex.

          Interleukin-6 (IL-6) is an immunoregulatory cytokine that activates a cell-surface signaling assembly composed of IL-6, the IL-6 alpha-receptor (IL-6Ralpha), and the shared signaling receptor gp130. The 3.65 angstrom-resolution structure of the extracellular signaling complex reveals a hexameric, interlocking assembly mediated by a total of 10 symmetry-related, thermodynamically coupled interfaces. Assembly of the hexameric complex occurs sequentially: IL-6 is first engaged by IL-6Ralpha and then presented to gp130in the proper geometry to facilitate a cooperative transition into the high-affinity, signaling-competent hexamer. The quaternary structures of other IL-6/IL-12 family signaling complexes are likely constructed by means of a similar topological blueprint.
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            Interleukin 17 is a chief orchestrator of immunity

             Marc Veldhoen (2017)
            Although interleukin 17 (IL-17) has modest activity on its own, it has a substantial impact in immunity through its synergistic action with other factors and its self-sustaining feedback loop. Veldhoen discusses the role of IL-17 during infections.
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              Therapeutic modulators of STAT signalling for human diseases.

              The signal transducer and activator of transcription (STAT) proteins have important roles in biological processes. The abnormal activation of STAT signalling pathways is also implicated in many human diseases, including cancer, autoimmune diseases, rheumatoid arthritis, asthma and diabetes. Over a decade has passed since the first inhibitor of a STAT protein was reported and efforts to discover modulators of STAT signalling as therapeutics continue. This Review discusses the outcomes of the ongoing drug discovery research endeavours against STAT proteins, provides perspectives on new directions for accelerating the discovery of drug candidates, and highlights the noteworthy candidate therapeutics that have progressed to clinical trials.
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                Author and article information

                Contributors
                welrifai@med.miami.edu
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                10 July 2019
                10 July 2019
                2019
                : 10
                Affiliations
                [1 ]Department of Veterans Affairs, Miami Healthcare System, Miami, FL USA
                [2 ]ISNI 0000 0004 1936 8606, GRID grid.26790.3a, Department of Surgery, , University of Miami Miller School of Medicine, ; Miami, FL USA
                [3 ]Division of Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar
                [4 ]ISNI 0000 0004 1936 9916, GRID grid.412807.8, Department of Surgery, , Vanderbilt University Medical Center, ; Nashville, TN USA
                [5 ]ISNI 0000 0004 1936 9916, GRID grid.412807.8, Department of Medicine, , Vanderbilt University Medical Center, ; Nashville, TN USA
                [6 ]ISNI 0000 0004 1936 9916, GRID grid.412807.8, Department of Pathology, , Vanderbilt University Medical Center, ; Nashville, TN USA
                [7 ]ISNI 0000 0004 1936 8606, GRID grid.26790.3a, Department of Public Health Sciences, Division of Biostatistics, , University of Miami Miller School of Medicine, ; Miami, FL USA
                [8 ]ISNI 0000 0004 1936 8606, GRID grid.26790.3a, Sylvester Comprehensive Cancer Center, , University of Miami Miller School of Medicine, ; Miami, FL USA
                Article
                11011
                10.1038/s41467-019-11011-4
                6620282
                31292446
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                Funding
                Funded by: FundRef https://doi.org/10.13039/100000002, U.S. Department of Health & Human Services | National Institutes of Health (NIH);
                Award ID: R01CA93999
                Award Recipient :
                Categories
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                Custom metadata
                © The Author(s) 2019

                Uncategorized

                cancer, cell biology, gastroenterology

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