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      Status of kinases in Epstein-Barr virus and Helicobacter pylori Coinfection in gastric Cancer cells

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          Abstract

          Background

          Helicobacter pylori (H. pylori) and Epstein - Barr virus (EBV) plays a significant role in aggressive gastric cancer (GC). The investigation of genes associated with these pathogens and host kinases may be essential to understand the early and dynamic progression of GC.

          Aim

          The study aimed to demonstrate the coinfection of EBV and H. pylori in the AGS cells through morphological changes, expression of the kinase and the probable apoptotic pathways.

          Methods

          Genomic DNA isolation of H. pylori and its characterization from clinical samples were performed. RT-qPCR of kinases was applied to scrutinize the gene expression of kinases in co-infected GC in a direct and indirect (separated through insert size 0.45 μm) H. pylori infection set up. Morphological changes in co-infected GC were quantified by measuring the tapering ends of gastric epithelial cells. Gene expression profiling of apoptotic genes was assessed through RT-qPCR.

          Results

          An interleukin-2-inducible T-cell kinase (ITK) showed significant upregulation with indirect H. pylori infection. Moreover, Ephrin type-B receptor six precursors (EPHB6) and Tyrosine-protein kinase Fyn (FYN) showed significant upregulation with direct coinfection. The tapering ends in AGS cells were found to be extended after 12 h. A total of 24 kinase genes were selected, out of which EPHB6, ITK, FYN, and TYK2 showed high expression as early as 12 h. These kinases may lead to rapid morphological changes in co-infected gastric cells . Likewise, apoptotic gene expression such as APAF-1 and Bcl2 family genes such as BAD, BID, BIK, BIM, BAX, AND BAK were significantly down-regulated in co-infected AGS cells.

          Conclusion

          All the experiments were performed with novel isolates of H. pylori isolated from central India, for the functional assessment of GC. The effect of coinfection with EBV was more profoundly observed on morphological changes in AGS cells at 12 h as quantified by measuring the tapering of ends. This study also identifies the kinase and apoptotic genes modulated in co-infected cells, through direct and indirect approaches. We report that ITK, EPHB6, TYK2, FYN kinase are enhanced, whereas apoptotic genes such as APAF-1, BIK, FASL, BAX are significantly down-regulated in AGS cells coinfected with EBV and H. pylori.

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          Most cited references36

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          Triggering and modulation of apoptosis by oxidative stress.

          Cell survival requires multiple factors, including appropriate proportions of molecular oxygen and various antioxidants. Although most oxidative insults can be overcome by the cell's natural defenses, sustained perturbation of this balance may result in either apoptotic or necrotic cell death. Numerous, recent studies have shown that the mode of cell death that occurs depends on the severity of the insult. Oxidants and antioxidants can not only determine cell fate, but can also modulate the mode of cell death. Effects of oxidative stress on components of the apoptotic machinery may mediate this modulation. This review will address some of the current paradigms for oxidative stress and apoptosis, and discuss the potential mechanisms by which oxidants can modulate the apoptotic pathway.
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            Update on Epstein-Barr virus and gastric cancer (review).

            Epstein-Barr virus-associated gastric carcinoma (EBVaGC) is a distinct subtype that accounts for nearly 10% of gastric carcinomas. EBVaGC is defined by monoclonal proliferation of carcinoma cells with latent EBV infection, as demonstrated by EBV-encoded small RNA (EBER) in situ hybridization. EBVaGC has characteristic clinicopathological features, including predominance among males, a proximal location in the stomach, lymphoepithelioma-like histology and a favorable prognosis. EBVaGC belongs to latency type I or II, in which EBERs, EBNA-1, BARTs, LMP-2A and BART miRNAs are expressed. Previous studies have shown that some EBV latent genes have oncogenic properties. Recent advances in genome-wide and comprehensive molecular analyses have demonstrated that both genetic and epigenetic changes contribute to EBVaGC carcinogenesis. Genetic changes that are characteristic of EBVaGC include frequent mutations in PIK3CA and ARID1A and amplification of JAK2 and PD-L1/L2. Global CpG island hypermethylation, which induces epigenetic silencing of tumor suppressor genes, is also a unique feature of EBVaGC and is considered to be crucial for its carcinogenesis. Furthermore, post-transcriptional gene expression regulation by cellular and/or EBV-derived microRNAs has attracted considerable attention. These abnormalities result in significant alterations in gene expression related to cell proliferation, apoptosis, migration and immune signaling pathways. In the present review we highlight the latest findings on EBVaGC from clinicopathological and molecular perspectives to provide a better understanding of EBV involvement in gastric carcinogenesis.
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              Helicobacter pylori vacuolating cytotoxin inhibits T lymphocyte activation.

              Helicobacter pylori (Hp) vacuolating cytotoxin VacA induces cellular vacuolation in epithelial cells. We found that VacA could efficiently block proliferation of T cells by inducing a G1/S cell cycle arrest. It interfered with the T cell receptor/interleukin-2 (IL-2) signaling pathway at the level of the Ca2+-calmodulin-dependent phosphatase calcineurin. Nuclear translocation of nuclear factor of activated T cells (NFAT), a transcription factor acting as a global regulator of immune response genes, was abrogated, resulting in down-regulation of IL-2 transcription. VacA partially mimicked the activity of the immunosuppressive drug FK506 by possibly inducing a local immune suppression, explaining the extraordinary chronicity of Hp infections.
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                Author and article information

                Contributors
                hemcjha@iiti.ac.in
                Journal
                BMC Cancer
                BMC Cancer
                BMC Cancer
                BioMed Central (London )
                1471-2407
                29 September 2020
                29 September 2020
                2020
                : 20
                : 925
                Affiliations
                [1 ]GRID grid.450280.b, ISNI 0000 0004 1769 7721, The Discipline of Biosciences and Biomedical Engineering, , Indian Institute of Technology Indore, ; Room no. 302, School Building, IIT Indore, Khandwa Road, Simrol, Indore, 453552 India
                [2 ]GRID grid.414278.c, ISNI 0000 0004 1800 9070, Choithram Hospital and Research Centre Indore, ; Indore, Madhya Pradesh India
                Author information
                http://orcid.org/0000-0002-9698-4547
                Article
                7377
                10.1186/s12885-020-07377-0
                7523314
                32993565
                f1c26938-e5da-4104-9172-71d69c03e076
                © The Author(s) 2020

                Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/. 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 in a credit line to the data.

                History
                : 6 May 2020
                : 3 September 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001843, Science and Engineering Research Board;
                Award ID: EMR/2017/001637
                Award ID: SB/S2/RJN-132/20/5
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2020

                Oncology & Radiotherapy
                gastric cancer,helicobacter pylori,epstein barr virus,interleukin-2-inducible t-cell kinase,tyrosine-protein kinase fyn,adenocarcinoma gastric cell

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