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      Inflammation-Associated Senescence Promotes Helicobacter pylori–Induced Atrophic Gastritis

      research-article
      1 , 2 , 4 , 1 , 2 , 4 , 1 , 2 , 1 , 2 , 1 , 2 , 4 , 1 , 2 , 4 , 1 , 2 , 3 , 4 , 1 , 2 , 3 , 4 , 1 , 2 , 1 , 2 , 1 , 2 , 3 , , 1 , 2 ,
      Cellular and Molecular Gastroenterology and Hepatology
      Elsevier
      H pylori, Mucosa Atrophy, Senescent Cell, C-X-C Motif Chemokine Receptor 2, AG, atrophic gastritis, BrdU, bromodeoxyuridine, CagA, cytotoxin-associated gene A, CDKN, cyclin-dependent kinase inhibitor, CG, chronic gastritis, ChIP, chromatin immunoprecipitation, CXCL, C-X-C motif chemokine ligand, CXCR2, C-X-C motif chemokine receptor 2, DP, dysplasia, GEO, Gene Expression Omnibus, GSEA, gene set enrichment analysis, IHC, immunohistochemical, IL, interleukin, IM, intestinal metaplasia, MNU, N-methyl-N-nitrosourea, MOI, multiplicity of infection, mRNA, messenger RNA, NF-κB, nuclear factor-κB, NFKB1, nuclear factor-κB subunit 1, PBS, phosphate-buffered saline, PMSS1, pre-mouse Sydney strain 1, qPCR, quantitative polymerase chain reaction, RELA, RELA proto-oncogene, nuclear factor-κB subunit, SASP, senescence-associated secretory phenotype, TP53, tumor protein p53

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          Abstract

          Background & Aims

          The association between cellular senescence and Helicobacter pylori–induced atrophic gastritis is not clear. Here, we explore the role of cellular senescence in H pylori–induced atrophic gastritis and the underlying mechanism.

          Methods

          C57BL/6J mice were infected with H pylori for biological and mechanistic studies in vivo. Gastric precancerous lesions from patients and mouse models were collected and analyzed using senescence-associated beta-galactosidase, Sudan Black B, and immunohistochemical staining to analyze senescent cells, signaling pathways, and H pylori infection. Chromatin immunoprecipitation, luciferase reporter assays, and other techniques were used to explore the underlying mechanism in vitro.

          Results

          Gastric mucosa atrophy was highly associated with cellular senescence. H pylori promoted gastric epithelial cell senescence in vitro and in vivo in a manner that depended on C-X-C motif chemokine receptor 2 (CXCR2) signaling. Interestingly, H pylori infection not only up-regulated the expression of CXCR2 ligands, C-X-C motif chemokine ligands 1 and 8, but also transcriptionally up-regulated the expression of CXCR2 via the nuclear factor-κB subunit 1 directly. In addition, CXCR2 formed a positive feedback loop with p53 to continually enhance senescence. Pharmaceutical inhibition of CXCR2 in an H pylori–infected mouse model attenuated mucosal senescence and atrophy, and delayed further precancerous lesion progression.

          Conclusions

          Our study showed a new mechanism of H pylori–induced atrophic gastritis through CXCR2-mediated cellular senescence. Inhibition of CXCR2 signaling is suggested as a potential preventive therapy for targeting H pylori–induced atrophic gastritis. GEO data set accession numbers: GSE47797 and GSE3556.

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          Most cited references55

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          The Hallmarks of Aging

          Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. This deterioration is the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases. Aging research has experienced an unprecedented advance over recent years, particularly with the discovery that the rate of aging is controlled, at least to some extent, by genetic pathways and biochemical processes conserved in evolution. This Review enumerates nine tentative hallmarks that represent common denominators of aging in different organisms, with special emphasis on mammalian aging. These hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. A major challenge is to dissect the interconnectedness between the candidate hallmarks and their relative contributions to aging, with the final goal of identifying pharmaceutical targets to improve human health during aging, with minimal side effects. Copyright © 2013 Elsevier Inc. All rights reserved.
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            Persistent DNA damage signaling triggers senescence-associated inflammatory cytokine secretion

            Cellular senescence suppresses cancer by stably arresting the proliferation of damaged cells1. Paradoxically, senescent cells also secrete factors that alter tissue microenvironments2. The pathways regulating this secretion are unknown. We show that damaged human cells develop persistent chromatin lesions bearing hallmarks of DNA double-strand breaks (DSBs), which initiate increased secretion of inflammatory cytokines such as interleukin-6 (IL-6). Cytokine secretion occurred only after establishment of persistent DNA damage signaling, usually associated with senescence, not after transient DNA damage responses (DDR). Initiation and maintenance of this cytokine response required the DDR proteins ATM, NBS1 and CHK2, but not the cell cycle arrest enforcers p53 and pRb. ATM was also essential for IL-6 secretion during oncogene-induced senescence and by damaged cells that bypass senescence. Further, DDR activity and IL-6 were elevated in human cancers, and ATM-depletion suppressed the ability of senescent cells to stimulate IL-6-dependent cancer cell invasiveness. Thus, in addition to orchestrating cell cycle checkpoints and DNA repair, a novel and important role of the DDR is to allow damaged cells to communicate their compromised state to the surrounding tissue.
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              Chemokine signaling via the CXCR2 receptor reinforces senescence.

              Cells enter senescence, a state of stable proliferative arrest, in response to a variety of cellular stresses, including telomere erosion, DNA damage, and oncogenic signaling, which acts as a barrier against malignant transformation in vivo. To identify genes controlling senescence, we conducted an unbiased screen for small hairpin RNAs that extend the life span of primary human fibroblasts. Here, we report that knocking down the chemokine receptor CXCR2 (IL8RB) alleviates both replicative and oncogene-induced senescence (OIS) and diminishes the DNA-damage response. Conversely, ectopic expression of CXCR2 results in premature senescence via a p53-dependent mechanism. Cells undergoing OIS secrete multiple CXCR2-binding chemokines in a program that is regulated by the NF-kappaB and C/EBPbeta transcription factors and coordinately induce CXCR2 expression. CXCR2 upregulation is also observed in preneoplastic lesions in vivo. These results suggest that senescent cells activate a self-amplifying secretory network in which CXCR2-binding chemokines reinforce growth arrest.
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                Author and article information

                Contributors
                Journal
                Cell Mol Gastroenterol Hepatol
                Cell Mol Gastroenterol Hepatol
                Cellular and Molecular Gastroenterology and Hepatology
                Elsevier
                2352-345X
                2021
                05 November 2020
                : 11
                : 3
                : 857-880
                Affiliations
                [1 ]Center of Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
                [4 ]Laboratory of General Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
                [2 ]Center for Diagnosis and Treatment of Gastric Cancer, Sun Yat-sen University, Guangdong, China
                [3 ]Center for Digestive Disease, the Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
                Author notes
                [] Correspondence Address correspondence to: Jianbo Xu, MD, PhD, or Yulong He, MD, PhD, Center of Gastrointestinal Surgery, First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan 2nd Road Guangzhou, Guangdong Province, PR China 510080. fax: (86) 20-28823389. heyulong@ 123456mail.sysu.edu.cn xjianb@ 123456mail.sysu.edu.cn
                Article
                S2352-345X(20)30179-X
                10.1016/j.jcmgh.2020.10.015
                7859172
                33161156
                f0d6a7c5-9dfe-4794-b1cc-9b1533e736ee
                © 2020 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 16 January 2020
                : 29 October 2020
                Categories
                Original Research

                h pylori,mucosa atrophy,senescent cell,c-x-c motif chemokine receptor 2,ag, atrophic gastritis,brdu, bromodeoxyuridine,caga, cytotoxin-associated gene a,cdkn, cyclin-dependent kinase inhibitor,cg, chronic gastritis,chip, chromatin immunoprecipitation,cxcl, c-x-c motif chemokine ligand,cxcr2, c-x-c motif chemokine receptor 2,dp, dysplasia,geo, gene expression omnibus,gsea, gene set enrichment analysis,ihc, immunohistochemical,il, interleukin,im, intestinal metaplasia,mnu, n-methyl-n-nitrosourea,moi, multiplicity of infection,mrna, messenger rna,nf-κb, nuclear factor-κb,nfkb1, nuclear factor-κb subunit 1,pbs, phosphate-buffered saline,pmss1, pre-mouse sydney strain 1,qpcr, quantitative polymerase chain reaction,rela, rela proto-oncogene, nuclear factor-κb subunit,sasp, senescence-associated secretory phenotype,tp53, tumor protein p53

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