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Kubo S, Ninomiya R, Kajiwara T, Tokunaga A, Matsuda S, Murakami K, Yamaoka Y, Aigaki T, Hamada F. Helicobacter pylori virulence factor CagA promotes Snail-mediated epithelial-mesenchymal transition and invasive behavior by downregulating Semaphorin 5A in gastric epithelial cells. Biochem Biophys Res Commun 2025; 750:151421. [PMID: 39892055 DOI: 10.1016/j.bbrc.2025.151421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Accepted: 01/28/2025] [Indexed: 02/03/2025]
Abstract
Helicobacter pylori (H. pylori) infection is one of the major risk factors of stomach cancer. Strains carrying the oncogenic cytotoxin CagA (cytotoxin-associated gene A) induce epithelial-mesenchymal transition (EMT) and contribute to tumor progression and metastasis. However, the mechanism in which CagA induces EMT has not been defined. In this study, using genetic methods in Drosophila, we identified Semaphorin 5A (SEMA5A) as a new target for CagA. We showed that infection with CagA-positive H. pylori downregulated the expression level of SEMA5A to induce expression of EMT-driving transcription factor Snail and mesenchymal marker N-cadherin, and promote invasive behavior in gastric epithelial cells. Furthermore, we demonstrated that transient over-expression of SEMA5A in H. pylori-infected cells inhibited CagA-mediated gain of mesenchymal phenotype. These results suggest that SEMA5A could be a key mediator of EMT and gastric carcinogenesis caused by CagA-positive H. pylori infection.
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Affiliation(s)
- Shuichi Kubo
- Department of Anatomy, Faculty of Medicine, Oita University, Yufu, Oita, 879-5593, Japan
| | - Ryo Ninomiya
- Department of Anatomy, Faculty of Medicine, Oita University, Yufu, Oita, 879-5593, Japan
| | - Tooru Kajiwara
- Department of Anatomy, Faculty of Medicine, Oita University, Yufu, Oita, 879-5593, Japan
| | - Akinori Tokunaga
- Division of Laboratory Animal Resources, Life Science Research Laboratory, University of Fukui, Eiheiji, Fukui, 910-1193, Japan
| | - Seiji Matsuda
- Department of Anatomy and Embryology, Ehime University Graduate School of Medicine, Toon, Ehime, 791-0295, Japan
| | - Kazunari Murakami
- Department of Gastroenterology, Faculty of Medicine, Oita University, Yufu, Oita, 879-5593, Japan
| | - Yoshio Yamaoka
- Department of Environmental and Preventive Medicine, Faculty of Medicine, Oita University, Yufu, Oita, 879-5593, Japan; Department of Gastroenterology and Hepatology, Baylor College of Medicine and Michael DeBakey Veterans Affairs Medical Center, Houston, TX, 77030-4211, USA
| | - Toshiro Aigaki
- Department of Biological Sciences, Tokyo Metropolitan University, Hachioji, Tokyo, 192-0397, Japan
| | - Fumihiko Hamada
- Department of Anatomy, Faculty of Medicine, Oita University, Yufu, Oita, 879-5593, Japan.
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Verma J, Anwar MT, Linz B, Backert S, Pachathundikandi SK. The Influence of Gastric Microbiota and Probiotics in Helicobacter pylori Infection and Associated Diseases. Biomedicines 2024; 13:61. [PMID: 39857645 PMCID: PMC11761556 DOI: 10.3390/biomedicines13010061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 12/23/2024] [Accepted: 12/24/2024] [Indexed: 01/27/2025] Open
Abstract
The role of microbiota in human health and disease is becoming increasingly clear as a result of modern microbiome studies in recent decades. The gastrointestinal tract is the major habitat for microbiota in the human body. This microbiota comprises several trillion microorganisms, which is equivalent to almost ten times the total number of cells of the human host. Helicobacter pylori is a known pathogen that colonizes the gastric mucosa of almost half of the world population. H. pylori is associated with several gastric diseases, including gastric cancer (GC) development. However, the impact of the gastric microbiota in the colonization, chronic infection, and pathogenesis is still not fully understood. Several studies have documented qualitative and quantitative changes in the microbiota's composition in the presence or absence of this pathogen. Among the diverse microflora in the stomach, the Firmicutes represent the most notable. Bacteria such as Prevotella sp., Clostridium sp., Lactobacillus sp., and Veillonella sp. were frequently found in the healthy human stomach. In contrast, H.pylori is very dominant during chronic gastritis, increasing the proportion of Proteobacteria in the total microbiota to almost 80%, with decreasing relative proportions of Firmicutes. Likewise, H. pylori and Streptococcus are the most abundant bacteria during peptic ulcer disease. While the development of H. pylori-associated intestinal metaplasia is accompanied by an increase in Bacteroides, the stomachs of GC patients are dominated by Firmicutes such as Lactobacillus and Veillonella, constituting up to 40% of the total microbiota, and by Bacteroidetes such as Prevotella, whereas the numbers of H. pylori are decreasing. This review focuses on some of the consequences of changes in the gastric microbiota and the function of probiotics to modulate H. pylori infection and dysbiosis in general.
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Affiliation(s)
- Jagriti Verma
- Department of Environmental Microbiology, School of Earth and Environmental Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow 226025, India
| | - Md Tanveer Anwar
- Department of Environmental Microbiology, School of Earth and Environmental Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow 226025, India
| | - Bodo Linz
- Chair of Microbiology, Department of Biology, Friedrich Alexander University Erlangen-Nürnberg, Staudtstr. 5, 91058 Erlangen, Germany
| | - Steffen Backert
- Chair of Microbiology, Department of Biology, Friedrich Alexander University Erlangen-Nürnberg, Staudtstr. 5, 91058 Erlangen, Germany
| | - Suneesh Kumar Pachathundikandi
- Department of Environmental Microbiology, School of Earth and Environmental Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow 226025, India
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Elger W, Tegtmeyer N, Rohde M, Linz B, Hirsch C, Backert S. Cultivation and molecular characterization of viable Helicobacter pylori from the root canal of 170 deciduous teeth of children. Cell Commun Signal 2024; 22:578. [PMID: 39627817 PMCID: PMC11613870 DOI: 10.1186/s12964-024-01948-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 11/16/2024] [Indexed: 12/08/2024] Open
Abstract
BACKGROUND Helicobacter pylori is a persistent pathogen in the human stomach. However, the proposed transmission route via the oral cavity is not understood and under intense debate. While dozens of studies have shown by PCR that H. pylori DNA is frequently present in the oral cavity, data on the growth and characterization of viable H. pylori from this compartment are very scarce, and it is unclear whether the bacteria can survive in the oral cavity for longer time periods or even colonize it. METHODS Selective growth methods, scanning electron microscopy, urease assay, Western blotting, PCR, and gene sequencing were applied to identify and examine viable H. pylori in decayed milk teeth. RESULTS Here, we studied viable H. pylori in the plaque and root canals of 170 endodontically infected deciduous teeth that were extracted from 54 children. While H. pylori DNA was detected in several plaque and many root canal samples by PCR, live bacteria could only be cultivated from 28 root canals, but not from plaque. These 28 isolates have been identified as H. pylori by PCR and sequencing of vacA, cagA and htrA genes, phylogenetic analyses, protein expression of major H. pylori virulence factors, and by signal transduction events during infection of human cell lines. CONCLUSIONS Thus, the microaerobic environment in the root canals of endodontically infected teeth may represent a protected and transient reservoir for live H. pylori, especially in individuals with poor dental hygiene, which could serve as a potential source for re-infection of the stomach after antibiotic therapy or for transmission to other individuals.
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Affiliation(s)
- Wieland Elger
- Department of Paediatric Dentistry, University School of Dental Medicine, University of Leipzig, Leipzig, Germany
| | - Nicole Tegtmeyer
- Division of Microbiology, Department Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Manfred Rohde
- Central Facility for Microscopy, Helmholtz Centre for Infection Research, Brunswick, Germany
| | - Bodo Linz
- Division of Microbiology, Department Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Christian Hirsch
- Department of Paediatric Dentistry, University School of Dental Medicine, University of Leipzig, Leipzig, Germany.
| | - Steffen Backert
- Division of Microbiology, Department Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
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Ji X, Wu Q, Cao X, Liu S, Zhang J, Chen S, Shan J, Zhang Y, Li B, Zhao H. Helicobacter pylori East Asian type CagA hijacks more SHIP2 by its EPIYA-D motif to potentiate the oncogenicity. Virulence 2024; 15:2375549. [PMID: 38982595 PMCID: PMC11238919 DOI: 10.1080/21505594.2024.2375549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/11/2024] Open
Abstract
CagA is a significant oncogenic factor injected into host cells by Helicobacter pylori, which is divided into two subtypes: East Asian type (CagAE), characterized by the EPIYA-D motif, and western type (CagAW), harboring the EPIYA-C motif. CagAE has been reported to have higher carcinogenicity than CagAW, although the underlying reason is not fully understood. SHIP2 is an intracellular phosphatase that can be recruited by CagA to perturb the homeostasis of intracellular signaling pathways. In this study, we found that SHIP2 contributes to the higher oncogenicity of CagAE. Co-Immunoprecipitation and Pull-down assays showed that CagAE bind more SHIP2 than CagAW. Immunofluorescence staining showed that a higher amount of SHIP2 recruited by CagAE to the plasma membrane catalyzes the conversion of PI(3,4,5)P3 into PI(3,4)P2. This alteration causes higher activation of Akt signaling, which results in enhanced IL-8 secretion, migration, and invasion of the infected cells. SPR analysis showed that this stronger interaction between CagAE and SHIP2 stems from the higher affinity between the EPIYA-D motif of CagAE and the SH2 domain of SHIP2. Structural analysis revealed the crucial role of the Phe residue at the Y + 5 position in EPIYA-D. After mutating Phe of CagAE into Asp (the corresponding residue in the EPIYA-C motif) or Ala, the activation of downstream Akt signaling was reduced and the malignant transformation of infected cells was alleviated. These findings revealed that CagAE hijacks SHIP2 through its EPIYA-D motif to enhance its carcinogenicity, which provides a better understanding of the higher oncogenic risk of H. pylori CagAE.
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Affiliation(s)
- Xiaofei Ji
- School of Basic Medical Sciences, Binzhou Medical University, Yantai, Shandong, China
| | - Qianwen Wu
- The Second School of Clinical Medicine, Binzhou Medical University, Yantai, Shandong, China
| | - Xinying Cao
- School of Basic Medical Sciences, Binzhou Medical University, Yantai, Shandong, China
| | - Shuzhen Liu
- School of Basic Medical Sciences, Binzhou Medical University, Yantai, Shandong, China
| | - Jianhui Zhang
- School of Basic Medical Sciences, Binzhou Medical University, Yantai, Shandong, China
| | - Si Chen
- School of Basic Medical Sciences, Binzhou Medical University, Yantai, Shandong, China
| | - Jiangfan Shan
- School of Basic Medical Sciences, Binzhou Medical University, Yantai, Shandong, China
| | - Ying Zhang
- The Second School of Clinical Medicine, Binzhou Medical University, Yantai, Shandong, China
| | - Boqing Li
- School of Basic Medical Sciences, Binzhou Medical University, Yantai, Shandong, China
| | - Huilin Zhao
- School of Basic Medical Sciences, Binzhou Medical University, Yantai, Shandong, China
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Xue ZJ, Gong YN, He LH, Sun L, You YH, Fan DJ, Zhang MJ, Yan XM, Zhang JZ. Amino acid deletions at positions 893 and 894 of cytotoxin-associated gene A protein affect Helicobacter pylori gastric epithelial cell interactions. World J Gastroenterol 2024; 30:4449-4460. [PMID: 39534413 PMCID: PMC11551673 DOI: 10.3748/wjg.v30.i41.4449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 09/29/2024] [Accepted: 10/12/2024] [Indexed: 10/23/2024] Open
Abstract
BACKGROUND Helicobacter pylori (H. pylori) persistently colonizes the human gastric mucosa in more than 50% of the global population, leading to various gastroduodenal diseases ranging from chronic gastritis to gastric carcinoma. Cytotoxin-associated gene A (CagA) protein, an important oncoprotein, has highly polymorphic Glu-Pro-Ile-Tyr-Ala segments at the carboxyl terminus, which play crucial roles in pathogenesis. Our previous study revealed a significant association between amino acid deletions at positions 893 and 894 and gastric cancer. AIM To investigate the impact of amino acid deletions at positions 893 and 894 on CagA function. METHODS We selected a representative HZT strain from a gastric cancer patient with amino acid deletions at positions 893 and 894. The cagA gene was amplified and mutated into cagA-NT and cagA-NE (sequence characteristics of strains from nongastric cancer patients), cloned and inserted into pAdtrack-CMV, and then transfected into AGS cells. The expression of cagA and its mutants was examined using real-time polymerase chain reaction and Western blotting, cell elongation via cell counting, F-actin cytoskeleton visualization using fluorescence staining, and interleukin-8 (IL-8) secretion via enzyme-linked immunosorbent assay. RESULTS The results revealed that pAdtrack/cagA induced a more pronounced hummingbird phenotype than pAdtrack/cagA-NT and pAdtrack/cagA-NE (40.88 ± 3.10 vs 32.50 ± 3.17, P < 0.001 and 40.88 ± 3.10 vs 32.17 ± 3.00, P < 0.001) at 12 hours after transfection. At 24 hours, pAdtrack/cagA-NE induced significantly fewer hummingbird phenotypes than pAdtrack/cagA and pAdtrack/cagA-NT (46.02 ± 2.12 vs 53.90 ± 2.10, P < 0.001 and 46.02 ± 2.12 vs 51.15 ± 3.74, P < 0.001). The total amount of F-actin caused by pAdtrack/cagA was significantly lower than that caused by pAdtrack/cagA-NT and pAdtrack/cagA-NE (27.54 ± 17.37 vs 41.51 ± 11.90, P < 0.001 and 27.54 ± 17.37 vs 41.39 ± 14.22, P < 0.001) at 12 hours after transfection. Additionally, pAdtrack/cagA induced higher IL-8 secretion than pAdtrack/cagA-NT and pAdtrack/cagA-NE at different times after transfection. CONCLUSION Amino acid deletions at positions 893 and 894 enhance CagA pathogenicity, which is crucial for revealing the pathogenic mechanism of CagA and identifying biomarkers of highly pathogenic H. pylori.
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Affiliation(s)
- Zhi-Jing Xue
- Research Center of Translational Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, Shandong Province, China
| | - Ya-Nan Gong
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China
| | - Li-Hua He
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China
| | - Lu Sun
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China
| | - Yuan-Hai You
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China
| | - Dong-Jie Fan
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China
| | - Mao-Jun Zhang
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China
| | - Xiao-Mei Yan
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China
| | - Jian-Zhong Zhang
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China
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Naing C, Aung HH, Aye SN, Poovorawan Y, Whittaker MA. CagA toxin and risk of Helicobacter pylori-infected gastric phenotype: A meta-analysis of observational studies. PLoS One 2024; 19:e0307172. [PMID: 39173001 PMCID: PMC11341061 DOI: 10.1371/journal.pone.0307172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 07/01/2024] [Indexed: 08/24/2024] Open
Abstract
BACKGROUND Helicobacter pylori (H. pylori) is frequently associated with non-cardia type gastric cancer, and it is designated as a group I carcinogen. This study aimed to systematically review and meta-analyze the evidence on the prevalence of CagA status in people with gastric disorders in the Indo-Pacific region, and to examine the association of CagA positive in the risk of gastric disorders. This study focused on the Indo-Pacific region owing to the high disability adjusted life-years related to these disorders, the accessibility of efficient treatments for this common bacterial infection, and the varying standard of care for these disorders, particularly among the elderly population in the region. METHODS Relevant studies were identified in the health-related electronic databases including PubMed, Ovid, Medline, Ovid Embase, Index Medicus, and Google Scholar that were published in English between 1 January 2000, and 18 November 2023. For pooled prevalence, meta-analysis of proportional studies was done, after Freeman-Tukey double arcsine transformation of data. A random-effect model was used to compute the pooled odds ratio (OR) and 95% confidence interval (CI) to investigate the relationship between CagA positivity and gastric disorders. RESULTS Twenty-four studies from eight Indo-Pacific countries (Bhutan, India, Indonesia, Malaysia, Myanmar, Singapore, Thailand, Vietnam) were included. Overall pooled prevalence of CagA positivity in H. pylori-infected gastric disorders was 83% (95%CI = 73-91%). Following stratification, the pooled prevalence of CagA positivity was 78% (95%CI = 67-90%) in H. pylori-infected gastritis, 86% (95%CI = 73-96%) in peptic ulcer disease, and 83% (95%CI = 51-100%) in gastric cancer. Geographic locations encountered variations in CagA prevalence. There was a greater risk of developing gastric cancer in those with CagA positivity compared with gastritis (OR = 2.53,95%CI = 1.15-5.55). CONCLUSION Findings suggest that the distribution of CagA in H. pylori-infected gastric disorders varies among different type of gastric disorders in the study countries, and CagA may play a role in the development of gastric cancer. It is important to provide a high standard of care for the management of gastric diseases, particularly in a region where the prevalence of these disorders is high. Better strategies for effective treatment for high-risk groups are required for health programs to revisit this often-neglected infectious disease.
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Affiliation(s)
- Cho Naing
- College of Public Health, Medical and Veterinary Sciences, James Cook University, Queensland, Australia
| | - Htar Htar Aung
- School of Medicine, IMU University, Kuala Lumpur, Malaysia
| | - Saint Nway Aye
- School of Medicine, IMU University, Kuala Lumpur, Malaysia
| | - Yong Poovorawan
- Center of Excellence in Clinical Virology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Maxine A. Whittaker
- College of Public Health, Medical and Veterinary Sciences, James Cook University, Queensland, Australia
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Morin C, Verma VT, Arya T, Casu B, Jolicoeur E, Ruel R, Marinier A, Sygusch J, Baron C. Structure-based design of small molecule inhibitors of the cagT4SS ATPase Cagα of Helicobacter pylori. Biochem Cell Biol 2024; 102:226-237. [PMID: 38377487 DOI: 10.1139/bcb-2023-0331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/22/2024] Open
Abstract
We here describe the structure-based design of small molecule inhibitors of the type IV secretion system of Helicobacter pylori. The secretion system is encoded by the cag pathogenicity island, and we chose Cagα, a hexameric ATPase and member of the family of VirB11-like proteins, as target for inhibitor design. We first solved the crystal structure of Cagα in a complex with the previously identified small molecule inhibitor 1G2. The molecule binds at the interface between two Cagα subunits and mutagenesis of the binding site identified Cagα residues F39 and R73 as critical for 1G2 binding. Based on the inhibitor binding site we synthesized 98 small molecule derivates of 1G2 to improve binding of the inhibitor. We used the production of interleukin-8 of gastric cancer cells during H. pylori infection to screen the potency of inhibitors and we identified five molecules (1G2_1313, 1G2_1338, 1G2_2886, 1G2_2889, and 1G2_2902) that have similar or higher potency than 1G2. Differential scanning fluorimetry suggested that these five molecules bind Cagα, and enzyme assays demonstrated that some are more potent ATPase inhibitors than 1G2. Finally, scanning electron microscopy revealed that 1G2 and its derivatives inhibit the assembly of T4SS-determined extracellular pili suggesting a mechanism for their anti-virulence effect.
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Affiliation(s)
- Claire Morin
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Université de Montréal, Québec, Canada
| | - Vijay Tailor Verma
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Université de Montréal, Québec, Canada
| | - Tarun Arya
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Université de Montréal, Québec, Canada
| | - Bastien Casu
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Université de Montréal, Québec, Canada
| | - Eric Jolicoeur
- Institut de Recherche en Immunologie et Cancérologie, Université de Montréal, Québec, Canada
| | - Réjean Ruel
- Institut de Recherche en Immunologie et Cancérologie, Université de Montréal, Québec, Canada
| | - Anne Marinier
- Institut de Recherche en Immunologie et Cancérologie, Université de Montréal, Québec, Canada
- Department of Chemistry, Faculty of Arts and Sciences, Université de Montréal, Québec, Canada
| | - Jurgen Sygusch
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Université de Montréal, Québec, Canada
| | - Christian Baron
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Université de Montréal, Québec, Canada
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8
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Apoorva E, Jacob R, Rao DN, Kumar S. Helicobacter pylori enhances HLA-C expression in the human gastric adenocarcinoma cells AGS and can protect them from the cytotoxicity of natural killer cells. Helicobacter 2024; 29:e13069. [PMID: 38516860 DOI: 10.1111/hel.13069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 03/05/2024] [Accepted: 03/08/2024] [Indexed: 03/23/2024]
Abstract
Helicobacter pylori (H. pylori) seems to play causative roles in gastric cancers. H. pylori has also been detected in established gastric cancers. How the presence of H. pylori modulates immune response to the cancer is unclear. The cytotoxicity of natural killer (NK) cells, toward infected or malignant cells, is controlled by the repertoire of activating and inhibitory receptors expressed on their surface. Here, we studied H. pylori-induced changes in the expression of ligands, of activating and inhibitory receptors of NK cells, in the gastric adenocarcinoma AGS cells, and their impacts on NK cell responses. AGS cells lacked or had low surface expression of the class I major histocompatibility complex (MHC-I) molecules HLA-E and HLA-C-ligands of the major NK cell inhibitory receptors NKG2A and killer-cell Ig-like receptor (KIR), respectively. However, AGS cells had high surface expression of ligands of activating receptors DNAM-1 and CD2, and of the adhesion molecules LFA-1. Consistently, AGS cells were sensitive to killing by NK cells despite the expression of inhibitory KIR on NK cells. Furthermore, H. pylori enhanced HLA-C surface expression on AGS cells. H. pylori infection enhanced HLA-C protein synthesis, which could explain H. pylori-induced HLA-C surface expression. H. pylori infection enhanced HLA-C surface expression also in the hepatoma Huh7 and HepG2 cells. Furthermore, H. pylori-induced HLA-C surface expression on AGS cells promoted inhibition of NK cells by KIR, and thereby protected AGS cells from NK cell cytotoxicity. These results suggest that H. pylori enhances HLA-C expression in host cells and protects them from the cytotoxic attack of NK cells expressing HLA-C-specific inhibitory receptors.
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Affiliation(s)
- Etikala Apoorva
- CSIR-Centre for Cellular and Molecular Biology, Hyderabad, Telangana, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Rini Jacob
- CSIR-Centre for Cellular and Molecular Biology, Hyderabad, Telangana, India
| | - Desirazu N Rao
- Department of Biochemistry, Indian Institute of Science, Bangalore, India
| | - Santosh Kumar
- CSIR-Centre for Cellular and Molecular Biology, Hyderabad, Telangana, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
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Rasouli M, Safari F, Sobhani N, Alavi M, Roudi R. Regulation of Cellular-Signaling Pathways by Mammalian Proteins Containing Bacterial EPIYA or EPIYA-Like Motifs Predicted to be Phosphorylated. DNA Cell Biol 2024; 43:74-84. [PMID: 38153368 DOI: 10.1089/dna.2023.0350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2023] Open
Abstract
The effector proteins of several pathogenic bacteria contain the Glu-Pro-Ile-Tyr-Ala (EPIYA) motif or other similar motifs. The EPIYA motif is delivered into the host cells by type III and IV secretion systems, through which its tyrosine residue undergoes phosphorylation by host kinases. These motifs atypically interact with a wide range of Src homology 2 (SH2) domain-containing mammalian proteins through tyrosine phosphorylation, which leads to the perturbation of multiple signaling cascades, the spread of infection, and improved bacterial colonization. Interestingly, it has been reported that EPIYA (or EPIYA-like) motifs exist in mammalian proteomes and regulate mammalian cellular-signaling pathways, leading to homeostasis and disease pathophysiology. It is possible that pathogenic bacteria have exploited EPIYA (or EPIYA-like) motifs from mammalian proteins and that the mammalian EPIYA (or EPIYA-like) motifs have evolved to have highly specific interactions with SH2 domain-containing proteins. In this review, we focus on the regulation of mammalian cellular-signaling pathways by mammalian proteins containing these motifs.
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Affiliation(s)
- Mohammad Rasouli
- Department of Biology, Faculty of Science, University of Guilan, Rasht, Iran
| | - Fatemeh Safari
- Department of Biology, Faculty of Science, University of Guilan, Rasht, Iran
| | - Navid Sobhani
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Mana Alavi
- Department of Biology, Faculty of Science, University of Guilan, Rasht, Iran
| | - Raheleh Roudi
- Molecular Imaging Program at Stanford (MIPS), Department of Radiology, Stanford University, Stanford, California, USA
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10
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Rezaei F, Alebouyeh M, Mirbagheri SZ, Ebrahimi A, Foroushani AR, Bakhtiari R. Transcriptional analysis of Helicobacter pylori cytotoxic-associated gene-pathogenicity island in response to different pH levels and proton pump inhibitor exposure. Indian J Gastroenterol 2023; 42:686-693. [PMID: 37665542 DOI: 10.1007/s12664-023-01422-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Accepted: 06/21/2023] [Indexed: 09/05/2023]
Abstract
BACKGROUND Long-term use of proton pump inhibitors (PPIs) can increase the risk of gastric cancer in Helicobacter pylori-infected patients; nevertheless, there is no data about their impact on the pathogenicity of H. pylori. This study aimed at investigating the transcriptional alteration of key gene mediators of cytotoxin-associated gene-pathogenicity island (cag-PAI) among clinical H. pylori isolates in response to omeprazole at different pH levels. METHODS Accordingly, H. pylori isolates with the same virulence genotypes selected from the gastric biopsies of patients and transcriptional alteration in the cag-PAI genes studied in the presence or absence of omeprazole (2 mg/mL) at pH 2.0, 4.0 and 7.0 after 30 and 90 minutes of the treatment. Relative changes in the transcriptional levels were recorded in each assay, separately. RESULTS Of 18 H. pylori isolates, the cag-PAI empty site was detected in four strains, while the presence of cagA, cagL and cagY was characterized in 77.7%, 83.3% and 83.3% of the cag-PAI-positive strains, respectively. Transcriptional analysis of the selected strains showed up-regulation of cagA and cagL, mainly at pH 2.0 and 4.0 after 30 and 90-minute exposure. A diversity in the expression levels of cag-PAI genes was seen among the strains at the extent and time of induction. CONCLUSION Our results showed that omeprazole could increase the expression of H. pylori cagA and cagL at acidic pH. Heterogeneity among the strains probably has an impact on the extent of their interplay with PPIs. Further studies are needed to establish this correlation.
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Affiliation(s)
- Fatemeh Rezaei
- Department of Pathobiology, School of Public Health and Institute Health Research, Tehran University of Medical Sciences, Tehran, Iran
| | - Masoud Alebouyeh
- Pediatric Infections Research Centre, Research Institute for Children's Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyedeh Zohre Mirbagheri
- Department of Pathobiology, School of Public Health and Institute Health Research, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Ebrahimi
- Department of Pathobiology, School of Public Health and Institute Health Research, Tehran University of Medical Sciences, Tehran, Iran
| | - Abbas Rahimi Foroushani
- Department of Epidemiology and Biostatistics, School of Public Health and Institute Health Research, Tehran University of Medical Sciences, Tehran, Iran
| | - Ronak Bakhtiari
- Department of Pathobiology, School of Public Health and Institute Health Research, Tehran University of Medical Sciences, Tehran, Iran.
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11
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Noiri Y, Nagata R. Current status of gastric and oral infection/diseases caused by Helicobacter pylori. ORAL SCIENCE INTERNATIONAL 2023; 20:182-189. [DOI: 10.1002/osi2.1172] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Accepted: 01/17/2023] [Indexed: 01/06/2025]
Abstract
AbstractHelicobacter pylori is found in the stomach, which is its optimal habitat, and is considered an important factor in various serious diseases, including stomach cancer. The World Health Organization has identified H. pylori as a causative agent of gastric cancer, as confirmed by animal experiments in rodents. The fact that H. pylori can live in the harsh environment of stomach acid was the greatest hindrance to the discovery of H. pylori. It was not so long ago, in 1983, that it was successfully isolated and cultured. Subsequently, H. pylori eradication therapy was established, and it became possible to control gastric cancer to some extent. However, the mechanism, route, and mode of H. pylori infection still remain unclear. Furthermore, currently, the prevention of first‐episode gastric cancer and control of recurrent gastric cancer are not perfect. One of the reasons for this may be that the status of H. pylori in the oral cavity, which is the entry point for the organism (the beginning of the digestive system: the first route of infection), is still unknown. Therefore, we reviewed the current status of H. pylori infection in the stomach and oral cavity, focusing on (1) the mechanism of infection, (2) pathogenic factors, (3) the actual status of eradication therapy, and (4) control strategies.
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Affiliation(s)
- Yuichiro Noiri
- Division of Cariology, Operative Dentistry and Endodontics, Faculty of Dentistry and Graduate School of Medical and Dental Sciences Niigata University Niigata Japan
| | - Ryoko Nagata
- Division of Cariology, Operative Dentistry and Endodontics, Faculty of Dentistry and Graduate School of Medical and Dental Sciences Niigata University Niigata Japan
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12
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Fathi D, Elballal MS, Elesawy AE, Abulsoud AI, Elshafei A, Elsakka EG, Ismail A, El-Mahdy HA, Elrebehy MA, Doghish AS. An emphasis on the interaction of signaling pathways highlights the role of miRNAs in the etiology and treatment resistance of gastric cancer. Life Sci 2023; 322:121667. [PMID: 37023952 DOI: 10.1016/j.lfs.2023.121667] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 04/01/2023] [Accepted: 04/03/2023] [Indexed: 04/07/2023]
Abstract
Gastric cancer (GC) is 4th in incidence and mortality rates globally. Several genetic and epigenetic factors, including microRNAs (miRNAs), affect its initiation and progression. miRNAs are short chains of nucleic acids that can regulate several cellular processes by controlling their gene expression. So, dysregulation of miRNAs expressions is associated with GC initiation, progression, invasion capacity, apoptosis evasions, angiogenesis, promotion and EMT enhancement. Of important pathways in GC and controlled by miRNAs are Wnt/β-catenin signaling, HMGA2/mTOR/P-gp, PI3K/AKT/c-Myc, VEGFR and TGFb signaling. Hence, this review was conducted to review an updated view of the role of miRNAs in GC pathogenesis and their modulatory effects on responses to different GC treatment modalities.
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13
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Shin WS, Xie F, Chen B, Yu P, Yu J, To KF, Kang W. Updated Epidemiology of Gastric Cancer in Asia: Decreased Incidence but Still a Big Challenge. Cancers (Basel) 2023; 15:cancers15092639. [PMID: 37174105 PMCID: PMC10177574 DOI: 10.3390/cancers15092639] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 05/02/2023] [Accepted: 05/02/2023] [Indexed: 05/15/2023] Open
Abstract
Despite the decline in incidence and mortality rates, gastric cancer (GC) is the fifth leading cause of cancer deaths worldwide. The incidence and mortality of GC are exceptionally high in Asia due to high H. pylori infection, dietary habits, smoking behaviors, and heavy alcohol consumption. In Asia, males are more susceptible to developing GC than females. Variations in H. pylori strains and prevalence rates may contribute to the differences in incidence and mortality rates across Asian countries. Large-scale H. pylori eradication was one of the effective ways to reduce GC incidences. Treatment methods and clinical trials have evolved, but the 5-year survival rate of advanced GC is still low. Efforts should be put towards large-scale screening and early diagnosis, precision medicine, and deep mechanism studies on the interplay of GC cells and microenvironments for dealing with peritoneal metastasis and prolonging patients' survival.
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Affiliation(s)
- Wing Sum Shin
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Fuda Xie
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong 999077, China
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong 999077, China
- CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen 518000, China
| | - Bonan Chen
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong 999077, China
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong 999077, China
- CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen 518000, China
| | - Peiyao Yu
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Jun Yu
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong 999077, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Ka Fai To
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong 999077, China
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Wei Kang
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong 999077, China
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong 999077, China
- CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen 518000, China
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14
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Nguyen QA, Schmitt L, Mejías-Luque R, Gerhard M. Effects of Helicobacter pylori adhesin HopQ binding to CEACAM receptors in the human stomach. Front Immunol 2023; 14:1113478. [PMID: 36891299 PMCID: PMC9986547 DOI: 10.3389/fimmu.2023.1113478] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 02/06/2023] [Indexed: 02/22/2023] Open
Abstract
Helicobacter pylori has developed several strategies using its diverse virulence factors to trigger and, at the same time, limit the host's inflammatory responses in order to establish a chronic infection in the human stomach. One of the virulence factors that has recently received more attention is a member of the Helicobacter outer membrane protein family, the adhesin HopQ, which binds to the human Carcinoembryonic Antigen-related Cell Adhesion Molecules (CEACAMs) on the host cell surface. The HopQ-CEACAM interaction facilitates the translocation of the cytotoxin-associated gene A (CagA), an important effector protein of H. pylori, into host cells via the Type IV secretion system (T4SS). Both the T4SS itself and CagA are important virulence factors that are linked to many aberrant host signaling cascades. In the last few years, many studies have emphasized the prerequisite role of the HopQ-CEACAM interaction not only for the adhesion of this pathogen to host cells but also for the regulation of cellular processes. This review summarizes recent findings about the structural characteristics of the HopQ-CEACAM complex and the consequences of this interaction in gastric epithelial cells as well as immune cells. Given that the upregulation of CEACAMs is associated with many H. pylori-induced gastric diseases including gastritis and gastric cancer, these data may enable us to better understand the mechanisms of H. pylori's pathogenicity.
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Affiliation(s)
- Quynh Anh Nguyen
- Institute for Medical Microbiology, Immunology and Hygiene, School of Medicine, Technical University Munich, Munich, Germany
| | - Leonard Schmitt
- Institute for Medical Microbiology, Immunology and Hygiene, School of Medicine, Technical University Munich, Munich, Germany
| | - Raquel Mejías-Luque
- Institute for Medical Microbiology, Immunology and Hygiene, School of Medicine, Technical University Munich, Munich, Germany
| | - Markus Gerhard
- Institute for Medical Microbiology, Immunology and Hygiene, School of Medicine, Technical University Munich, Munich, Germany
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15
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Guzmán-Herrador DL, Fernández-Gómez A, Llosa M. Recruitment of heterologous substrates by bacterial secretion systems for transkingdom translocation. Front Cell Infect Microbiol 2023; 13:1146000. [PMID: 36949816 PMCID: PMC10025392 DOI: 10.3389/fcimb.2023.1146000] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 02/22/2023] [Indexed: 03/08/2023] Open
Abstract
Bacterial secretion systems mediate the selective exchange of macromolecules between bacteria and their environment, playing a pivotal role in processes such as horizontal gene transfer or virulence. Among the different families of secretion systems, Type III, IV and VI (T3SS, T4SS and T6SS) share the ability to inject their substrates into human cells, opening up the possibility of using them as customized injectors. For this to happen, it is necessary to understand how substrates are recruited and to be able to engineer secretion signals, so that the transmembrane machineries can recognize and translocate the desired substrates in place of their own. Other factors, such as recruiting proteins, chaperones, and the degree of unfolding required to cross through the secretion channel, may also affect transport. Advances in the knowledge of the secretion mechanism have allowed heterologous substrate engineering to accomplish translocation by T3SS, and to a lesser extent, T4SS and T6SS into human cells. In the case of T4SS, transport of nucleoprotein complexes adds a bonus to its biotechnological potential. Here, we review the current knowledge on substrate recognition by these secretion systems, the many examples of heterologous substrate translocation by engineering of secretion signals, and the current and future biotechnological and biomedical applications derived from this approach.
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16
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Freire de Melo F, Marques HS, Rocha Pinheiro SL, Lemos FFB, Silva Luz M, Nayara Teixeira K, Souza CL, Oliveira MV. Influence of Helicobacter pylori oncoprotein CagA in gastric cancer: A critical-reflective analysis. World J Clin Oncol 2022; 13:866-879. [PMID: 36483973 PMCID: PMC9724182 DOI: 10.5306/wjco.v13.i11.866] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Revised: 09/20/2022] [Accepted: 10/11/2022] [Indexed: 11/21/2022] Open
Abstract
Gastric cancer is the fifth most common malignancy and third leading cancer-related cause of death worldwide. Helicobacter pylori is a Gram-negative bacterium that inhabits the gastric environment of 60.3% of the world’s population and represents the main risk factor for the onset of gastric neoplasms. CagA is the most important virulence factor in H. pylori, and is a translocated oncoprotein that induces morphofunctional modifications in gastric epithelial cells and a chronic inflammatory response that increases the risk of developing precancerous lesions. Upon translocation and tyrosine phosphorylation, CagA moves to the cell membrane and acts as a pathological scaffold protein that simultaneously interacts with multiple intracellular signaling pathways, thereby disrupting cell proliferation, differentiation and apoptosis. All these alterations in cell biology increase the risk of damaged cells acquiring pro-oncogenic genetic changes. In this sense, once gastric cancer sets in, its perpetuation is independent of the presence of the oncoprotein, characterizing a “hit-and-run” carcinogenic mechanism. Therefore, this review aims to describe H. pylori- and CagA-related oncogenic mechanisms, to update readers and discuss the novelties and perspectives in this field.
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Affiliation(s)
- Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Brazil
| | - Hanna Santos Marques
- Campus Vitória da Conquista, Universidade Estadual do Sudoeste da Bahia, Vitória da Conquista 45029-094, Brazil
| | - Samuel Luca Rocha Pinheiro
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Brazil
| | - Fabian Fellipe Bueno Lemos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Brazil
| | - Marcel Silva Luz
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Brazil
| | | | - Cláudio Lima Souza
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Brazil
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17
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Freire de Melo F, Marques HS, Fellipe Bueno Lemos F, Silva Luz M, Rocha Pinheiro SL, de Carvalho LS, Souza CL, Oliveira MV. Role of nickel-regulated small RNA in modulation of Helicobacter pylori virulence factors. World J Clin Cases 2022; 10:11283-11291. [PMID: 36387830 PMCID: PMC9649571 DOI: 10.12998/wjcc.v10.i31.11283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 08/14/2022] [Accepted: 09/06/2022] [Indexed: 02/05/2023] Open
Abstract
Helicobacter pylori (H. pylori) is a Gram-negative bacterium that infects about half of the world's population. H. pylori infection prevails by several mechanisms of adaptation of the bacteria and by its virulence factors including the cytotoxin associated antigen A (CagA). CagA is an oncoprotein that is the protagonist of gastric carcinogenesis associated with prolonged H. pylori infection. In this sense, small regulatory RNAs (sRNAs) are important macromolecules capable of inhibiting and activating gene expression. This function allows sRNAs to act in adjusting to unstable environmental conditions and in responding to cellular stresses in bacterial infections. Recent discoveries have shown that nickel-regulated small RNA (NikS) is a post-transcriptional regulator of virulence properties of H. pylori, including the oncoprotein CagA. Notably, high concentrations of nickel cause the reduction of NikS expression and consequently this increases the levels of CagA. In addition, NikS expression appears to be lower in clinical isolates from patients with gastric cancer when compared to patients without. With that in mind, this minireview approaches, in an accessible way, the most important and current aspects about the role of NikS in the control of virulence factors of H. pylori and the potential clinical repercussions of this modulation.
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Affiliation(s)
- Fabrício Freire de Melo
- Institution Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Brazil
| | - Hanna Santos Marques
- Campus Vitória da Conquista, Universidade Estadual do Sudoeste da Bahia, Vitória da Conquista 45083-900, Brazil
| | - Fabian Fellipe Bueno Lemos
- Institution Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Brazil
| | - Marcel Silva Luz
- Institution Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Brazil
| | - Samuel Luca Rocha Pinheiro
- Institution Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Brazil
| | - Lorena Sousa de Carvalho
- Institution Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Brazil
| | - Cláudio Lima Souza
- Institution Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Brazil
| | - Márcio Vasconcelos Oliveira
- Institution Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Brazil
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18
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Host Cell Antimicrobial Responses against Helicobacter pylori Infection: From Biological Aspects to Therapeutic Strategies. Int J Mol Sci 2022; 23:ijms231810941. [PMID: 36142852 PMCID: PMC9504325 DOI: 10.3390/ijms231810941] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 09/13/2022] [Accepted: 09/16/2022] [Indexed: 02/07/2023] Open
Abstract
The colonization of Helicobacter pylori (H. pylori) in human gastric mucosa is highly associated with the occurrence of gastritis, peptic ulcer, and gastric cancer. Antibiotics, including amoxicillin, clarithromycin, furazolidone, levofloxacin, metronidazole, and tetracycline, are commonly used and considered the major treatment regimens for H. pylori eradication, which is, however, becoming less effective by the increasing prevalence of H pylori resistance. Thus, it is urgent to understand the molecular mechanisms of H. pylori pathogenesis and develop alternative therapeutic strategies. In this review, we focus on the virulence factors for H. pylori colonization and survival within host gastric mucosa and the host antimicrobial responses against H. pylori infection. Moreover, we describe the current treatments for H. pylori eradication and provide some insights into new therapeutic strategies for H. pylori infection.
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19
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Microbiome in cancer: Role in carcinogenesis and impact in therapeutic strategies. Biomed Pharmacother 2022; 149:112898. [PMID: 35381448 DOI: 10.1016/j.biopha.2022.112898] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 03/25/2022] [Accepted: 03/25/2022] [Indexed: 11/21/2022] Open
Abstract
Cancer is the world's second-leading cause of death, and the involvement of microbes in a range of diseases, including cancer, is well established. The gut microbiota is known to play an important role in the host's health and physiology. The gut microbiota and its metabolites may activate immunological and cellular pathways that kill invading pathogens and initiate a cancer-fighting immune response. Cancer is a multiplex illness, characterized by the persistence of several genetic and physiological anomalies in malignant tissue, complicating disease therapy and control. Humans have coevolved with a complex bacterial, fungal, and viral microbiome over millions of years. Specific long-known epidemiological links between certain bacteria and cancer have recently been grasped at the molecular level. Similarly, advances in next-generation sequencing technology have enabled detailed research of microbiomes, such as the human gut microbiome, allowing for the finding of taxonomic and metabolomic linkages between the microbiome and cancer. These investigations have found causative pathways for both microorganisms within tumors and bacteria in various host habitats far from tumors using direct and immunological procedures. Anticancer diagnostic and therapeutic solutions could be developed using this review to tackle the threat of anti-cancer medication resistance as well through the wide-ranging involvement of the microbiota in regulating host metabolic and immunological homeostasis. We reviewed the significance of gut microbiota in cancer initiation as well as cancer prevention. We look at certain microorganisms that may play a role in the development of cancer. Several bacteria with probiotic qualities may be employed as bio-therapeutic agents to re-establish the microbial population and trigger a strong immune response to remove malignancies, and further study into this should be conducted.
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20
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Nguyen TH, Ho TTM, Nguyen-Hoang TP, Qumar S, Pham TTD, Bui QN, Bulach D, Nguyen TV, Rahman M. The endemic Helicobacter pylori population in Southern Vietnam has both South East Asian and European origins. Gut Pathog 2021; 13:57. [PMID: 34593031 PMCID: PMC8482589 DOI: 10.1186/s13099-021-00452-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Accepted: 09/17/2021] [Indexed: 12/15/2022] Open
Abstract
Background The burden of Helicobacter pylori-induced gastric cancer varies based on predominant H. pylori population in various geographical regions. Vietnam is a high H. pylori burden country with the highest age-standardized incidence rate of gastric cancer (16.3 cases/100,000 for both sexes) in Southeast Asia, despite this data on the H. pylori population is scanty. We examined the global context of the endemic H. pylori population in Vietnam and present a contextual and comparative genomics analysis of 83 H. pylori isolates from patients in Vietnam. Results There are at least two major H. pylori populations are circulating in symptomatic Vietnamese patients. The majority of the isolates (~ 80%, 66/83) belong to the hspEastAsia and the remaining belong to hpEurope population (~ 20%, 17/83). In total, 66 isolates (66/83) were cagA positive, 64 were hspEastAsia isolates and two were hpEurope isolates. Examination of the second repeat region revealed that most of the cagA genes were ABD type (63/66; 61 were hspEastAsia isolates and two were hpEurope isolates). The remaining three isolates (all from hspEastAsia isolates) were ABC or ABCC types. We also detected that 4.5% (3/66) cagA gene from hspEastAsia isolates contained EPIYA-like sequences, ESIYA at EPIYA-B segments. Analysis of the vacA allelic type revealed 98.8% (82/83) and 41% (34/83) of the strains harboured the s1 and m1 allelic variant, respectively; 34/83 carried both s1m1 alleles. The most frequent genotypes among the cagA positive isolates were vacA s1m1/cagA + and vacA s1m2/cagA + , accounting for 51.5% (34/66) and 48.5% (32/66) of the isolates, respectively. Conclusions There are two predominant lineages of H. pylori circulating in Vietnam; most of the isolates belong to the hspEastAsia population. The hpEurope population is further divided into two smaller clusters. Supplementary Information The online version contains supplementary material available at 10.1186/s13099-021-00452-2.
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Affiliation(s)
- Trang Hoa Nguyen
- Oxford University Clinical Research Unit, 764 Vo Van Kiet Street, Ward 1, District 5, Ho Chi Minh City, Vietnam
| | - Trang Thi My Ho
- Department of Genetics, Faculty of Biology and Biotechnology, Ho Chi Minh University of Science, Ho Chi Minh City, Vietnam
| | - Thien-Phuc Nguyen-Hoang
- Department of Genetics, Faculty of Biology and Biotechnology, Ho Chi Minh University of Science, Ho Chi Minh City, Vietnam
| | | | - Thuc Tran Dang Pham
- Department of Genetics, Faculty of Biology and Biotechnology, Ho Chi Minh University of Science, Ho Chi Minh City, Vietnam
| | - Quy Nhuan Bui
- Department of Gastroenterology, Gia Dinh Hospital, Ho Chi Minh City, Vietnam
| | - Dieter Bulach
- Melbourne Bioinformatics, The University of Melbourne and Doherty Applied Microbial Genomics, The Doherty Institute, Melbourne, Australia
| | - Thuy-Vy Nguyen
- Department of Genetics, Faculty of Biology and Biotechnology, Ho Chi Minh University of Science, Ho Chi Minh City, Vietnam
| | - Motiur Rahman
- Oxford University Clinical Research Unit, 764 Vo Van Kiet Street, Ward 1, District 5, Ho Chi Minh City, Vietnam. .,Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, Oxford University, Oxford, UK.
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Georgiou K, Marinov B, Farooqi AA, Gazouli M. Gut Microbiota in Lung Cancer: Where Do We Stand? Int J Mol Sci 2021; 22:10429. [PMID: 34638770 PMCID: PMC8508914 DOI: 10.3390/ijms221910429] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 09/19/2021] [Accepted: 09/26/2021] [Indexed: 02/06/2023] Open
Abstract
The gut microbiota (GM) is considered to constitute a powerful "organ" capable of influencing the majority of the metabolic, nutritional, physiological, and immunological processes of the human body. To date, five microbial-mediated mechanisms have been revealed that either endorse or inhibit tumorigenesis. Although the gastrointestinal and respiratory tracts are distant physically, they have common embryonic origin and similarity in structure. The lung microbiota is far less understood, and it is suggested that the crosslink between the human microbiome and lung cancer is a complex, multifactorial relationship. Several pathways linking their respective microbiota have reinforced the existence of a gut-lung axis (GLA). Regarding implications of specific GM in lung cancer therapy, a few studies showed that the GM considerably affects immune checkpoint inhibitor (ICI) therapy by altering the differentiation of regulatory T cells and thus resulting in changes in immunomodulation mechanisms, as discovered by assessing drug metabolism directly and by assessing the host immune modulation response. Additionally, the GM may increase the efficacy of chemotherapeutic treatment in lung cancer. The mechanism underlying the role of the GLA in the pathogenesis and progression of lung cancer and its capability for diagnosis, manipulation, and treatment need to be further explored.
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Affiliation(s)
- Konstantinos Georgiou
- 1st Department of Propaedeutic Surgery, Hippokration General Hospital of Athens, Athens Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Blagoi Marinov
- Medical Simulation Training Center at Research Institute of Medical University of Plovdiv, Tsentar, 4002 Plovdiv, Bulgaria;
| | - Ammad Ahmad Farooqi
- Institute of Biomedical and Genetic Engineering (IBGE), 24 Mauve Area, Sector G-9/1, Islamabad 54000, Pakistan;
| | - Maria Gazouli
- Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
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Chen ZM, Hu J, Xu YM, He W, Meng L, Huang T, Ying SC, Jiang Z, Xu AM. Cryptotanshinone inhibits cytotoxin-associated gene A-associated development of gastric cancer and mucosal erosions. World J Gastrointest Oncol 2021; 13:693-705. [PMID: 34322198 PMCID: PMC8299932 DOI: 10.4251/wjgo.v13.i7.693] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 04/19/2021] [Accepted: 06/01/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Approximately 90% of new cases of noncardiac gastric cancer (GC) are related to Helicobacter pylori (H. pylori), and cytotoxin-associated gene A (CagA) is one of the main pathogenic factors. Recent studies have shown that the pharmacological effects of cryptotanshinone (CTS) can be used to treat a variety of tumors. However, the effects of CTS on H. pylori, especially CagA+ strain-induced gastric mucosal lesions, on the development of GC is unknown.
AIM To assess the role of CTS in CagA-induced proliferation and metastasis of GC cells, and determine if CagA+ H. pylori strains causes pathological changes in the gastric mucosa of mice.
METHODS The effects of CTS on the proliferation of GC cells were assessed using the Cell Counting Kit-8 (CCK-8) assay, and the abnormal growth, migration and invasion caused by CagA were detected by CCK-8 and transwell assays. After transfection with pSR-HA-CagA and treatment with CTS, proliferation and metastasis were evaluated by CCK-8 and transwell assays, respectively, and the expression of Src homology 2 (SH2) domain–containing phosphatase 2 (SHP2) and phosphorylated SHP2 (p-SHP2) was detected using western blotting in AGS cells. The enzyme-linked immunosorbent assay was used to determine the immunoglobulin G (IgG) level against CagA in patient serum. Mice were divided into four groups and administered H. pylori strains (CagA+ or CagA-) and CTS (or PBS) intragastrically, and establishment of the chronic infection model was verified using polymerase chain reaction and sequencing of isolated strains. Hematoxylin and eosin staining was used to assess mucosal erosion in the stomach and toxicity to the liver and kidney.
RESULTS CTS inhibited the growth of GC cells in dose- and time-dependent manners. Overexpression of CagA promoted the growth, migration, and invasion of GC cells. Importantly, we demonstrated that CTS significantly inhibited the CagA-induced abnormal proliferation, migration, and invasion of GC cells. Moreover, the expression of p-SHP2 protein in tumor tissue was related to the expression of IgG against CagA in the serum of GC patients. Additionally, CTS suppressed the protein expression levels of both SHP2 and p-SHP2 in GC cells. CTS suppressed CagA+ H. pylori strain-induced mucosal erosion in the stomach of mice but had no obvious effects on the CagA- H. pylori strain group.
CONCLUSION CTS inhibited CagA-induced proliferation and the epithelial-mesenchymal transition of GC cells in vitro, and CagA+ H. pylori strains caused mucosal erosions of the stomach in vivo by decreasing the protein expression of SHP2.
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Affiliation(s)
- Zhang-Ming Chen
- Department of General Surgery, Fourth Affiliated Hospital of Anhui Medical University, Hefei 230001, Anhui Province, China
| | - Jie Hu
- Department of General Surgery, Fourth Affiliated Hospital of Anhui Medical University, Hefei 230001, Anhui Province, China
| | - Yuan-Min Xu
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui Province, China
| | - Wei He
- Department of Surgery, East District of First Affiliated Hospital of Anhui Medical University (Feidong People's Hospital), Hefei 230001, Anhui Province, China
| | - Lei Meng
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui Province, China
| | - Ting Huang
- Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, Anhui Province, China
| | - Song-Cheng Ying
- Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, Anhui Province, China
| | - Zhe Jiang
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui Province, China
| | - A-Man Xu
- Department of General Surgery, Fourth Affiliated Hospital of Anhui Medical University, Hefei 230001, Anhui Province, China
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Chen ZM, Hu J, Xu YM, He W, Meng L, Huang T, Ying SC, Jiang Z, Xu AM. Cryptotanshinone inhibits cytotoxin-associated gene A-associated development of gastric cancer and mucosal erosions. World J Gastrointest Oncol 2021. [DOI: 10.4251/wjgo.v13.i7.518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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24
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de Lima Silva LL, Oliveira AKS, Gama AR, Ramos AFPL, Silva AMTC, Blanco AJV, Vieira JDG, Rasmussem LT, Carneiro LC, Barbosa MS. Helicobacter pylori virulence dupA gene: risk factor or protective factor? Braz J Microbiol 2021; 52:1921-1927. [PMID: 34255308 DOI: 10.1007/s42770-021-00553-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 06/21/2021] [Indexed: 12/19/2022] Open
Abstract
Helicobacter pylori is the etiological agent of chronic gastritis, peptic ulcer, and gastric cancer. The duodenal ulcer-promoting gene dupA, which is located in the plasticity region of the H. pylori genome, is homologous to the virB gene which encodes a type IV secretion protein in Agrobacterium tumefaciens. Studies have shown associations between H. pylori dupA-positive strains and gastroduodenal diseases. However, whether dupA acts as a risk factor or protective factor in these diseases remains unclear. Therefore, in this study, we aimed to verify the presence of the dupA gene in infectious H. pylori strains in the Brazilian mid-west and to investigate its association with the clinical outcomes of patients with dyspepsia. Additionally, the phylogenetic origin of the strains was determined. Gastric biopsies from 117 patients with dyspepsia were analyzed using histological and molecular techniques. The hpx gene (16S rRNA) was used to screen for H. pylori infection, and positive samples were then subjected to dupA gene detection and sequencing. The estimated prevalence of H. pylori infection was 64.1%, with the dupA gene being detected in a high proportion of infectious strains (70.7%). Furthermore, a risk analysis revealed that for women, a dupA-positive H. pylori infection increased the chance of developing gastritis by twofold. The partial dupA sequences from isolated infectious strains in this work are similar to those of strains isolated in westerns countries. This study provides useful insights for understanding the role of the H. pylori dupA gene in disease development.
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Affiliation(s)
- Lucas Luiz de Lima Silva
- Instituto de Patologia Tropical e Saúde Pública, Núcleo de Estudo da Helicobacter pylori, Departamento de Biociências e Tecnologia, Universidade Federal de Goiás, Leste Universitário, Goiânia, GO, Brazil
| | - Ana Karoline Silva Oliveira
- Instituto de Patologia Tropical e Saúde Pública, Núcleo de Estudo da Helicobacter pylori, Departamento de Biociências e Tecnologia, Universidade Federal de Goiás, Leste Universitário, Goiânia, GO, Brazil
| | - Aline Rodrigues Gama
- Instituto de Patologia Tropical e Saúde Pública, Núcleo de Estudo da Helicobacter pylori, Departamento de Biociências e Tecnologia, Universidade Federal de Goiás, Leste Universitário, Goiânia, GO, Brazil
| | - Amanda Ferreira Paes Landim Ramos
- Instituto de Patologia Tropical e Saúde Pública, Núcleo de Estudo da Helicobacter pylori, Departamento de Biociências e Tecnologia, Universidade Federal de Goiás, Leste Universitário, Goiânia, GO, Brazil
| | | | - Angel José Vieira Blanco
- Departamento de Áreas Acadêmicas, Instituto Federal de Educação Ciência e Tecnologia, Campus Inhumas, Inhumas, GO, Brazil
| | - José Daniel Gonçalves Vieira
- Instituto de Patologia Tropical e Saúde Pública, Núcleo de Estudo da Helicobacter pylori, Departamento de Biociências e Tecnologia, Universidade Federal de Goiás, Leste Universitário, Goiânia, GO, Brazil
| | | | - Lilian Carla Carneiro
- Instituto de Patologia Tropical e Saúde Pública, Núcleo de Estudo da Helicobacter pylori, Departamento de Biociências e Tecnologia, Universidade Federal de Goiás, Leste Universitário, Goiânia, GO, Brazil
| | - Mônica Santiago Barbosa
- Instituto de Patologia Tropical e Saúde Pública, Núcleo de Estudo da Helicobacter pylori, Departamento de Biociências e Tecnologia, Universidade Federal de Goiás, Leste Universitário, Goiânia, GO, Brazil.
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25
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Elagan SK, Almalki SJ, Alharthi MR, Mohamed MS, EL-Badawy MF. Role of Bacteria in the Incidence of Common GIT Cancers: The Dialectical Role of Integrated Bacterial DNA in Human Carcinogenesis. Infect Drug Resist 2021; 14:2003-2014. [PMID: 34103947 PMCID: PMC8179827 DOI: 10.2147/idr.s309051] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 05/05/2021] [Indexed: 12/13/2022] Open
Abstract
Despite the wide medical knowledge about the direct role of many viruses in the pathogenesis of certain cancers, there is still ambiguity and hazy vision about the direct role of bacteria in cancer incidence. Understanding the role of bacteria in carcinogenesis is no longer a scientific luxury, but it has become an urgent and extremely important necessity to realize the pathogenesis of cancer caused by oncogenic bacteria as an attempt to overcome the oncogenic mechanisms exhibited by these oncogenic bacteria. This review shed the light on the indirect role of the host's inflammatory and immunological responses in the pathogenesis of bacteria-induced cancer. Also, this review discussed the indirect role of the bacterial toxins and virulence factors in the induction of common gastrointestinal cancers, such as gallbladder cancer (GBC), colorectal cancer (CRC), and gastric cancer (GC). Finally, this review dealt with the debate about the possibility of bacterial DNA integration into the human genome and cancer incidence.
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Affiliation(s)
- Sayed K Elagan
- Department of Mathematics and Statistics, College of Science, Taif University, Taif, 21944, Saudi Arabia
| | - Saad J Almalki
- Department of Mathematics and Statistics, College of Science, Taif University, Taif, 21944, Saudi Arabia
| | - M R Alharthi
- Department of Mathematics and Statistics, College of Science, Taif University, Taif, 21944, Saudi Arabia
| | - Mohamed S Mohamed
- Department of Mathematics and Statistics, College of Science, Taif University, Taif, 21944, Saudi Arabia
| | - Mohamed F EL-Badawy
- Department of Microbiology and Immunology, Faculty of Pharmacy, University of Sadat City, Sadat City, 32958, Egypt
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26
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Do AD, Chang CC, Su CH, Hsu YM. Lactobacillus rhamnosus JB3 inhibits Helicobacter pylori infection through multiple molecular actions. Helicobacter 2021; 26:e12806. [PMID: 33843101 DOI: 10.1111/hel.12806] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 03/22/2021] [Accepted: 03/26/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Eradication of Helicobacter pylori infection is the most direct and effective way for preventing gastric cancer. Lactic acid bacteria are considered as alternative therapeutic agents against H. pylori infection. METHODS Effects of Lactobacillus rhamnosus JB3 (LR-JB3) on the virulence gene expression of H. pylori and infection-induced cellular responses of AGS cells were investigated by co-cultivating infected AGS cells with different multiplicity of infections (MOIs) of LR-JB3. RESULTS LR-JB3, specifically at a MOI of 25, suppressed the association ability of H. pylori and its induced IL-8 levels, as well as the mRNA levels of vacA, sabA, and fucT of H. pylori, infection-induced Lewis (Le)x antigen and Toll-like receptor 4 (TLR4) expressions in AGS cells. However, the apoptosis mediated by infection was inhibited by LR-JB3 in a dose-dependent manner. In addition, autoinducer (AI)-2 was observed to have increased the association ability and fucT expression of H. pylori, and Lex antigen and TLR4 expression of AGS cells. Interestingly, an unknown bioactive cue was hypothesized to have been secreted from LR-JB3 at a MOI of 25 to act as an antagonist of AI-2. CONCLUSIONS LR-JB3 possesses various means to interfere with H. pylori pathogenesis and infection-induced cellular responses of AGS cells to fight against infection.
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Affiliation(s)
- Anh Duy Do
- Department of Biological Science and Technology, China Medical University, Taichung, Taiwan
| | - Chun-Chi Chang
- Department of Biological Science and Technology, China Medical University, Taichung, Taiwan
| | - Chiu-Hsian Su
- Department of Biological Science and Technology, China Medical University, Taichung, Taiwan
| | - Yuan-Man Hsu
- Department of Biological Science and Technology, China Medical University, Taichung, Taiwan
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27
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Keikha M, Karbalaei M. EPIYA motifs of Helicobacter pylori cagA genotypes and gastrointestinal diseases in the Iranian population: a systematic review and meta-analysis. New Microbes New Infect 2021; 41:100865. [PMID: 33912350 PMCID: PMC8066700 DOI: 10.1016/j.nmni.2021.100865] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 03/01/2021] [Accepted: 03/07/2021] [Indexed: 02/08/2023] Open
Abstract
Helicobacter pylori is one of the best risk factors for gastric cancer. Recent studies have examined the relationship between virulence factors, in particular CagA toxin, and the development of gastrointestinal diseases. According to the literature, there is a significant relationship between the polymorphism of cagA-EPIYA motifs and progression to severe clinical outcomes. The main goal of our study was to determine the possible association between cagA genotypes and the risk of severe clinical outcomes in the Iranian population. We investigated these ambiguities using a comprehensive meta-analysis study, in which we evaluated data from 1762 Iranian patients for a potential correlation between all cagA gene genotypes and gastrointestinal diseases. According to statistical analysis, the frequencies of cagA genotypes including ABC, ABCC, AB and ABCCC in the Iranian population were estimated at 80.18%, 22.81%, 5.52% and 2.76%, respectively; the ABD genotype was not detected in these PCR-based studies. There was a significant relationship between cagA genotypes ABCC and ABCCC and severe clinical outcomes of infection such as peptic ulcer and gastric cancer. Overall, it can be concluded that there is a positive correlation with the number of copies of EPIYA-C and the increase of gastric cancer. Therefore, according to our results, it seems that the EPIYA-ABCCC motif has a strong positive relationship with gastric cancer in the Iranian population.
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Affiliation(s)
- M. Keikha
- Department of Microbiology and Virology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - M. Karbalaei
- Department of Microbiology and Virology, School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran
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28
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Draveny M, Ghali A, Nüsse O. [The HopQ-CEACAM interaction controls CagA translocation, phosphorylation, and phagocytosis of Helicobacter pylori in neutrophilic granulocytes]. Med Sci (Paris) 2021; 37:403-405. [PMID: 33908861 DOI: 10.1051/medsci/2021042] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Affiliation(s)
- Margot Draveny
- M1 Biologie Santé, Université Paris-Saclay, 91405 Orsay, France
| | - Assmaa Ghali
- M1 Biologie Santé, Université Paris-Saclay, 91405 Orsay, France
| | - Oliver Nüsse
- Institut de chimie physique, UMR8000, Université Paris-Saclay, 91405 Orsay, France
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29
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Ninomiya R, Kubo S, Baba T, Kajiwara T, Tokunaga A, Nabeka H, Doihara T, Shimokawa T, Matsuda S, Murakami K, Aigaki T, Yamaoka Y, Hamada F. Inhibition of low-density lipoprotein uptake by Helicobacter pylori virulence factor CagA. Biochem Biophys Res Commun 2021; 556:192-198. [PMID: 33845309 DOI: 10.1016/j.bbrc.2021.03.170] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 03/30/2021] [Indexed: 01/01/2023]
Abstract
Helicobacter pylori (H. pylori) infection mainly causes gastroduodenal diseases, including chronic gastritis, peptic ulcer disease and gastric cancer. In recent years, several studies have demonstrated that infection with H. pylori, especially strains harboring the virulence factor CagA (cytotoxin-associated gene A), contribute to the development of non-gastric systemic diseases, including hypercholesterolemia and atherosclerotic cardiovascular diseases. However, mechanisms underlying this association has not been defined. In this study, we carried out a large-scale genetic screen using Drosophila and identified a novel CagA target low-density lipoprotein receptor (LDLR), which aids in the clearance of circulating LDL. We showed that CagA physically interacted with LDLR via its carboxy-terminal region and inhibited LDLR-mediated LDL uptake into cells. Since deficiency of LDLR-mediated LDL uptake has been known to increase plasma LDL and accelerate atherosclerosis, our findings may provide a novel mechanism for the association between infection with CagA-positive H. pylori and hypercholesterolemia leading to atherosclerotic cardiovascular diseases.
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Affiliation(s)
- Ryo Ninomiya
- Department of Anatomy, Faculty of Medicine, Oita University, Yufu, Oita, 879-5593, Japan
| | - Shuichi Kubo
- Department of Anatomy, Faculty of Medicine, Oita University, Yufu, Oita, 879-5593, Japan
| | - Takehiro Baba
- Department of Anatomy, Faculty of Medicine, Oita University, Yufu, Oita, 879-5593, Japan
| | - Tooru Kajiwara
- Department of Anatomy, Faculty of Medicine, Oita University, Yufu, Oita, 879-5593, Japan
| | - Akinori Tokunaga
- Division of Laboratory Animal Resources, Life Science Research Laboratory, University of Fukui, Eiheiji, Fukui, 910-1193, Japan
| | - Hiroaki Nabeka
- Department of Anatomy and Embryology, Ehime University Graduate School of Medicine, Toon, Ehime, 791-0295, Japan
| | - Takuya Doihara
- Department of Anatomy and Embryology, Ehime University Graduate School of Medicine, Toon, Ehime, 791-0295, Japan
| | - Tetsuya Shimokawa
- Department of Anatomy and Embryology, Ehime University Graduate School of Medicine, Toon, Ehime, 791-0295, Japan
| | - Seiji Matsuda
- Department of Anatomy and Embryology, Ehime University Graduate School of Medicine, Toon, Ehime, 791-0295, Japan
| | - Kazunari Murakami
- Department of Gastroenterology, Faculty of Medicine, Oita University, Yufu, Oita, 879-5593, Japan
| | - Toshiro Aigaki
- Department of Biological Sciences, Tokyo Metropolitan University, Hachioji, Tokyo, 192-0397, Japan
| | - Yoshio Yamaoka
- Department of Environmental and Preventive Medicine, Faculty of Medicine, Oita University, Yufu, Oita, 879-5593, Japan; Department of Gastroenterology and Hepatology, Baylor College of Medicine and Michael DeBakey Veterans Affairs Medical Center, Houston, TX, 77030-4211, USA
| | - Fumihiko Hamada
- Department of Anatomy, Faculty of Medicine, Oita University, Yufu, Oita, 879-5593, Japan.
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30
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Lu H, Han X, Ren J, Ren K, Li Z, Zhang Q. Metformin attenuates synergic effect of diabetes mellitus and Helicobacter pylori infection on gastric cancer cells proliferation by suppressing PTEN expression. J Cell Mol Med 2021; 25:4534-4542. [PMID: 33760349 PMCID: PMC8107109 DOI: 10.1111/jcmm.15967] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Revised: 09/20/2020] [Accepted: 09/22/2020] [Indexed: 12/17/2022] Open
Abstract
It has been reported that CagA of Helicobacter pylori reduced PTEN expression by enhancing its promoter methylation. Furthermore, diabetes mellitus (DM) may also promote the methylation status of PTEN, a tumour suppressor gene in gastric cancer (GC). It is intriguing to explore whether DM may strengthen the tumorigenic effect of H pylori (HP) by promoting the methylation of PTEN promoter and whether the administration of metformin may reduce the risk of GC by suppressing the methylation of PTEN promoter. In this study, we enrolled 107 GC patients and grouped them as HP(-)DM(-) group, HP(+)DM(-) group and HP(+)DM(+) group. Bisulphite sequencing PCR evaluated methylation of PTEN promoter. Quantitative real-time PCR, immunohistochemistry and Western blot, immunofluorescence, flow cytometry and MTT assay were performed accordingly. DNA methylation of PTEN promoter was synergistically enhanced in HP(+)DM(+) patients, and the expression of PTEN was suppressed in HP(+)DM(+) patients. Cell apoptosis was decreased in HP(+)DM(+) group. Metformin showed an apparent effect on restoring CagA-induced elevation of PTEN promoter methylation, thus attenuating the PTEN expression. The reduced PTEN level led to increased proliferation and inhibited apoptosis of HGC-27 cells. In this study, we collected GC tumour tissues from GC patients with or without DM/HP to compare their PTEN methylation and expression while testing the effect of metformin on the methylation of PTEN promoter. In summary, our study suggested that DM could strengthen the tumorigenic effect of HP by promoting the PTEN promoter methylation, while metformin reduces GC risk by suppressing PTEN promoter methylation.
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Affiliation(s)
- Huibin Lu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xinwei Han
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jianzhuang Ren
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Kewei Ren
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zongming Li
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Quanhui Zhang
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Qumar S, Nguyen TH, Nahar S, Sarker N, Baker S, Bulach D, Ahmed N, Rahman M. A comparative whole genome analysis of Helicobacter pylori from a human dense South Asian setting. Helicobacter 2021; 26:e12766. [PMID: 33073485 PMCID: PMC7816255 DOI: 10.1111/hel.12766] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 08/31/2020] [Accepted: 09/20/2020] [Indexed: 12/23/2022]
Abstract
Helicobacter pylori, a Gram-negative bacterium, is associated with a wide range of gastric diseases such as gastritis, duodenal ulcer, and gastric cancer. The prevalence of H pylori and risk of disease vary in different parts of the world based on the prevailing bacterial lineage. Here, we present a contextual and comparative genomics analysis of 20 clinical isolates of H pylori from patients in Bangladesh. Despite a uniform host ethnicity (Bengali), isolates were classified as being part of the HpAsia2 (50%) or HpEurope (50%) population. Out of twenty isolates, eighteen isolates were cagA positive, with two HpEurope isolates being cagA negative, three EPIYA motif patterns (AB, AB-C, and ABC-C) were observed among the cagA-positive isolates. Three vacA genotypes were observed with the s1m1i1dic1 genotype observed in 75% of isolates; the s1m2i1d1c2 and s2m2i2d2c2 genotypes were found to be 15% and 10% of isolates, respectively. The non-virulent genotypes s2m2i2d2c2 was only observed in HpEurope population isolates. Genotypic analysis of oipA gene, present in all isolates, revealed five different patterns of the CT repeat; all HpAsia2 isolates were in "ON" while 20% of HpEurope isolates were genotypically "OFF." The three blood group antigen binding adhesins encoded genes (bab genes) examined and we observed that the most common genotype was (babA/babB/-) found in eight isolates, notably six were HpAsia2 isolates. The babA gene was found in all HpAsia2 isolates but present in only half of the HpEurope isolates. In silico antibiotic susceptibility analysis revealed that 40% of the strains were multi-drug resistant. Mutations associated with resistance to metronidazole, fluoroquinolone, and clarithromycin were detected 90%, 45%, and 5%, respectively, in H pylori strain. In conclusion, it is evident that two populations of H pylori with similar antibiotic profiles are predominant in Bangladesh, and it appears that genotypically the HpAisa2 isolates are potentially more virulent than the HpEurope isolates.
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Affiliation(s)
- Shamsul Qumar
- Department of Biotechnology and BioinformaticsUniversity of HyderabadHyderabadIndia
| | - Trang Hoa Nguyen
- The Hospital for Tropical DiseasesOxford University Clinical Research UnitHo Chi Minh CityVietnam
| | - Shamsun Nahar
- International Center for Diarrhoeal Disease Research BangladeshDhakaBangladesh
| | - Nishat Sarker
- International Center for Diarrhoeal Disease Research BangladeshDhakaBangladesh
| | - Stephen Baker
- Cambridge Institute of Therapeutic Immunology & Infectious DiseaseCambridge UniversityCambridgeUK
| | - Dieter Bulach
- The University of Melbourne and The Peter Doherty Institute for Infection and ImmunityMelbourneVICAustralia
| | - Niyaz Ahmed
- Department of Biotechnology and BioinformaticsUniversity of HyderabadHyderabadIndia,International Center for Diarrhoeal Disease Research BangladeshDhakaBangladesh
| | - Motiur Rahman
- The Hospital for Tropical DiseasesOxford University Clinical Research UnitHo Chi Minh CityVietnam,Centre for Tropical Medicine and Global HealthNuffield Department of Clinical MedicineOxford UniversityOxfordUK
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32
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Eisenbart SK, Alzheimer M, Pernitzsch SR, Dietrich S, Stahl S, Sharma CM. A Repeat-Associated Small RNA Controls the Major Virulence Factors of Helicobacter pylori. Mol Cell 2020; 80:210-226.e7. [PMID: 33002424 DOI: 10.1016/j.molcel.2020.09.009] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 07/29/2020] [Accepted: 09/04/2020] [Indexed: 12/12/2022]
Abstract
Many bacterial pathogens regulate their virulence genes via phase variation, whereby length-variable simple sequence repeats control the transcription or coding potential of those genes. Here, we have exploited this relationship between DNA structure and physiological function to discover a globally acting small RNA (sRNA) regulator of virulence in the gastric pathogen Helicobacter pylori. Our study reports the first sRNA whose expression is affected by a variable thymine (T) stretch in its promoter. We show the sRNA post-transcriptionally represses multiple major pathogenicity factors of H. pylori, including CagA and VacA, by base pairing to their mRNAs. We further demonstrate transcription of the sRNA is regulated by the nickel-responsive transcriptional regulator NikR (thus named NikS for nickel-regulated sRNA), thereby linking virulence factor regulation to nickel concentrations. Using in-vitro infection experiments, we demonstrate NikS affects host cell internalization and epithelial barrier disruption. Together, our results show NikS is a phase-variable, post-transcriptional global regulator of virulence properties in H. pylori.
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Affiliation(s)
- Sara K Eisenbart
- Chair of Molecular Infection Biology II, Institute of Molecular Infection Biology (IMIB), University of Würzburg, 97080 Würzburg, Germany
| | - Mona Alzheimer
- Chair of Molecular Infection Biology II, Institute of Molecular Infection Biology (IMIB), University of Würzburg, 97080 Würzburg, Germany
| | - Sandy R Pernitzsch
- Chair of Molecular Infection Biology II, Institute of Molecular Infection Biology (IMIB), University of Würzburg, 97080 Würzburg, Germany
| | - Sascha Dietrich
- Core Unit Systems Medicine, Interdisciplinary Center for Clinical Research (IZKF) of the University Hospital Würzburg, 97080 Würzburg, Germany
| | - Stephanie Stahl
- Chair of Molecular Infection Biology II, Institute of Molecular Infection Biology (IMIB), University of Würzburg, 97080 Würzburg, Germany
| | - Cynthia M Sharma
- Chair of Molecular Infection Biology II, Institute of Molecular Infection Biology (IMIB), University of Würzburg, 97080 Würzburg, Germany.
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Schaalan M, Mohamed W, Fathy S. MiRNA-200c, MiRNA-139 and ln RNA H19; new predictors of treatment response in H-pylori- induced gastric ulcer or progression to gastric cancer. Microb Pathog 2020; 149:104442. [PMID: 32795593 DOI: 10.1016/j.micpath.2020.104442] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 08/03/2020] [Accepted: 08/05/2020] [Indexed: 02/07/2023]
Abstract
Recent evidence indicates that the pathogenesis of gastric ulcer and progression to gastric cancer could be attributed to altered inflammatory/immunological response and associated differential non-coding RNAs expression signatures. However, co-expression profiling of lncRNA-miRNAs in GU/GC patients are scarcely focused on. Therefore, in the present study the expression of H19 and related miRNAs including miR-139, and miR-200 were assayed in the plasma samples of treatment responsive GU vs nonresponsive GC patients. This study is a case-control study carried out on 130 subjects recruited from the Gastrointestinal Endoscopy Unit in Al-Kasr Al-Aini Hospital, in Egypt. All recruited patients were diagnosed with H-pylori infection, 50 of them were gastric cancer patients (GC), with previous H-pylori induced gastric ulcer but were treatment non-respondent. Real-time PCR was performed to evaluate the expression level of serum non-coding RNA; miRNA-200c, miR-139, Ln RNA H19 in patients with peptic ulcer treatment non-respondent, who progressed to GC vs non-progressed gastric ulcer patients (GU) (n = 50), and compared to early diagnosed H-pylori-gastric ulcer patients (n = 30). The association between these miRNAs and the FGF-18/FGF-R signaling indicators of H-pylori-GC pathogenesis were then investigated. RESULTS: showed that the H19 level was significantly elevated while miR-139 and miR-200c expression were significantly down-regulated in GC patients, compared to GU participants (P < 0.01). The herein investigated ncRNAs are correlated to the disease duration with Ln H19 being significantly correlated with all inflammatory markers; TNF-α, INF-γ, TAC, MMP-9, and FGF18/FGFR2. A significant correlation was also observed between miRNA 200c and each of miRNA 139 and FGFR2. Moreover, ROC analysis revealed that miRNA 200c showed the highest AUC (0.906) and 81.2% sensitivity and 100% specificity. Moreover, the combined analysis of miRNA 200c/miRNA 139 revealed superior AUC (0.96) and 93% sensitivity and 100% specificity, than each separately. As for discriminative accuracy between stages III to IV of gastric cancer, LncRNA H19 showed the highest diagnostic accuracy (95.5%), specificity (100%), and sensitivity (90.9%). The current study demonstrated that the combination of serum miRNA 200c/miRNA 139 expression levels (down-regulation) could provide a new potential prognostic panel for GU predictive response and potential sequelae. In conclusion, LncRNA H19 and related miRNAs, miRNA 200c/miRNA 139, could serve as a potential diagnostic biomarker for early gastric cancer diagnosis.
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Affiliation(s)
- Mona Schaalan
- Department of Clinical Pharmacy, Clinical and Translational Research Unit, Faculty of Pharmacy, Misr International University, Cairo, Egypt.
| | - Waleed Mohamed
- Department of Internal Medicine, Kasr El Aini Teaching Hospitals, Cairo University, Cairo, Egypt.
| | - Shimaa Fathy
- Department of Clinical Pharmacy, Clinical and Translational Research Unit, Faculty of Pharmacy, Misr International University, Cairo, Egypt.
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Helicobacter pylori Oncogenicity: Mechanism, Prevention, and Risk Factors. ScientificWorldJournal 2020; 2020:3018326. [PMID: 32765194 PMCID: PMC7374235 DOI: 10.1155/2020/3018326] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 06/04/2020] [Accepted: 06/23/2020] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori (H. pylori) is the most common cause of gastric ulcer; however, its association with gastric cancer has been proved through a variety of studies. Importantly, H. pylori infection affects around half of the world's population leading to a variety of gastric problems and is mostly present in asymptomatic form. Although about 20% of people infected with H. pylori develop preneoplastic gastric lesions in later stages of their life, around 2% of infected individuals develop gastric cancer. Nevertheless, the outcome of H. pylori infection is determined by complex interaction between the host genetics, its environment, and virulence factors of infecting strain. There are several biomarkers/traits of H. pylori that have been linked with the onset of cancer. Among these, presence of certain major virulence factors including cytotoxin-associated gene A (CagA), vacuolating cytotoxin (VacA), and outer inflammatory protein A (OipA) plays a significant role in triggering gastric cancer. These factors of H. pylori make it a potent carcinogen. Therefore, eradication of H. pylori infection has shown positive effects on decreasing the risk of gastric cancer, but this has become a challenge due to the development of antibiotic resistance in H. pylori against the antibiotics of choice. Thus, the unmet need is to develop new and effective treatments for H. pylori infection, considering the antimicrobial resistance in different regions of the world. This review discusses the properties of H. pylori associated with increased risk of gastric cancer, antibiotic resistance pattern, and the possible role of eradication of H. pylori in preventing gastric cancer.
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Rizzato C, Torres J, Obazee O, Camorlinga-Ponce M, Trujillo E, Stein A, Mendez-Tenorio A, Bravo MM, Canzian F, Kato I. Variations in cag pathogenicity island genes of Helicobacter pylori from Latin American groups may influence neoplastic progression to gastric cancer. Sci Rep 2020; 10:6570. [PMID: 32300197 PMCID: PMC7162905 DOI: 10.1038/s41598-020-63463-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Accepted: 03/20/2020] [Indexed: 12/11/2022] Open
Abstract
Helicobacter pylori (HP) colonizes the human stomach and induces acute gastritis, peptic ulcer disease, atrophic gastritis, and gastric adenocarcinoma. Increased virulence in HP isolates derives from harboring the cag (cytotoxin-associated genes) pathogenicity island (cagPAI). We analyzed the microvariants in cagPAI genes with the hypothesis that they may play an important role in determining HP virulence. We tested DNAs from cagA positive patients HP isolates; a total of 74 patients with chronic gastritis (CG, N = 37), intestinal metaplasia (IM, N = 21) or gastric cancer (GC, N = 16) from Mexico and Colombia. We selected 520 non-synonymous variants with at least 7.5% frequency in the original sequence outputs or with a minimum of 5 isolates with minor allele. After adjustment for multiple comparisons, no variants were statistically significantly associated with IM or GC. However, 19 non-synonymous showed conventional P-values < 0.05 comparing the frequency of the alleles between the isolates from subjects with gastritis and isolates from subjects with IM or GC; 12 of these showed a significant correlation with the severity of the disease. The present study revealed that several cagPAI genes from Latin American Western HP strains contains a number of non-synonymous variants in relatively high frequencies which could influence on the clinical outcome. However, none of the associations remained statistically significant after adjustment for multiple comparison.
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Affiliation(s)
- Cosmeri Rizzato
- Department of Translation Research and of New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
| | - Javier Torres
- Unidad de Investigación en Enfermedades Infecciosas, UMAE Pediatría, Instituto Mexicano del Seguro Social, Mexico City, Mexico
| | - Ofure Obazee
- Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Margarita Camorlinga-Ponce
- Unidad de Investigación en Enfermedades Infecciosas, UMAE Pediatría, Instituto Mexicano del Seguro Social, Mexico City, Mexico
| | - Esperanza Trujillo
- Grupo de Investigación en Biología del Cáncer. Instituto Nacional de Cancerología, Bogotá, Colombia
| | - Angelika Stein
- Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Alfonso Mendez-Tenorio
- Laboratorio de Biotecnología y Bioinformática Genómica, ENCB, Instituto Politécnico Nacional, México City, México
| | - Maria Mercedes Bravo
- Grupo de Investigación en Biología del Cáncer. Instituto Nacional de Cancerología, Bogotá, Colombia
| | - Federico Canzian
- Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Ikuko Kato
- Department of Oncology and Pathology, Wayne State University School of Medicine, Detroit, MI, USA
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The HopQ-CEACAM Interaction Controls CagA Translocation, Phosphorylation, and Phagocytosis of Helicobacter pylori in Neutrophils. mBio 2020; 11:mBio.03256-19. [PMID: 32019805 PMCID: PMC7002351 DOI: 10.1128/mbio.03256-19] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Helicobacter pylori is highly adapted to humans and evades host immunity to allow its lifelong colonization. However, the H. pylori mouse model is artificial for H. pylori, and few adapted strains allow gastric colonization. Here, we show that human or CEACAM-humanized, but not mouse neutrophils are manipulated by the H. pylori HopQ-CEACAM interaction. Human CEACAMs are responsible for CagA phosphorylation, activation, and processing in neutrophils, whereas CagA translocation and tyrosine phosphorylation in DCs and macrophages is independent of the HopQ-CEACAM interaction. H. pylori affects the secretion of distinct chemokines in CEACAM-humanized neutrophils and macrophages. Most importantly, human CEACAMs on neutrophils enhance binding, oxidative burst, and phagocytosis of H. pylori and enhance bacterial survival in the phagosome. The H. pylori-CEACAM interaction modulates PMNs to reduce the H. pylori CagA translocation efficiency in vivo and to fine-tune the expression of CEACAM receptors on neutrophils to limit translocation of CagA and gastric pathology. The cag type IV secretion system (cag-T4SS) of Helicobacter pylori exploits specific cellular carcinoembryonic antigen-related cell adhesion molecules (CEACAMs), such as CEACAM1, -3, -5, and -6, as cellular receptors for CagA translocation into human gastric epithelial cells. We studied the interaction of H. pylori with human CEACAM1, CEACAM3, and CEACAM6 receptors (hCEACAMs) expressed on myeloid cells from CEACAM-humanized mice. Human and CEACAM-humanized mouse polymorphonuclear neutrophils (PMNs) allowed a specific HopQ-dependent interaction strongly enhancing CagA translocation. Translocated CagA was tyrosine phosphorylated, which was not seen in wild-type (wt) murine neutrophils. In contrast, human or murine bone marrow-derived macrophages and dendritic cells (DCs) revealed a low hCEACAM expression and bacterial binding. CagA translocation and tyrosine-phosphorylation was low and independent of the HopQ-CEACAM interaction. Neutrophils, but not macrophages or DCs, from CEACAM-humanized mice, significantly upregulated the proinflammatory chemokine MIP-1α. However, macrophages showed a significantly reduced amount of CXCL1 (KC) and CCL2 (MCP-1) secretion in CEACAM-humanized versus wt cells. Thus, H. pylori, via the HopQ-CEACAM interaction, controls the production and secretion of chemokines differently in PMNs, macrophages, and DCs. We further show that upon H. pylori contact the oxidative burst of neutrophils and phagocytosis of H. pylori was strongly enhanced, but hCEACAM3/6 expression on neutrophils allowed the extended survival of H. pylori within neutrophils in a HopQ-dependent manner. Finally, we demonstrate that during a chronic mouse infection, H. pylori is able to systemically downregulate hCEACAM1 and hCEACAM6 receptor expression on neutrophils, probably to limit CagA translocation efficiency and most likely gastric pathology.
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Zhang H, Liao Y, Zhang H, Wu J, Zheng D, Chen Z. Cytotoxin-associated gene A increases carcinogenicity of helicobacter pylori in colorectal adenoma. Int J Biol Markers 2020; 35:19-25. [PMID: 31971064 DOI: 10.1177/1724600819877193] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE This study aimed to investigate the correlation of Helicobacter pylori (Hp) infection with disease risk and severity of colorectal adenoma, also to explore the association of cytotoxin-associated gene A (CagA) positive (CagA+)-Hp infection with gastrin and ki-67 expressions in colorectal adenoma patients. METHODS There were 1000 colorectal adenoma patients and 1500 controls consecutively enrolled, then Hp infection status was determined by 14C urea breath test and rapid urease test. Also, serum CagA expression and gastrin expression of colorectal adenoma patients were determined by enzyme-linked immunosorbent assay. Ki-67 expression in adenoma tissue of colorectal adenoma patients was assessed using immunohistochemistry. RESULTS Hp+ rate in colorectal adenoma patients (623 (62.3%)) was more elevated than that in controls (814 (54.3%)). Multivariate logistic regression model analysis disclosed that Hp+ was an independent risk factor for colorectal adenoma. Additionally, Hp+ was positively associated with tumor size and high-grade intraepithelial neoplasia in colorectal adenoma patients. Also, serum gastrin expression and intratumoral ki-67 expression were higher in Hp+ CagA+ patients and Hp+ CagA- patients compared to Hp- patients, and they were also higher in Hp+ CagA+ patients compared to Hp+ CagA- patients. CONCLUSION Hp infection positively associates with higher disease risk and worse disease conditions of colorectal adenoma, and CagA enhances the carcinogenicity of Hp in colorectal adenoma.
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Affiliation(s)
- Heng Zhang
- Department of Gastroenterology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology; Clinical Research Center for Intestinal & Colorectal Diseases of Hubei Province; Key Laboratory for Molecular Diagnosis of Hubei Province, Wuhan, China
| | - Yusheng Liao
- Department of Gastroenterology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology; Clinical Research Center for Intestinal & Colorectal Diseases of Hubei Province; Key Laboratory for Molecular Diagnosis of Hubei Province, Wuhan, China
| | - Hongfeng Zhang
- Department of Pathology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jie Wu
- Department of Gastroenterology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology; Clinical Research Center for Intestinal & Colorectal Diseases of Hubei Province; Key Laboratory for Molecular Diagnosis of Hubei Province, Wuhan, China
| | - Dan Zheng
- Department of Gastroenterology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology; Clinical Research Center for Intestinal & Colorectal Diseases of Hubei Province; Key Laboratory for Molecular Diagnosis of Hubei Province, Wuhan, China
| | - Zhitao Chen
- Department of Gastroenterology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology; Clinical Research Center for Intestinal & Colorectal Diseases of Hubei Province; Key Laboratory for Molecular Diagnosis of Hubei Province, Wuhan, China
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Ansari S, Yamaoka Y. Helicobacter pylori Virulence Factors Exploiting Gastric Colonization and its Pathogenicity. Toxins (Basel) 2019; 11:E677. [PMID: 31752394 PMCID: PMC6891454 DOI: 10.3390/toxins11110677] [Citation(s) in RCA: 144] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 11/15/2019] [Accepted: 11/16/2019] [Indexed: 02/07/2023] Open
Abstract
Helicobacter pylori colonizes the gastric epithelial cells of at least half of the world's population, and it is the strongest risk factor for developing gastric complications like chronic gastritis, ulcer diseases, and gastric cancer. To successfully colonize and establish a persistent infection, the bacteria must overcome harsh gastric conditions. H. pylori has a well-developed mechanism by which it can survive in a very acidic niche. Despite bacterial factors, gastric environmental factors and host genetic constituents together play a co-operative role for gastric pathogenicity. The virulence factors include bacterial colonization factors BabA, SabA, OipA, and HopQ, and the virulence factors necessary for gastric pathogenicity include the effector proteins like CagA, VacA, HtrA, and the outer membrane vesicles. Bacterial factors are considered more important. Here, we summarize the recent information to better understand several bacterial virulence factors and their role in the pathogenic mechanism.
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Affiliation(s)
- Shamshul Ansari
- Department of Microbiology, Chitwan Medical College and Teaching Hospital, Bharatpur 44200, Chitwan, Nepal;
| | - Yoshio Yamaoka
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Idaigaoka, Hasama-machi, Yufu, Oita 879-5593, Japan
- Global Oita Medical Advanced Research Center for Health, Idaigaoka, Hasama-machi, Yufu, Oita 879-5593, Japan
- Department of Medicine, Gastroenterology and Hepatology Section, Baylor College of Medicine, 2002 Holcombe Blvd., Houston, TX 77030, USA
- Borneo Medical and Health Research Centre, Universiti Malaysia Sabah, Kota Kinabaru, Sabah 88400, Malaysia
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Activity and Functional Importance of Helicobacter pylori Virulence Factors. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1149:35-56. [PMID: 31016624 DOI: 10.1007/5584_2019_358] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Helicobacter pylori is a very successful Gram-negative pathogen colonizing the stomach of humans worldwide. Infections with this bacterium can generate pathologies ranging from chronic gastritis and peptic ulceration to gastric cancer. The best characterized H. pylori virulence factors that cause direct cell damage include an effector protein encoded by the cytotoxin-associated gene A (CagA), a type IV secretion system (T4SS) encoded in the cag-pathogenicity island (cag PAI), vacuolating cytotoxin A (VacA), γ-glutamyl transpeptidase (GGT), high temperature requirement A (HtrA, a serine protease) and cholesterol glycosyl-transferase (CGT). Since these H. pylori factors are either surface-exposed, secreted or translocated, they can directly interact with host cell molecules and are able to hijack cellular functions. Studies on these bacterial factors have progressed substantially in recent years. Here, we review the current status in the characterization of signaling cascades by these factors in vivo and in vitro, which comprise the disruption of cell-to-cell junctions, induction of membrane rearrangements, cytoskeletal dynamics, proliferative, pro-inflammatory, as well as, pro-apoptotic and anti-apoptotic responses or immune evasion. The impact of these signal transduction modules in the pathogenesis of H. pylori infections is discussed.
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Chichirau BE, Diechler S, Posselt G, Wessler S. Tyrosine Kinases in Helicobacter pylori Infections and Gastric Cancer. Toxins (Basel) 2019; 11:toxins11100591. [PMID: 31614680 PMCID: PMC6832112 DOI: 10.3390/toxins11100591] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 10/02/2019] [Accepted: 10/09/2019] [Indexed: 12/11/2022] Open
Abstract
Helicobacter pylori (H. pylori) has been identified as a leading cause of gastric cancer, which is one of the most frequent and malignant types of tumor. It is characterized by its rapid progression, distant metastases, and resistance to conventional chemotherapy. A number of receptor tyrosine kinases and non-receptor tyrosine kinases have been implicated in H. pylori-mediated pathogenesis and tumorigenesis. In this review, recent findings of deregulated EGFR, c-Met, JAK, FAK, Src, and c-Abl and their functions in H. pylori pathogenesis are summarized.
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Affiliation(s)
- Bianca E Chichirau
- Department of Biosciences, Paris-Lodron University of Salzburg, 5020 Salzburg, Austria.
| | - Sebastian Diechler
- Department of Biosciences, Paris-Lodron University of Salzburg, 5020 Salzburg, Austria.
| | - Gernot Posselt
- Department of Biosciences, Paris-Lodron University of Salzburg, 5020 Salzburg, Austria.
| | - Silja Wessler
- Cancer Cluster Salzburg, Department of Biosciences, Paris-Lodron University of Salzburg, 5020 Salzburg, Austria.
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Pachathundikandi SK, Gutiérrez-Escobar AJ, Tegtmeyer N. Tailor-Made Detection of Individual Phosphorylated and Non-Phosphorylated EPIYA-Motifs of Helicobacter pylori Oncoprotein CagA. Cancers (Basel) 2019; 11:cancers11081163. [PMID: 31412675 PMCID: PMC6721621 DOI: 10.3390/cancers11081163] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2019] [Revised: 07/25/2019] [Accepted: 08/08/2019] [Indexed: 02/07/2023] Open
Abstract
The gastric pathogen and carcinogen Helicobacter pylori(H. pylori) encodes a type IV secretion system for translocation of the effector protein CagA into host cells. Injected CagA becomes tyrosine-phosphorylated at the five amino acid residue Glutamate-Proline- Isoleucine-Tyrosine-Alanine (EPIYA)-sequence motifs. These phosphorylated EPIYA-sites represent recognition motifs for binding of multiple host factors, which then manipulate signaling pathways to trigger gastric disease. Thus, efficient detection of single phosphorylated EPIYA-motifs in CagA is required. Detection of phospho-CagA is primarily performed using commercial pan-phosphotyrosine antibodies. However, those antibodies were originally generated to recognize many phosphotyrosines in various mammalian proteins and are not optimized for use in bacteria. To address this important limitation, we synthesized 11-mer phospho- and non-phospho-peptides from EPIYA-motifs A, B, and C, and produced three phospho-specific and three non-phospho-specific rabbit polyclonal CagA antibodies. These antibodies specifically recognized the corresponding phosphorylated and non-phosphorylated EPIYA-motifs, while the EPIYA-C antibodies also recognized the related East-Asian EPIYA-D motif. Otherwise, no cross-reactivity of the antibodies among EPIYAs was observed. Western blotting demonstrated that each EPIYA-motif can be predominantly phosphorylated during H. pylori infection. This represents the first complete set of phospho-specific antibodies for an effector protein in bacteria, providing useful tools to gather information for the categorization of CagA phosphorylation, cancer signaling, and gastric disease progression.
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Affiliation(s)
- Suneesh Kumar Pachathundikandi
- Department of Biology, Division of Microbiology, Friedrich Alexander University Erlangen-Nuremberg, Staudtstraße 5, D-91058 Erlangen, Germany
| | - Andrés Julián Gutiérrez-Escobar
- Department of Biology, Division of Microbiology, Friedrich Alexander University Erlangen-Nuremberg, Staudtstraße 5, D-91058 Erlangen, Germany
| | - Nicole Tegtmeyer
- Department of Biology, Division of Microbiology, Friedrich Alexander University Erlangen-Nuremberg, Staudtstraße 5, D-91058 Erlangen, Germany.
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de Jesus Souza M, de Moraes JA, Da Silva VN, Helal-Neto E, Uberti AF, Scopel-Guerra A, Olivera-Severo D, Carlini CR, Barja-Fidalgo C. Helicobacter pylori urease induces pro-inflammatory effects and differentiation of human endothelial cells: Cellular and molecular mechanism. Helicobacter 2019; 24:e12573. [PMID: 30907046 DOI: 10.1111/hel.12573] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Revised: 01/21/2019] [Accepted: 01/30/2019] [Indexed: 12/26/2022]
Abstract
BACKGROUND Helicobacter pylori urease (HPU) is a key virulence factor that enables bacteria to colonize and survive in the stomach. We early demonstrated that HPU, independent of its catalytic activity, induced inflammatory and angiogenic responses in vivo and directly activated human neutrophils to produce reactive oxygen species (ROS). We have investigated the effects of HPU on endothelial cells, focusing on the signaling mechanism involved. METHODS Monolayers of human microvascular endothelial cells (HMEC-1) were stimulated with HPU (up to 10 nmol/L): Paracellular permeability was accessed through dextran-FITC passage. NO and ROS production was evaluated using intracellular probes. Proteins or mRNA expressions were detected by Western blotting and fluorescence microscopy or qPCR assays, respectively. RESULTS Treatment with HPU enhanced paracellular permeability of HMEC-1, preceded by VE-cadherin phosphorylation and its dissociation from cell-cell junctions. This caused profound alterations in actin cytoskeleton dynamics and focal adhesion kinase (FAK) phosphorylation. HPU triggered ROS and nitric oxide (NO) production by endothelial cells. Increased intracellular ROS resulted in nuclear factor kappa B (NF-κB) activation and upregulated expression of cyclooxygenase-2 (COX-2), hemeoxygenase-1 (HO-1), interleukin-1β (IL-1β), and intercellular adhesion molecule-1 (ICAM-1). Higher ICAM-1 and E-selectin expression was associated with increased neutrophil adhesion on HPU-stimulated HMEC monolayers. The effects of HPU on endothelial cells were dependent on ROS production and lipoxygenase pathway activation, being inhibited by esculetin. Additionally, HPU improved vascular endothelial growth factor receptor 2 (VEGFR-2) expression. CONCLUSION The data suggest that the pro-inflammatory properties of HPU drive endothelial cell to a ROS-dependent program of differentiation that contributes to the progression of H pylori infection.
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Affiliation(s)
- Mariele de Jesus Souza
- Laboratory of Cellular and Molecular Pharmacology, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil
| | - João Alfredo de Moraes
- Laboratory of Cellular and Molecular Pharmacology, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil.,Laboratory of Redox Biology, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Vany Nascimento Da Silva
- Laboratory of Cellular and Molecular Pharmacology, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Edward Helal-Neto
- Laboratory of Cellular and Molecular Pharmacology, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Augusto Frantz Uberti
- Laboratory of Neurotoxins, Brain Institute (BRAINS-InsCer), Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil
| | - Adriele Scopel-Guerra
- Center of Biotechnology, Universidade Federal Rio Grande do Sul, Porto Alegre, Brazil
| | - Deiber Olivera-Severo
- Center of Biotechnology, Universidade Federal Rio Grande do Sul, Porto Alegre, Brazil
| | - Célia R Carlini
- Laboratory of Neurotoxins, Brain Institute (BRAINS-InsCer), Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil.,Center of Biotechnology, Universidade Federal Rio Grande do Sul, Porto Alegre, Brazil
| | - Christina Barja-Fidalgo
- Laboratory of Cellular and Molecular Pharmacology, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil
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Mony TJ, Kwon HS, Won MK, Kang YM, Lee SH, Kim SY, Baek DY, Elahi F. Anti-urease immunoglobulin (IgY) from egg yolk prevents Helicobacter pylori infection in a mouse model. FOOD AGR IMMUNOL 2019. [DOI: 10.1080/09540105.2019.1617251] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Affiliation(s)
| | - Hyuck-Se Kwon
- Research Institute, ADBiotech CO., LTD, Chuncheon, Gangwon, South Korea
| | - Mi-Kyoung Won
- Research Institute, ADBiotech CO., LTD, Chuncheon, Gangwon, South Korea
| | - Yeon-Mi Kang
- Research Institute, ADBiotech CO., LTD, Chuncheon, Gangwon, South Korea
| | - Su-Hee Lee
- Research Institute, ADBiotech CO., LTD, Chuncheon, Gangwon, South Korea
| | - Su-Yeun Kim
- Research Institute, ADBiotech CO., LTD, Chuncheon, Gangwon, South Korea
| | - Doo-Yeon Baek
- Research Institute, ADBiotech CO., LTD, Chuncheon, Gangwon, South Korea
| | - Fazle Elahi
- Research Institute, ADBiotech CO., LTD, Chuncheon, Gangwon, South Korea
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Yadegar A, Mohabati Mobarez A, Zali MR. Genetic diversity and amino acid sequence polymorphism in Helicobacter pylori CagL hypervariable motif and its association with virulence markers and gastroduodenal diseases. Cancer Med 2019; 8:1619-1632. [PMID: 30873747 PMCID: PMC6488209 DOI: 10.1002/cam4.1941] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Revised: 11/22/2018] [Accepted: 12/03/2018] [Indexed: 12/19/2022] Open
Abstract
Genetic variability in cagL gene especially within the Helicobacter pylori CagL hypervariable motif (CagLHM) may affect the development of gastric cancer. Therefore, this study was conducted to investigate the association of CagL diversity with clinical outcomes and with H pylori virulence markers. A total of 126 patients with different gastric diseases including non-ulcer dyspepsia (NUD), peptic ulcer disease (PUD), gastric erosion (GE), and gastric cancer (GC) were enrolled. H pylori was cultured from gastric biopsies, and the isolates were screened for the presence of cagL, cagA, vacA, babA2, sabA, and cagPAI integrity by PCR. The amino acid polymorphisms of cagL were analyzed using DNA sequencing. We isolated 61 (48.4%) H pylori strains from 36 NUD, eight PUD, 12 GE, and five GC patients. Almost all isolates were cagL positive (97%), and their RGD, RHS, and SKIIVK motifs were highly conserved. Among 10 CagLHM variants identified, NEIGQ and NKIGQ were detected as the most prevalent sequences. Interestingly, a significant association was found between the presence of NKMGK and PUD (P = 0.002). Notably, the NEIGQ isolates with multiple C-type EPIYA repeat that carried intact cagPAI correlated with disease risk for PUD, GE, and GC (P = 0.021). In conclusion, we identified novel variants of H pylori CagLHM sequences in Iranian population such as NKMGK, which was associated with disease risk for PUD. Further studies using a large number of strains are required to better clarify the function of certain CagLHM motifs in gastric carcinogenesis and disease outcome.
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Affiliation(s)
- Abbas Yadegar
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ashraf Mohabati Mobarez
- Department of Bacteriology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Zou D, Xu L, Li H, Ma Y, Gong Y, Guo T, Jing Z, Xu X, Zhang Y. Role of abnormal microRNA expression in Helicobacter pylori associated gastric cancer. Crit Rev Microbiol 2019; 45:239-251. [PMID: 30776938 DOI: 10.1080/1040841x.2019.1575793] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Epidemiological studies have shown that Helicobacter pylori (HP) infection is a risk factor for gastric cancer (GC). HP infection may induce the release of pro-inflammatory mediators, and abnormally increase the level of reactive oxygen species (ROS), nitric oxide (NO), and cytokines in mucosal epithelial cells of the stomach. However, the specific mechanism underlying the pathogenesis of HP-associated GC is still poorly understood. Recent studies have revealed that abnormal microRNA expression may affect the proliferation, differentiation, and apoptosis of mucosal epithelial cells of the stomach to further influence GC occurrence, development, and metastasis. Herein, we summarize the role of abnormal microRNAs in the regulation of HP-associated GC progression. Abnormal microRNA expression in HP-positive GC may be a biomarker for GC diagnosis, occurrence, and development as well as its targeted treatment and prognosis.
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Affiliation(s)
- Dan Zou
- a The First laboratory of cancer institute , First Hospital of China Medical University , Shenyang , China
| | - Ling Xu
- b Department of Medical Oncology , First Hospital of China Medical University , Shenyang , China
| | - Heming Li
- b Department of Medical Oncology , First Hospital of China Medical University , Shenyang , China.,c Department of Oncology , Affiliated Zhongshan Hospital of Dalian University , Dalian , China
| | - Yanju Ma
- b Department of Medical Oncology , First Hospital of China Medical University , Shenyang , China.,d Department of Medical Oncology , Cancer Hospital of China Medical University , Shenyang , China
| | - Yuehua Gong
- e Department of Tumor Etiology and Screening Department of Cancer Institute and General Surgery, First Hospital of China Medical University , Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department , Shenyang , China
| | - Tianshu Guo
- b Department of Medical Oncology , First Hospital of China Medical University , Shenyang , China
| | - Zhitao Jing
- f Department of Neurosurgery , First Hospital of China Medical University , Shenyang , China
| | - Xiuying Xu
- g Department of Gastroenterology , First Hospital of China Medical University , Shenyang , China
| | - Ye Zhang
- a The First laboratory of cancer institute , First Hospital of China Medical University , Shenyang , China
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Posselt G, Wiesauer M, Chichirau BE, Engler D, Krisch LM, Gadermaier G, Briza P, Schneider S, Boccellato F, Meyer TF, Hauser-Kronberger C, Neureiter D, Müller A, Wessler S. Helicobacter pylori-controlled c-Abl localization promotes cell migration and limits apoptosis. Cell Commun Signal 2019; 17:10. [PMID: 30704478 PMCID: PMC6357398 DOI: 10.1186/s12964-019-0323-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Accepted: 01/22/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Deregulated c-Abl activity has been intensively studied in a variety of solid tumors and leukemia. The class-I carcinogen Helicobacter pylori (Hp) activates the non-receptor tyrosine kinase c-Abl to phosphorylate the oncoprotein cytotoxin-associated gene A (CagA). The role of c-Abl in CagA-dependent pathways is well established; however, the knowledge of CagA-independent c-Abl processes is scarce. METHODS c-Abl phosphorylation and localization were analyzed by immunostaining and immunofluorescence. Interaction partners were identified by tandem-affinity purification. Cell elongation and migration were analyzed in transwell-filter experiments. Apoptosis and cell survival were examined by FACS analyses and MTT assays. In mice experiments and human biopsies, the involvement of c-Abl in Hp pathogenesis was investigated. RESULTS Here, we investigated the activity and subcellular localization of c-Abl in vitro and in vivo and unraveled the contribution of c-Abl in CagA-dependent and -independent pathways to gastric Hp pathogenesis. We report a novel mechanism and identified strong c-Abl threonine 735 phosphorylation (pAblT735) mediated by the type-IV secretion system (T4SS) effector D-glycero-β-D-manno-heptose-1,7-bisphosphate (βHBP) and protein kinase C (PKC) as a new c-Abl kinase. pAblT735 interacted with 14-3-3 proteins, which caused cytoplasmic retention of c-Abl, where it potentiated Hp-mediated cell elongation and migration. Further, the nuclear exclusion of pAblT735 attenuated caspase-8 and caspase-9-dependent apoptosis. Importantly, in human patients suffering from Hp-mediated gastritis c-Abl expression and pAblT735 phosphorylation were drastically enhanced as compared to type C gastritis patients or healthy individuals. Pharmacological inhibition using the selective c-Abl kinase inhibitor Gleevec confirmed that c-Abl plays an important role in Hp pathogenesis in a murine in vivo model. CONCLUSIONS In this study, we identified a novel regulatory mechanism in Hp-infected gastric epithelial cells by which Hp determines the subcellular localization of activated c-Abl to control Hp-mediated EMT-like processes while decreasing cell death.
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Affiliation(s)
- Gernot Posselt
- Department of Biosciences, Division of Microbiology, University of Salzburg, Paris-Lodron University of Salzburg, Billroth Str. 11, A-5020 Salzburg, Austria
| | - Maria Wiesauer
- Department of Biosciences, Division of Microbiology, University of Salzburg, Paris-Lodron University of Salzburg, Billroth Str. 11, A-5020 Salzburg, Austria
| | - Bianca E. Chichirau
- Department of Biosciences, Division of Microbiology, University of Salzburg, Paris-Lodron University of Salzburg, Billroth Str. 11, A-5020 Salzburg, Austria
| | - Daniela Engler
- Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland
| | - Linda M. Krisch
- Department of Biosciences, Division of Microbiology, University of Salzburg, Paris-Lodron University of Salzburg, Billroth Str. 11, A-5020 Salzburg, Austria
| | - Gabriele Gadermaier
- Department of Biosciences, Division of Allergy and Immunology, University of Salzburg, Paris-Lodron University of Salzburg, Hellbrunner Str. 34, A-5020 Salzburg, Austria
| | - Peter Briza
- Department of Biosciences, Division of Allergy and Immunology, University of Salzburg, Paris-Lodron University of Salzburg, Hellbrunner Str. 34, A-5020 Salzburg, Austria
| | - Sabine Schneider
- Paul-Ehrlich-Institute, Paul-Ehrlich-Str. 51-59, D-63225 Langen, Germany
| | - Francesco Boccellato
- Max Planck Institute for Infection Biology, Charitéplatz 1, D-10117 Berlin, Germany
| | - Thomas F. Meyer
- Max Planck Institute for Infection Biology, Charitéplatz 1, D-10117 Berlin, Germany
| | - Cornelia Hauser-Kronberger
- Department of Pathology, Paracelsus Medical University Salzburg, Müllner Hauptstraße 48, A-5020 Salzburg, Austria
| | - Daniel Neureiter
- Department of Pathology, Paracelsus Medical University Salzburg, Müllner Hauptstraße 48, A-5020 Salzburg, Austria
- Cancer Cluster Salzburg, University of Salzburg, A-5020 Salzburg, Austria
| | - Anne Müller
- Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland
| | - Silja Wessler
- Department of Biosciences, Division of Microbiology, University of Salzburg, Paris-Lodron University of Salzburg, Billroth Str. 11, A-5020 Salzburg, Austria
- Cancer Cluster Salzburg, University of Salzburg, A-5020 Salzburg, Austria
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Role of a Stem-Loop Structure in Helicobacter pylori cagA Transcript Stability. Infect Immun 2019; 87:IAI.00692-18. [PMID: 30510104 DOI: 10.1128/iai.00692-18] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Accepted: 11/26/2018] [Indexed: 12/21/2022] Open
Abstract
Helicobacter pylori CagA is a secreted effector protein that contributes to gastric carcinogenesis. Previous studies showed that there is variation among H. pylori strains in the steady-state levels of CagA and that a strain-specific motif downstream of the cagA transcriptional start site (the +59 motif) is associated with both high levels of CagA and premalignant gastric histology. The cagA 5' untranslated region contains a predicted stem-loop-forming structure adjacent to the +59 motif. In the current study, we investigated the effect of the +59 motif and the adjacent stem-loop on cagA transcript levels and cagA mRNA stability. Using site-directed mutagenesis, we found that mutations predicted to disrupt the stem-loop structure resulted in decreased steady-state levels of both the cagA transcript and the CagA protein. Additionally, these mutations resulted in a decreased cagA mRNA half-life. Mutagenesis of the +59 motif without altering the stem-loop structure resulted in reduced steady-state cagA transcript and CagA protein levels but did not affect cagA transcript stability. cagA transcript stability was not affected by increased sodium chloride concentrations, an environmental factor known to augment cagA transcript levels and CagA protein levels. These results indicate that both a predicted stem-loop structure and a strain-specific +59 motif in the cagA 5' untranslated region influence the levels of cagA expression.
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Molina-Castro S, Garita-Cambronero J, Malespín-Bendaña W, Une C, Ramírez V. Virulence factor genotyping of Helicobacter pylori isolated from Costa Rican dyspeptic patients. Microb Pathog 2019; 128:276-280. [PMID: 30654009 DOI: 10.1016/j.micpath.2019.01.018] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Revised: 01/10/2019] [Accepted: 01/11/2019] [Indexed: 12/24/2022]
Abstract
BACKGROUND AND AIMS Costa Rica is one of the countries with the highest incidence and mortality rates for gastric cancer. Helicobacter pylori infection rates are high in the whole country. We have previously shown that H. pylori CagA+ is significantly associated with atrophic gastritis (AG) of the antrum in a dyspeptic population. The aim of this work is to determine if other H. pylori virulence factors (vacA, dupA, oipA, iceA and babA2) are associated with atrophic gastritis (AG) or duodenal ulcer (DU). METHODS The presence of virulence genes in Costa Rican H. pylori isolates was analyzed by PCR in 151 cultured strains from patients with dyspeptic symptoms. Endoscopic and histopathological diagnoses were available. Odds-ratio and 95% confidence intervals for AG patients vs. non-atrophic gastritis (NAG) or DU patients vs. no duodenal ulcer (NDU) patients were calculated. RESULTS Amongst the studied isolates, 82% had the cagA+, 76.2% had the vacA s1m1, 97.0% had the oipA+, 21.0% had the icea1, 79.0% had the iceA2, 44.0% had the babA2+ and 76.0% the dupA+ genotypes. Infection with H pylori cagA+, dupA+, oipA+, iceA, babA2+, and vacA s1m1 genotypes was not associated with AG risk. The frequency of the dupA gene was 78.7 and 60.9% in isolates from patients with NDU and DU, respectively, and its presence was significantly associated with decreased risk of duodenal ulcer [odds-ratio: 0.33, p = 0.024, confidence interval 95% (0.11-0.85)]. CONCLUSION H. pylori dupA genotype is inversely associated with DU risk in this population.
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Affiliation(s)
- Silvia Molina-Castro
- Institute for Health Research (INISA), University of Costa Rica, San Pedro, 11501, San José, Costa Rica; School of Medicine, University of Costa Rica, San Pedro, 11501, San José, Costa Rica.
| | - Jerson Garita-Cambronero
- Institute for Health Research (INISA), University of Costa Rica, San Pedro, 11501, San José, Costa Rica.
| | - Wendy Malespín-Bendaña
- Institute for Health Research (INISA), University of Costa Rica, San Pedro, 11501, San José, Costa Rica.
| | - Clas Une
- Institute for Health Research (INISA), University of Costa Rica, San Pedro, 11501, San José, Costa Rica.
| | - Vanessa Ramírez
- Institute for Health Research (INISA), University of Costa Rica, San Pedro, 11501, San José, Costa Rica.
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Zamperone A, Cohen D, Stein M, Viard C, Müsch A. Inhibition of polarity-regulating kinase PAR1b contributes to Helicobacter pylori inflicted DNA Double Strand Breaks in gastric cells. Cell Cycle 2019; 18:299-311. [PMID: 30580666 DOI: 10.1080/15384101.2018.1560121] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
The serine/threonine kinase Par1 is a core component of the machinery that sets up polarity in the embryo and regulates cell fate decisions but its role in the homeostasis of adult tissues is poorly understood. Inhibition of Par1 by the bacterium Helicobacter pylori (H. pylori) represents the only established pathology that affects Par1 function in an adult epithelium. Thus, during chronic H. pylori infection of the gastric mucosa Par1 is one of the targets of the non-obligate H.pylori cytotoxic protein and oncogene CagA, which stimulates inflammation and triggers morphological changes, both believed to contribute to the gastric cancer risk imposed by H. pylori infection. Based on Par1's role in cell polarity, it has been speculated that Par1 inhibition affects epithelial polarity. Here we report the unexpected finding that CagA-mediated Par1-inhibition promotes the generation of DNA Double Strand Breaks in primary gastric epithelial cells, which likely contributes to the reported accumulation of mutations in chronically infected mucosal cells. Abbreviations: AGS: human gastric adenocarcinoma cell line; CM: CagA Multimerization (and Par1 binding) domain; H. pylori: Helicobacter pylori; DSB: Double Strand Break; HGECs: human (primary) gastric epithelial cells; IB: immunoblot; IF: immunofluorescence; MOI: Multiplicity of Infection; ROS: reactive oxygen species; Par1: Partitioning Defective 1 kinase; WT: wild type.
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Affiliation(s)
- Andrea Zamperone
- a Department of Developmental & Molecular Biology , Albert Einstein College Medicine , Bronx , NY , USA
| | - David Cohen
- a Department of Developmental & Molecular Biology , Albert Einstein College Medicine , Bronx , NY , USA
| | - Markus Stein
- b Department of Health Sciences , Albany College of Pharmacy and Health Sciences , Albany , NY , USA
| | - Charlotte Viard
- a Department of Developmental & Molecular Biology , Albert Einstein College Medicine , Bronx , NY , USA
| | - Anne Müsch
- a Department of Developmental & Molecular Biology , Albert Einstein College Medicine , Bronx , NY , USA
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Genetic Polymorphisms in Inflammatory and Other Regulators in Gastric Cancer: Risks and Clinical Consequences. Curr Top Microbiol Immunol 2019; 421:53-76. [PMID: 31123885 DOI: 10.1007/978-3-030-15138-6_3] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Helicobacter pylori infection is associated with the development of a chronic inflammatory response, which may induce peptic ulcers, gastric cancer (GC), and mucosa-associated lymphoid tissue (MALT) lymphoma. Chronic H. pylori infection promotes the genetic instability of gastric epithelial cells and interferes with the DNA repair systems in host cells. Colonization of the stomach with H. pylori is an important cause of non-cardia GC and gastric MALT lymphoma. The reduction of GC development in patients who underwent anti-H. pylori eradication schemes has also been well described. Individual susceptibility to GC development depends on the host's genetic predisposition, H. pylori virulence factors, environmental conditions, and geographical determinants. Biological determinants are urgently sought to predict the clinical course of infection in individuals with confirmed H. pylori infection. Possible candidates for such biomarkers include genetic aberrations such as single-nucleotide polymorphisms (SNPs) found in various cytokines/growth factors (e.g., IL-1β, IL-2, IL-6, IL-8, IL-10, IL-13, IL-17A/B, IFN-γ, TNF, TGF-β) and their receptors (IL-RN, TGFR), innate immunity receptors (TLR2, TLR4, CD14, NOD1, NOD2), enzymes involved in signal transduction cascades (PLCE1, PKLR, PRKAA1) as well as glycoproteins (MUC1, PSCA), and DNA repair enzymes (ERCC2, XRCC1, XRCC3). Bacterial determinants related to GC development include infection with CagA-positive (particularly with a high number of EPIYA-C phosphorylation motifs) and VacA-positive isolates (in particular s1/m1 allele strains). The combined genotyping of bacterial and host determinants suggests that the accumulation of polymorphisms favoring host and bacterial features increases the risk for precancerous and cancerous lesions in patients.
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