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Lee BE, Park SJ, Kim GH, Joo DC, Lee MW. Anti-inflammatory effects of eupatilin on Helicobacter pylori CagA-induced gastric inflammation. PLoS One 2024; 19:e0313251. [PMID: 39499687 PMCID: PMC11537371 DOI: 10.1371/journal.pone.0313251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Accepted: 10/21/2024] [Indexed: 11/07/2024] Open
Abstract
BACKGROUND Eupatilin, a flavone isolated from Artemisia species, exerts anti-inflammatory, anti-oxidative, and anti-neoplastic activities. However, the effects of eupatilin on H. pylori-associated gastritis remain unclear. Thus, this study aimed to investigate the anti-inflammatory effects of eupatilin on gastric epithelial cells infected with cytotoxin-associated gene A (CagA)-positive Helicobacter pylori. MATERIALS AND METHODS AGS human gastric carcinoma cells were infected with a CagA-positive H. pylori strain and then treated with 10, 50, or 100 ng of eupatilin. After 24 h, the expression levels of CagA, phosphoinositide 3-kinase 1 (PI3K), nuclear factor (NF)-κB, interleukin (IL)-1β, and tumor necrosis factor (TNF)-α in the cell lysates were measured using western blotting, and the mRNA levels of IL-6, IL-8, and monocyte chemoattractant protein (MCP)-1 were measured using real-time polymerase chain reaction. RESULTS CagA translocation into AGS cells resulted in an elongated cell morphology, which was significantly suppressed by eupatilin treatment in a dose-dependent manner. Immunofluorescence staining for anti-CagA showed that eupatilin treatment dose-dependently inhibited CagA expression in the H. pylori-infected AGS cells. H. pylori infection increased the levels of pro-inflammatory cytokines including IL-1β, TNF-α, IL-6, IL-8, and MCP-1, and eupatilin treatment significantly reduced the levels of these cytokines in a dose-dependent manner. Additionally, eupatilin treatment dose-dependently suppressed the expression of PI3K and NF-κB. CONCLUSIONS Eupatilin treatment demonstrated anti-inflammatory effects on CagA-positive H. pylori-infected gastric epithelial cells by inhibiting CagA translocation, thereby suppressing the NF-κB signaling pathway. These results suggest that eupatilin plays a protective role against CagA-positive H. pylori-induced gastritis.
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Affiliation(s)
- Bong Eun Lee
- Department of Internal Medicine, Pusan National University School of Medicine, Busan, Korea
- Biomedical Research Institute, Pusan National University Hospital, Busan, Korea
| | - Su Jin Park
- Biomedical Research Institute, Pusan National University Hospital, Busan, Korea
| | - Gwang Ha Kim
- Department of Internal Medicine, Pusan National University School of Medicine, Busan, Korea
- Biomedical Research Institute, Pusan National University Hospital, Busan, Korea
| | - Dong Chan Joo
- Department of Internal Medicine, Pusan National University School of Medicine, Busan, Korea
- Biomedical Research Institute, Pusan National University Hospital, Busan, Korea
| | - Moon Won Lee
- Department of Internal Medicine, Pusan National University School of Medicine, Busan, Korea
- Biomedical Research Institute, Pusan National University Hospital, Busan, Korea
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2
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Morales P, Brown AJ, Sangaré LO, Yang S, Kuihon SVNP, Chen B, Saeij JPJ. The Toxoplasma secreted effector TgWIP modulates dendritic cell motility by activating host tyrosine phosphatases Shp1 and Shp2. Cell Mol Life Sci 2024; 81:294. [PMID: 38977495 PMCID: PMC11335217 DOI: 10.1007/s00018-024-05283-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 05/07/2024] [Accepted: 05/14/2024] [Indexed: 07/10/2024]
Abstract
The obligate intracellular parasite Toxoplasma gondii causes life-threatening toxoplasmosis to immunocompromised individuals. The pathogenesis of Toxoplasma relies on its swift dissemination to the central nervous system through a 'Trojan Horse' mechanism using infected leukocytes as carriers. Previous work found TgWIP, a protein secreted from Toxoplasma, played a role in altering the actin cytoskeleton and promoting cell migration in infected dendritic cells (DCs). However, the mechanism behind these changes was unknown. Here, we report that TgWIP harbors two SH2-binding motifs that interact with tyrosine phosphatases Shp1 and Shp2, leading to phosphatase activation. DCs infected with Toxoplasma exhibited hypermigration, accompanying enhanced F-actin stress fibers and increased membrane protrusions such as filopodia and pseudopodia. By contrast, these phenotypes were abrogated in DCs infected with Toxoplasma expressing a mutant TgWIP lacking the SH2-binding motifs. We further demonstrated that the Rho-associated kinase (Rock) is involved in the induction of these phenotypes, in a TgWIP-Shp1/2 dependent manner. Collectively, the data uncover a molecular mechanism by which TgWIP modulates the migration dynamics of infected DCs in vitro.
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Affiliation(s)
- Pavel Morales
- Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California, Davis, Davis, CA, USA
| | - Abbigale J Brown
- Roy J. Carver Department of Biochemistry, Biophysics & Molecular Biology, Iowa State University, Ames, IA, USA
| | - Lamba Omar Sangaré
- Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California, Davis, Davis, CA, USA
| | - Sheng Yang
- Roy J. Carver Department of Biochemistry, Biophysics & Molecular Biology, Iowa State University, Ames, IA, USA
- Target & Protein Sciences, Johnson & Johnson, New Brunswick, USA
| | - Simon V N P Kuihon
- Roy J. Carver Department of Biochemistry, Biophysics & Molecular Biology, Iowa State University, Ames, IA, USA
| | - Baoyu Chen
- Roy J. Carver Department of Biochemistry, Biophysics & Molecular Biology, Iowa State University, Ames, IA, USA
| | - Jeroen P J Saeij
- Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California, Davis, Davis, CA, USA.
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3
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Morales P, Brown AJ, Sangare LO, Yang S, Kuihon S, Chen B, Saeij J. The Toxoplasma secreted effector TgWIP modulates dendritic cell motility by activating host tyrosine phosphatases Shp1 and Shp2. RESEARCH SQUARE 2024:rs.3.rs-4539584. [PMID: 38978596 PMCID: PMC11230507 DOI: 10.21203/rs.3.rs-4539584/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/10/2024]
Abstract
The obligate intracellular parasite Toxoplasma gondii causes life-threatening toxoplasmosis to immunocompromised individuals. The pathogenesis of Toxoplasma relies on its swift dissemination to the central nervous system through a 'Trojan Horse' mechanism using infected leukocytes as carriers. Previous work found TgWIP, a protein secreted from Toxoplasma, played a role in altering the actin cytoskeleton and promoting cell migration in infected dendritic cells (DCs). However, the mechanism behind these changes was unknown. Here, we report that TgWIP harbors two SH2-binding motifs that interact with tyrosine phosphatases Shp1 and Shp2, leading to phosphatase activation. DCs infected with Toxoplasma exhibited hypermigration, accompanying enhanced F-actin stress fibers and increased membrane protrusions such as filopodia and pseudopodia. By contrast, these phenotypes were abrogated in DCs infected with Toxoplasma expressing a mutant TgWIP lacking the SH2-binding motifs. We further demonstrated that the Rho-associated kinase (Rock) is involved in the induction of these phenotypes, in a TgWIP-Shp1/2 dependent manner. Collectively, the data uncover a molecular mechanism by which TgWIP modulates the migration dynamics of infected DCs in vitro.
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Affiliation(s)
| | | | | | | | | | | | - Jeroen Saeij
- University of California Davis School of Veterinary Medicine
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4
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Chew DCH, Yim CHH, Ali RA, El‐Omar EM. Epidemiology, Microbiome, and Risk Factors Involved in Carcinogenesis of Esophagus, Gastric, and Intestine. GASTROINTESTINAL ONCOLOGY ‐ A CRITICAL MULTIDISCIPLINARY TEAM APPROACH 2E 2024:2-22. [DOI: 10.1002/9781119756422.ch1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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5
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Tran SC, Bryant KN, Cover TL. The Helicobacter pylori cag pathogenicity island as a determinant of gastric cancer risk. Gut Microbes 2024; 16:2314201. [PMID: 38391242 PMCID: PMC10896142 DOI: 10.1080/19490976.2024.2314201] [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: 11/18/2023] [Accepted: 01/31/2024] [Indexed: 02/24/2024] Open
Abstract
Helicobacter pylori strains can be broadly classified into two groups based on whether they contain or lack a chromosomal region known as the cag pathogenicity island (cag PAI). Colonization of the human stomach with cag PAI-positive strains is associated with an increased risk of gastric cancer and peptic ulcer disease, compared to colonization with cag PAI-negative strains. The cag PAI encodes a secreted effector protein (CagA) and components of a type IV secretion system (Cag T4SS) that delivers CagA and non-protein substrates into host cells. Animal model experiments indicate that CagA and the Cag T4SS stimulate a gastric mucosal inflammatory response and contribute to the development of gastric cancer. In this review, we discuss recent studies defining structural and functional features of CagA and the Cag T4SS and mechanisms by which H. pylori strains containing the cag PAI promote the development of gastric cancer and peptic ulcer disease.
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Affiliation(s)
- Sirena C. Tran
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Kaeli N. Bryant
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Timothy L. Cover
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA
- Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, USA
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6
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Li J, Li X, Zhang Z, Wang S, Huang X, Min L, Li P. Helicobacter pylori promotes gastric fibroblast proliferation and migration by expulsing exosomal miR-124-3p. Microbes Infect 2024; 26:105236. [PMID: 37813158 DOI: 10.1016/j.micinf.2023.105236] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 09/22/2023] [Accepted: 10/02/2023] [Indexed: 10/11/2023]
Abstract
Gastric fibroblasts (GFs) are direct targets of Helicobacter pylori (H. pylori). GFs infected with H. pylori exhibit marked changes in their morphology and biological behavior. However, the molecular mechanisms by which H. pylori regulates GFs remain unknown. In this study, we cocultured GFs with H. pylori for 48 h. As a result, GFs exhibited an elongated and spindle-shaped morphology. Further, cancer-associated fibroblast (CAF) biomarkers were increased, and related behaviors were significantly enhanced in H. pylori-activated GFs. The number of extracellular vesicles (EVs) secreted by H. pylori-activated GFs remarkably increased. The miR-124-3p level was increased in secreted EVs but decreased in the cytoplasm of H. pylori-activated GFs. Overexpression of miRNA-124-3p in the original GFs significantly suppressed their proliferation and migration. In addition, the migration-promoting effects of H. pylori-activated GFs were suppressed by miR-124-3p and GW4869, which blocked EV generation. Finally, pull-down and luciferase assays revealed that SNAI2 is a target of miR-124-3p. The migration-inhibitory effects of GFs treated with miR-124-3p were eliminated by the overexpression of SNAI2, and the upregulation of SNAI2 in H. pylori-activated GFs was partially alleviated by miR-124-3p or GW4869. Overall, H. pylori infection promotes the proliferation and migration of GFs by accelerating the expulsion of EVs carrying miRNA-124-3p, a SNAI2 inhibitor.
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Affiliation(s)
- Jun Li
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, 100050 Beijing, PR China; Department of Gastroenterology, Chui Yang Liu Hospital Affiliated to Tsinghua University, 100020 Beijing, PR China
| | - Xiangji Li
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, 100050 Beijing, PR China
| | - Zheng Zhang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, 100050 Beijing, PR China
| | - Shidong Wang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, 100050 Beijing, PR China
| | - Xinyuan Huang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, 100050 Beijing, PR China
| | - Li Min
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, 100050 Beijing, PR China.
| | - Peng Li
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, 100050 Beijing, PR China.
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Beccaceci G, Sigal M. Unwelcome guests - the role of gland-associated Helicobacter pylori infection in gastric carcinogenesis. Front Oncol 2023; 13:1171003. [PMID: 37152042 PMCID: PMC10160455 DOI: 10.3389/fonc.2023.1171003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 04/04/2023] [Indexed: 05/09/2023] Open
Abstract
Helicobacter pylori (H. pylori) are Gram-negative bacteria that cause chronic gastritis and are considered the main risk factor for the development of gastric cancer. H. pylori have evolved to survive the harsh luminal environment of the stomach and are known to cause damage and signaling aberrations in gastric epithelial cells, which can result in premalignant and malignant pathology. As well as colonizing the gastric mucus and surface epithelial cells, a subpopulation of H. pylori can invade deep into the gastric glands and directly interact with progenitor and stem cells. Gland colonization therefore bears the potential to cause direct injury to long-lived cells. Moreover, this bacterial subpopulation triggers a series of host responses that cause an enhanced proliferation of stem cells. Here, we review recent insights into how gastric gland colonization by H. pylori is established, the resulting pro-carcinogenic epithelial signaling alterations, as well as new insights into stem cell responses to infection. Together these point towards a critical role of gland-associated H. pylori in the development of gastric cancer.
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Affiliation(s)
- Giulia Beccaceci
- Medical Department, Division of Gastroenterology and Hepatology, Charité-Universtitätsmedizin Berlin, Berlin, Germany
- The Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine, Berlin, Germany
| | - Michael Sigal
- Medical Department, Division of Gastroenterology and Hepatology, Charité-Universtitätsmedizin Berlin, Berlin, Germany
- The Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine, Berlin, Germany
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8
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Varshney N, Kashyap D, Behra SK, Saini V, Chaurasia A, Kumar S, Jha HC. Predictive profiling of gram-negative antibiotics in CagA oncoprotein inactivation: a molecular dynamics simulation approach. SAR AND QSAR IN ENVIRONMENTAL RESEARCH 2023; 34:501-521. [PMID: 37462112 DOI: 10.1080/1062936x.2023.2230876] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 06/24/2023] [Indexed: 07/20/2023]
Abstract
Gastric cancer (GC) is the fifth most prevalent form of cancer worldwide. CagA - positive Helicobacter pylori infects more than 60% of the human population. Moreover, chronic infection of CagA-positive H. pylori can directly affect GC incidence. In the current study, we have repurposed FDA-approved antibiotics that are viable alternatives to current regimens and can potentially be used as combination therapy against the CagA of H. pylori. The 100 FDA-approved gram negative antibiotics were screened against CagA protein using the AutoDock 4.2 tool. Further, top nine compounds were selected based on higher binding affinity with CagA. The trajectory analysis of MD simulations reflected that binding of these drugs with CagA stabilizes the system. Nonetheless, atomic density map and principal component analysis also support the notion of stable binding of antibiotics to the protein. The residues ASP96, GLN100, PRO184, and THR185 of compound cefpiramide, doxycycline, delafloxacin, metacycline, oxytetracycline, and ertapenem were involved in the binding with CagA protein. These residues are crucial for the CagA that aids in entry or pathogenesis of the bacterium. The screened FDA-approved antibiotics have a potential druggability to inhibit CagA and reduce the progression of H. pylori borne diseases.
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Affiliation(s)
- N Varshney
- Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, India
| | - D Kashyap
- Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, India
| | - S K Behra
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Ahmedabad, Gandhinagar, India
| | - V Saini
- Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, India
| | - A Chaurasia
- Division of Crop Protection, ICAR -Indian Institute of Vegetable Research, Varanasi, India
| | - S Kumar
- Division of Agricultural Bioinformatics (CABIN), ICAR-Indian Agricultural Statistics Research Institute (IASRI), Delhi, India
| | - H C Jha
- Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, India
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9
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Domínguez-Martínez DA, Fontes-Lemus JI, García-Regalado A, Juárez-Flores Á, Fuentes-Pananá EM. IL-8 Secreted by Gastric Epithelial Cells Infected with Helicobacter pylori CagA Positive Strains Is a Chemoattractant for Epstein-Barr Virus Infected B Lymphocytes. Viruses 2023; 15:651. [PMID: 36992360 PMCID: PMC10054738 DOI: 10.3390/v15030651] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 02/09/2023] [Accepted: 02/14/2023] [Indexed: 03/05/2023] Open
Abstract
Helicobacter pylori and EBV are considered the main risk factors in developing gastric cancer. Both pathogens establish life-lasting infections and both are considered carcinogenic in humans. Different lines of evidence support that both pathogens cooperate to damage the gastric mucosa. Helicobacter pylori CagA positive virulent strains induce the gastric epithelial cells to secrete IL-8, which is a potent chemoattractant for neutrophils and one of the most important chemokines for the bacterium-induced chronic gastric inflammation. EBV is a lymphotropic virus that persists in memory B cells. The mechanism by which EBV reaches, infects and persists in the gastric epithelium is not presently understood. In this study, we assessed whether Helicobacter pylori infection would facilitate the chemoattraction of EBV-infected B lymphocytes. We identified IL-8 as a powerful chemoattractant for EBV-infected B lymphocytes, and CXCR2 as the main IL-8 receptor whose expression is induced by the EBV in infected B lymphocytes. The inhibition of expression and/or function of IL-8 and CXCR2 reduced the ERK1/2 and p38 MAPK signaling and the chemoattraction of EBV-infected B lymphocytes. We propose that IL-8 at least partially explains the arrival of EBV-infected B lymphocytes to the gastric mucosa, and that this illustrates a mechanism of interaction between Helicobacter pylori and EBV.
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Affiliation(s)
- Diana A. Domínguez-Martínez
- Research Unit on Virology and Cancer, Children’s Hospital of Mexico Federico Gómez, Mexico City 06720, Mexico
| | - José I. Fontes-Lemus
- Research Unit on Virology and Cancer, Children’s Hospital of Mexico Federico Gómez, Mexico City 06720, Mexico
| | - Alejandro García-Regalado
- Research Unit on Virology and Cancer, Children’s Hospital of Mexico Federico Gómez, Mexico City 06720, Mexico
| | - Ángel Juárez-Flores
- Research Unit on Virology and Cancer, Children’s Hospital of Mexico Federico Gómez, Mexico City 06720, Mexico
- Unidad de Investigación Médica en Inmunoquímica, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México 06720, Mexico
| | - Ezequiel M. Fuentes-Pananá
- Research Unit on Virology and Cancer, Children’s Hospital of Mexico Federico Gómez, Mexico City 06720, Mexico
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Wroblewski LE, Peek RM. Clinical Pathogenesis, Molecular Mechanisms of Gastric Cancer Development. Curr Top Microbiol Immunol 2023; 444:25-52. [PMID: 38231214 PMCID: PMC10924282 DOI: 10.1007/978-3-031-47331-9_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2024]
Abstract
The human pathogen Helicobacter pylori is the strongest known risk factor for gastric disease and cancer, and gastric cancer remains a leading cause of cancer-related death across the globe. Carcinogenic mechanisms associated with H. pylori are multifactorial and are driven by bacterial virulence constituents, host immune responses, environmental factors such as iron and salt, and the microbiota. Infection with strains that harbor the cytotoxin-associated genes (cag) pathogenicity island, which encodes a type IV secretion system (T4SS) confer increased risk for developing more severe gastric diseases. Other important H. pylori virulence factors that augment disease progression include vacuolating cytotoxin A (VacA), specifically type s1m1 vacA alleles, serine protease HtrA, and the outer-membrane adhesins HopQ, BabA, SabA and OipA. Additional risk factors for gastric cancer include dietary factors such as diets that are high in salt or low in iron, H. pylori-induced perturbations of the gastric microbiome, host genetic polymorphisms, and infection with Epstein-Barr virus. This chapter discusses in detail host factors and how H. pylori virulence factors augment the risk of developing gastric cancer in human patients as well as how the Mongolian gerbil model has been used to define mechanisms of H. pylori-induced inflammation and cancer.
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Affiliation(s)
- Lydia E Wroblewski
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Richard M Peek
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
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Naumann M, Ferino L, Sharafutdinov I, Backert S. Gastric Epithelial Barrier Disruption, Inflammation and Oncogenic Signal Transduction by Helicobacter pylori. Curr Top Microbiol Immunol 2023; 444:207-238. [PMID: 38231220 DOI: 10.1007/978-3-031-47331-9_8] [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: 01/18/2024]
Abstract
Helicobacter pylori exemplifies one of the most favourable bacterial pathogens worldwide. The bacterium colonizes the gastric mucosa in about half of the human population and constitutes a major risk factor for triggering gastric diseases such as stomach cancer. H. pylori infection represents a prime example of chronic inflammation and cancer-inducing bacterial pathogens. The microbe utilizes a remarkable set of virulence factors and strategies to control cellular checkpoints of inflammation and oncogenic signal transduction. This chapter emphasizes on the pathogenicity determinants of H. pylori such as the cytotoxin-associated genes pathogenicity island (cagPAI)-encoded type-IV secretion system (T4SS), effector protein CagA, lipopolysaccharide (LPS) metabolite ADP-glycero-β-D-manno-heptose (ADP-heptose), cytotoxin VacA, serine protease HtrA, and urease, and how they manipulate various key host cell signaling networks in the gastric epithelium. In particular, we highlight the H. pylori-induced disruption of cell-to-cell junctions, pro-inflammatory activities, as well as proliferative, pro-apoptotic and anti-apoptotic responses. Here we review these hijacked signal transduction events and their impact on gastric disease development.
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Affiliation(s)
- Michael Naumann
- Institute of Experimental Internal Medicine, Medical Faculty, Otto Von Guericke University, Leipziger Str. 44, 39120, Magdeburg, Germany.
| | - Lorena Ferino
- Institute of Experimental Internal Medicine, Medical Faculty, Otto Von Guericke University, Leipziger Str. 44, 39120, Magdeburg, Germany
| | - Irshad Sharafutdinov
- Dept. Biology, Division of Microbiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Staudtstr. 5, 91058, Erlangen, Germany
| | - Steffen Backert
- Dept. Biology, Division of Microbiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Staudtstr. 5, 91058, Erlangen, Germany.
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12
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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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Dey P, Ray Chaudhuri S. Cancer-Associated Microbiota: From Mechanisms of Disease Causation to Microbiota-Centric Anti-Cancer Approaches. BIOLOGY 2022; 11:757. [PMID: 35625485 PMCID: PMC9138768 DOI: 10.3390/biology11050757] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 05/08/2022] [Accepted: 05/12/2022] [Indexed: 02/07/2023]
Abstract
Helicobacter pylori infection is the only well-established bacterial cause of cancer. However, due to the integral role of tissue-resident commensals in maintaining tissue-specific immunometabolic homeostasis, accumulated evidence suggests that an imbalance of tissue-resident microbiota that are otherwise considered as commensals, can also promote various types of cancers. Therefore, the present review discusses compelling evidence linking tissue-resident microbiota (especially gut bacteria) with cancer initiation and progression. Experimental evidence supporting the cancer-causing role of gut commensal through the modulation of host-specific processes (e.g., bile acid metabolism, hormonal effects) or by direct DNA damage and toxicity has been discussed. The opportunistic role of commensal through pathoadaptive mutation and overcoming colonization resistance is discussed, and how chronic inflammation triggered by microbiota could be an intermediate in cancer-causing infections has been discussed. Finally, we discuss microbiota-centric strategies, including fecal microbiota transplantation, proven to be beneficial in preventing and treating cancers. Collectively, this review provides a comprehensive understanding of the role of tissue-resident microbiota, their cancer-promoting potentials, and how beneficial bacteria can be used against cancers.
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Affiliation(s)
- Priyankar Dey
- Department of Biotechnology, Thapar Institute of Engineering and Technology, Patiala 147004, India
| | - Saumya Ray Chaudhuri
- Council of Scientific and Industrial Research (CSIR), Institute of Microbial Technology, Chandigarh 160036, India;
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14
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Jang S, Hansen LM, Su H, Solnick JV, Cha JH. Host immune response mediates changes in cagA copy number and virulence potential of Helicobacter pylori. Gut Microbes 2022; 14:2044721. [PMID: 35289715 PMCID: PMC8928821 DOI: 10.1080/19490976.2022.2044721] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 02/15/2022] [Indexed: 02/04/2023] Open
Abstract
Helicobacter pylori is the major risk factor for gastric cancer. H. pylori harboring the type IV secretion system (T4SS) and its effector CagA encoded on the cag pathogenicity Island (cagPAI) increases the risk. H. pylori PMSS1 has a multi-cagA genotype, modulating cagA copy number dynamically from zero to four copies. To examine the effect of the immune response on cagA copy number change, we utilized a mouse model with different immune status. PMSS1 recovered from Rag1-/- mice, lacking functional T or B cells, retained more cagA copies. PMSS1 recovered from Il10-/- mice, showing intense inflammation, had fewer cagA copies compared to those recovered from wild-type mice. Moreover, cagA copy number of PMSS1 recovered from wild-type and Il10-/- mice was positively correlated with the capacity to induce IL-8 secretion at four weeks of infection. Since recombination in cagY influences T4SS function, including CagA translocation and IL-8 induction, we constructed a multiple linear regression model to predict H. pylori-induced IL-8 expression based on cagA copy number and cagY recombination status; H. pylori induces more IL-8 secretion when the strain has more cagA copies and intact cagY. This study shows that H. pylori PMSS1 in mice with less intense immune response possess higher cagA copy number than those infected in mice with more intense immune response and thus the multi-cagA genotype, along with cagY recombination, functions as an immune-sensitive regulator of H. pylori virulence.
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Affiliation(s)
- Sungil Jang
- Department of Oral Biology, Oral Science Research Center, Department of Applied Life Science, The Graduate School, BK21 Four Project, Yonsei University College of Dentistry, Seoul, Republic of Korea
- Department of Oral Biochemistry, School of Dentistry, Jeonbuk National University, Jeonju, Republic of Korea
| | - Lori M. Hansen
- Center for Immunology and Infectious Diseases; Departments of Medicine and of Microbiology and Immunology, School of Medicine; University of California Davis, Davis, CA, USA
| | - Hanfu Su
- Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, Guangdong, China
| | - Jay V. Solnick
- Center for Immunology and Infectious Diseases; Departments of Medicine and of Microbiology and Immunology, School of Medicine; University of California Davis, Davis, CA, USA
| | - Jeong-Heon Cha
- Department of Oral Biology, Oral Science Research Center, Department of Applied Life Science, The Graduate School, BK21 Four Project, Yonsei University College of Dentistry, Seoul, Republic of Korea
- Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, Guangdong, China
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15
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Prashar A, Capurro MI, Jones NL. Under the Radar: Strategies Used by Helicobacter pylori to Evade Host Responses. Annu Rev Physiol 2021; 84:485-506. [PMID: 34672717 DOI: 10.1146/annurev-physiol-061121-035930] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The body depends on its physical barriers and innate and adaptive immune responses to defend against the constant assault of potentially harmful microbes. In turn, successful pathogens have evolved unique mechanisms to adapt to the host environment and manipulate host defenses. Helicobacter pylori (Hp), a human gastric pathogen that is acquired in childhood and persists throughout life, is an example of a bacterium that is very successful at remodeling the host-pathogen interface to promote a long-term persistent infection. Using a combination of secreted virulence factors, immune subversion, and manipulation of cellular mechanisms, Hp can colonize and persist in the hostile environment of the human stomach. Here, we review the most recent and relevant information regarding how this successful pathogen overcomes gastric epithelial host defense responses to facilitate its own survival and establish a chronic infection. Expected final online publication date for the Annual Review of Physiology, Volume 84 is February 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Affiliation(s)
- Akriti Prashar
- Program in Cell Biology, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada;
| | - Mariana I Capurro
- Program in Cell Biology, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada;
| | - Nicola L Jones
- Program in Cell Biology, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada; .,Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, Ontario, Canada.,Departments of Paediatrics and Physiology, University of Toronto, Toronto, Ontario, Canada
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16
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Aziz F, Khan I, Shukla S, Dey DK, Yan Q, Chakraborty A, Yoshitomi H, Hwang SK, Sonwal S, Lee H, Haldorai Y, Xiao J, Huh YS, Bajpai VK, Han YK. Partners in crime: The Lewis Y antigen and fucosyltransferase IV in Helicobacter pylori-induced gastric cancer. Pharmacol Ther 2021; 232:107994. [PMID: 34571111 DOI: 10.1016/j.pharmthera.2021.107994] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 09/09/2021] [Accepted: 09/13/2021] [Indexed: 02/05/2023]
Abstract
Helicobacter pylori (H. pylori) is a major causative agent of chronic gastritis, gastric ulcer and gastric carcinoma. H. pylori cytotoxin associated antigen A (CagA) plays a crucial role in the development of gastric cancer. Gastric cancer is associated with glycosylation alterations in glycoproteins and glycolipids on the cell surface. H. pylori cytotoxin associated antigen A (CagA) plays a significant role in the progression of gastric cancer through post-translation modification of fucosylation to develop gastric cancer. The involvement of a variety of sugar antigens in the progression and development of gastric cancer has been investigated, including type II blood group antigens. Lewis Y (LeY) is overexpressed on the tumor cell surface either as a glycoprotein or glycolipid. LeY is a difucosylated oligosaccharide, which is catalyzed by fucosyltransferases such as FUT4 (α1,3). FUT4/LeY overexpression may serve as potential correlative biomarkers for the prognosis of gastric cancer. We discuss the various aspects of H. pylori in relation to fucosyltransferases (FUT1-FUT9) and its fucosylated Lewis antigens (LeY, LeX, LeA, and LeB) and gastric cancer. In this review, we summarize the carcinogenic effect of H. pylori CagA in association with LeY and its synthesis enzyme FUT4 in the development of gastric cancer as well as discuss its importance in the prognosis and its inhibition by combination therapy of anti-LeY antibody and celecoxib through MAPK signaling pathway preventing gastric carcinogenesis.
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Affiliation(s)
- Faisal Aziz
- The Hormel Institute-University of Minnesota, Austin, MN 55912, USA; Department of Biochemistry and Molecular Biology, Dalian Medical University, Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, Dalian 116044, PR China.
| | - Imran Khan
- The Hormel Institute-University of Minnesota, Austin, MN 55912, USA
| | - Shruti Shukla
- TERI-Deakin Nanobiotechnology Centre, The Energy and Resources Institute, Gwal Pahari, Gurugram, Haryana 122003, India
| | - Debasish Kumar Dey
- Department of Biotechnology, College of Engineering, Daegu University, Gyeongsan 38453, Republic of Korea
| | - Qiu Yan
- Department of Biochemistry and Molecular Biology, Dalian Medical University, Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, Dalian 116044, PR China
| | | | - Hisae Yoshitomi
- The Hormel Institute-University of Minnesota, Austin, MN 55912, USA
| | - Seung-Kyu Hwang
- Department of Biological Engineering, NanoBio High-Tech Materials Research Center, Inha University, 100 Inha-ro, Nam-gu, Incheon 22212, Republic of Korea
| | - Sonam Sonwal
- Department of Biological Engineering, NanoBio High-Tech Materials Research Center, Inha University, 100 Inha-ro, Nam-gu, Incheon 22212, Republic of Korea
| | - Hoomin Lee
- Department of Biological Engineering, NanoBio High-Tech Materials Research Center, Inha University, 100 Inha-ro, Nam-gu, Incheon 22212, Republic of Korea
| | - Yuvaraj Haldorai
- Department of Nanoscience and Technology, Bharathiar University, Coimbatore, Tamilnadu 641046, India
| | - Jianbo Xiao
- Institute of Food Safety and Nutrition, Jinan University, Guangzhou 510632, China; University of Vigo, Nutrition and Bromatology Group, Department of Analytical Chemistry and Food Science, Faculty of Science, E32004 Ourense, Spain.
| | - Yun Suk Huh
- Department of Biological Engineering, NanoBio High-Tech Materials Research Center, Inha University, 100 Inha-ro, Nam-gu, Incheon 22212, Republic of Korea.
| | - Vivek K Bajpai
- Department of Energy and Materials Engineering, Dongguk University-Seoul, 30 Pildong-ro 1-gil, Seoul 04620, Republic of Korea.
| | - Young-Kyu Han
- Department of Energy and Materials Engineering, Dongguk University-Seoul, 30 Pildong-ro 1-gil, Seoul 04620, Republic of Korea.
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17
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Yang J, Zhou X, Liu X, Ling Z, Ji F. Role of the Gastric Microbiome in Gastric Cancer: From Carcinogenesis to Treatment. Front Microbiol 2021; 12:641322. [PMID: 33790881 PMCID: PMC8005548 DOI: 10.3389/fmicb.2021.641322] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 02/22/2021] [Indexed: 01/10/2023] Open
Abstract
The development of sequencing technology has expanded our knowledge of the human gastric microbiome, which is now known to play a critical role in the maintenance of homeostasis, while alterations in microbial community composition can promote the development of gastric diseases. Recently, carcinogenic effects of gastric microbiome have received increased attention. Gastric cancer (GC) is one of the most common malignancies worldwide with a high mortality rate. Helicobacter pylori is a well-recognized risk factor for GC. More than half of the global population is infected with H. pylori, which can modulate the acidity of the stomach to alter the gastric microbiome profile, leading to H. pylori-associated diseases. Moreover, there is increasing evidence that bacteria other than H. pylori and their metabolites also contribute to gastric carcinogenesis. Therefore, clarifying the contribution of the gastric microbiome to the development and progression of GC can lead to improvements in prevention, diagnosis, and treatment. In this review, we discuss the current state of knowledge regarding changes in the microbial composition of the stomach caused by H. pylori infection, the carcinogenic effects of H. pylori and non-H. pylori bacteria in GC, as well as the potential therapeutic role of gastric microbiome in H. pylori infection and GC.
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Affiliation(s)
- Jinpu Yang
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xinxin Zhou
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaosun Liu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zongxin Ling
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Feng Ji
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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18
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Clerici SP, Oliveira PFDS, Akagi EM, Cordeiro HG, Azevedo-Martins JM, Faria AVDS, Ferreira-Halder CV. A comprehensive review on the role of protein tyrosine phosphatases in gastric cancer development and progression. Biol Chem 2021; 402:663-674. [PMID: 33544466 DOI: 10.1515/hsz-2020-0355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 01/15/2021] [Indexed: 12/09/2022]
Abstract
The main post-translational reversible modulation of proteins is phosphorylation and dephosphorylation, catalyzed by protein kinases (PKs) and protein phosphatases (PPs) which is crucial for homeostasis. Imbalance in this crosstalk can be related to diseases, including cancer. Plenty of evidence indicates that protein tyrosine phosphatases (PTPs) can act as tumor suppressors and tumor promoters. In gastric cancer (GC), there is a lack of understanding of the molecular aspects behind the tumoral onset and progression. Here we describe several members of the PTP family related to gastric carcinogenesis. We discuss the associated molecular mechanisms which support the down or up modulation of different PTPs. We emphasize the Helicobacter pylori (H. pylori) virulence which is in part associated with the activation of PTP receptors. We also explore the involvement of intracellular redox state in response to H. pylori infection. In addition, some PTP members are under influence by genetic mutations, epigenetics mechanisms, and miRNA modulation. The understanding of multiple aspects of PTPs in GC may provide new targets and perspectives on drug development.
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Affiliation(s)
- Stefano Piatto Clerici
- Department of Biochemistry and Tissue Biology, University of Campinas, UNICAMP, Rua Monteiro Lobato 255, 13083-862Campinas, São Paulo, Brazil
| | | | - Erica Mie Akagi
- Department of Biochemistry and Tissue Biology, University of Campinas, UNICAMP, Rua Monteiro Lobato 255, 13083-862Campinas, São Paulo, Brazil
| | - Helon Guimarães Cordeiro
- Department of Biochemistry and Tissue Biology, University of Campinas, UNICAMP, Rua Monteiro Lobato 255, 13083-862Campinas, São Paulo, Brazil
| | - Jordana Maria Azevedo-Martins
- Department of Biochemistry and Tissue Biology, University of Campinas, UNICAMP, Rua Monteiro Lobato 255, 13083-862Campinas, São Paulo, Brazil
| | - Alessandra Valéria de Sousa Faria
- Department of Biochemistry and Tissue Biology, University of Campinas, UNICAMP, Rua Monteiro Lobato 255, 13083-862Campinas, São Paulo, Brazil
| | - Carmen Veríssima Ferreira-Halder
- Department of Biochemistry and Tissue Biology, University of Campinas, UNICAMP, Rua Monteiro Lobato 255, 13083-862Campinas, São Paulo, Brazil
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19
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Hatakeyama M. The role of Helicobacter pylori CagA oncoprotein in neoplastic transformation of gastric epithelial cells. RESEARCH AND CLINICAL APPLICATIONS OF TARGETING GASTRIC NEOPLASMS 2021:119-144. [DOI: 10.1016/b978-0-323-85563-1.00005-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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20
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Ansari S, Yamaoka Y. Helicobacter pylori Virulence Factor Cytotoxin-Associated Gene A (CagA)-Mediated Gastric Pathogenicity. Int J Mol Sci 2020; 21:ijms21197430. [PMID: 33050101 PMCID: PMC7582651 DOI: 10.3390/ijms21197430] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 10/06/2020] [Accepted: 10/06/2020] [Indexed: 12/12/2022] Open
Abstract
Helicobacter pylori causes persistent infection in the gastric epithelium of more than half of the world’s population, leading to the development of severe complications such as peptic ulcer diseases, gastric cancer, and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Several virulence factors, including cytotoxin-associated gene A (CagA), which is translocated into the gastric epithelium via the type 4 secretory system (T4SS), have been indicated to play a vital role in disease development. Although infection with strains harboring the East Asian type of CagA possessing the EPIYA-A, -B, and -D sequences has been found to potentiate cell proliferation and disease pathogenicity, the exact mechanism of CagA involvement in disease severity still remains to be elucidated. Therefore, we discuss the possible role of CagA in gastric pathogenicity.
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Affiliation(s)
- Shamshul Ansari
- Department of Microbiology, Chitwan Medical College, Bharatpur 44200, Nepal;
| | - Yoshio Yamaoka
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu, Oita 879-5593, Japan
- Global Oita Medical Advanced Research Center for Health (GO-MARCH), Yufu, Oita 879-5593, Japan
- Department of Medicine, Gastroenterology and Hepatology Section, Baylor College of Medicine, Houston, TX 77030, USA
- Borneo Medical and Health Research Centre, Universiti Malaysia Sabah, Kota Kinabalu, Sabah 88400, Malaysia
- Correspondence: ; Tel.: +81-97-586-5740; Fax: +81-97-586-5749
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21
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Kim SH, Kim H. Transcriptome Analysis of the Inhibitory Effect of Astaxanthin on Helicobacter pylori-Induced Gastric Carcinoma Cell Motility. Mar Drugs 2020; 18:md18070365. [PMID: 32679742 PMCID: PMC7404279 DOI: 10.3390/md18070365] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Revised: 07/14/2020] [Accepted: 07/14/2020] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori (H. pylori) infection promotes the metastasis of gastric carcinoma cells by modulating signal transduction pathways that regulate cell proliferation, motility, and invasion. Astaxanthin (ASTX), a xanthophyll carotenoid, is known to inhibit cancer cell migration and invasion, however the mechanism of action of ASTX in H. pylori-infected gastric epithelial cells is not well understood. To gain insight into this process, we carried out a comparative RNA sequencing (RNA-Seq) analysis of human gastric cancer AGS (adenocarcinoma gastric) cells as a function of H. pylori infection and ASTX administration. The results were used to identify genes that are differently expressed in response to H. pylori and ASTX. Gene ontology (GO) analysis identified differentially expressed genes (DEGs) to be associated with cell cytoskeleton remodeling, motility, and/or migration. Among the 20 genes identified, those encoding c-MET, PI3KC2, PLCγ1, Cdc42, and ROCK1 were selected for verification by real-time PCR analysis. The verified genes were mapped, using signaling networks contained in the KEGG database, to create a signaling pathway through which ASTX might mitigate the effects of H. pylori-infection. We propose that H. pylori-induced upregulation of the upstream regulator c-MET, and hence, its downstream targets Cdc42 and ROCK1, is suppressed by ASTX. ASTX is also suggested to counteract H. pylori-induced activation of PI3K and PLCγ. In conclusion, ASTX can suppress H. pylori-induced gastric cancer progression by inhibiting cytoskeleton reorganization and reducing cell motility through downregulation of c-MET, EGFR, PI3KC2, PLCγ1, Cdc42, and ROCK1.
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22
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CagA-ASPP2 complex mediates loss of cell polarity and favors H. pylori colonization of human gastric organoids. Proc Natl Acad Sci U S A 2020; 117:2645-2655. [PMID: 31964836 DOI: 10.1073/pnas.1908787117] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The main risk factor for stomach cancer, the third most common cause of cancer death worldwide, is infection with Helicobacter pylori bacterial strains that inject cytotoxin-associated gene A (CagA). As the first described bacterial oncoprotein, CagA causes gastric epithelial cell transformation by promoting an epithelial-to-mesenchymal transition (EMT)-like phenotype that disrupts junctions and enhances motility and invasiveness of the infected cells. However, the mechanism by which CagA disrupts gastric epithelial cell polarity to achieve its oncogenicity is not fully understood. Here we found that the apoptosis-stimulating protein of p53 2 (ASPP2), a host tumor suppressor and an important CagA target, contributes to the survival of cagA-positive H. pylori in the lumen of infected gastric organoids. Mechanistically, the CagA-ASPP2 interaction is a key event that promotes remodeling of the partitioning-defective (PAR) polarity complex and leads to loss of cell polarity of infected cells. Blockade of cagA-positive H. pylori ASPP2 signaling by inhibitors of the EGFR (epidermal growth factor receptor) signaling pathway-identified by a high-content imaging screen-or by a CagA-binding ASPP2 peptide, prevents the loss of cell polarity and decreases the survival of H. pylori in infected organoids. These findings suggest that maintaining the host cell-polarity barrier would reduce the detrimental consequences of infection by pathogenic bacteria, such as H. pylori, that exploit the epithelial mucosal surface to colonize the host environment.
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23
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Abstract
Bacteria participate in a wide diversity of symbiotic associations with eukaryotic hosts that require precise interactions for bacterial recognition and persistence. Most commonly, host-associated bacteria interfere with host gene expression to modulate the immune response to the infection. However, many of these bacteria also interfere with host cellular differentiation pathways to create a hospitable niche, resulting in the formation of novel cell types, tissues, and organs. In both of these situations, bacterial symbionts must interact with eukaryotic regulatory pathways. Here, we detail what is known about how bacterial symbionts, from pathogens to mutualists, control host cellular differentiation across the central dogma, from epigenetic chromatin modifications, to transcription and mRNA processing, to translation and protein modifications. We identify four main trends from this survey. First, mechanisms for controlling host gene expression appear to evolve from symbionts co-opting cross-talk between host signaling pathways. Second, symbiont regulatory capacity is constrained by the processes that drive reductive genome evolution in host-associated bacteria. Third, the regulatory mechanisms symbionts exhibit correlate with the cost/benefit nature of the association. And, fourth, symbiont mechanisms for interacting with host genetic regulatory elements are not bound by native bacterial capabilities. Using this knowledge, we explore how the ubiquitous intracellular Wolbachia symbiont of arthropods and nematodes may modulate host cellular differentiation to manipulate host reproduction. Our survey of the literature on how infection alters gene expression in Wolbachia and its hosts revealed that, despite their intermediate-sized genomes, different strains appear capable of a wide diversity of regulatory manipulations. Given this and Wolbachia's diversity of phenotypes and eukaryotic-like proteins, we expect that many symbiont-induced host differentiation mechanisms will be discovered in this system.
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Affiliation(s)
- Shelbi L Russell
- Department of Molecular Cell and Developmental Biology, University of California, Santa Cruz, CA, USA.
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24
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Molecular anatomy and pathogenic actions of Helicobacter pylori CagA that underpin gastric carcinogenesis. Cell Mol Immunol 2019; 17:50-63. [PMID: 31804619 PMCID: PMC6952403 DOI: 10.1038/s41423-019-0339-5] [Citation(s) in RCA: 151] [Impact Index Per Article: 25.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 11/13/2019] [Accepted: 11/13/2019] [Indexed: 12/15/2022] Open
Abstract
Chronic infection with Helicobacter pylori cagA-positive strains is the strongest risk factor for gastric cancer. The cagA gene product, CagA, is delivered into gastric epithelial cells via the bacterial type IV secretion system. Delivered CagA then undergoes tyrosine phosphorylation at the Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs in its C-terminal region and acts as an oncogenic scaffold protein that physically interacts with multiple host signaling proteins in both tyrosine phosphorylation-dependent and -independent manners. Analysis of CagA using in vitro cultured gastric epithelial cells has indicated that the nonphysiological scaffolding actions of CagA cell-autonomously promote the malignant transformation of the cells by endowing the cells with multiple phenotypic cancer hallmarks: sustained proliferation, evasion of growth suppressors, invasiveness, resistance to cell death, and genomic instability. Transgenic expression of CagA in mice leads to in vivo oncogenic action of CagA without any overt inflammation. The in vivo oncogenic activity of CagA is further potentiated in the presence of chronic inflammation. Since Helicobacter pylori infection triggers a proinflammatory response in host cells, a feedforward stimulation loop that augments the oncogenic actions of CagA and inflammation is created in CagA-injected gastric mucosa. Given that Helicobacter pylori is no longer colonized in established gastric cancer lesions, the multistep nature of gastric cancer development should include a “hit-and-run” process of CagA action. Thus, acquisition of genetic and epigenetic alterations that compensate for CagA-directed cancer hallmarks may be required for completion of the “hit-and-run” process of gastric carcinogenesis.
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25
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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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26
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Wroblewski LE, Choi E, Petersen C, Delgado AG, Piazuelo MB, Romero-Gallo J, Lantz TL, Zavros Y, Coffey RJ, Goldenring JR, Zemper AE, Peek RM. Targeted mobilization of Lrig1 + gastric epithelial stem cell populations by a carcinogenic Helicobacter pylori type IV secretion system. Proc Natl Acad Sci U S A 2019; 116:19652-19658. [PMID: 31488717 PMCID: PMC6765285 DOI: 10.1073/pnas.1903798116] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Helicobacter pylori-induced gastritis is the strongest risk factor for gastric adenocarcinoma, a malignancy preceded by a series of well-defined histological stages, including metaplasia. One microbial constituent that augments cancer risk is the cag type 4 secretion system (T4SS), which translocates the oncoprotein CagA into host cells. Aberrant stem cell activation is linked to carcinogenesis, and Lrig1 (leucine-rich repeats and Ig-like domains 1) marks a distinct population of progenitor cells. We investigated whether microbial effectors with carcinogenic potential influence Lrig1 progenitor cells ex vivo and via lineage expansion within H. pylori-infected gastric mucosa. Lineage tracing was induced in Lrig1-CreERT2/+;R26R-YFP/+ (Lrig1/YFP) mice that were uninfected or subsequently infected with cag+H. pylori or an isogenic cagE- mutant (nonfunctional T4SS). In contrast to infection with wild-type (WT) H. pylori for 2 wk, infection for 8 wk resulted in significantly increased inflammation and proliferation in the corpus and antrum compared with uninfected or mice infected with the cagE- mutant. WT H. pylori-infected mice harbored significantly higher numbers of Lrig1/YFP epithelial cells that coexpressed UEA1 (surface cell marker). The number of cells coexpressing intrinsic factor (chief cell marker), YFP (lineage marker), and GSII lectin (spasmolytic polypeptide-expressing metaplasia marker) were increased only by WT H. pylori In human samples, Lrig1 expression was significantly increased in lesions with premalignant potential compared with normal mucosa or nonatrophic gastritis. In conclusion, chronic H. pylori infection stimulates Lrig1-expressing progenitor cells in a cag-dependent manner, and these reprogrammed cells give rise to a full spectrum of differentiated cells.
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Affiliation(s)
- Lydia E Wroblewski
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232;
| | - Eunyoung Choi
- Nashville VA Medical Center, US Department of Veterans Affairs, Nashville, TN 37212
- Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, TN 37232
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232
| | - Christine Petersen
- Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, TN 37232
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232
| | - Alberto G Delgado
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
| | - M Blanca Piazuelo
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
| | - Judith Romero-Gallo
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
| | - Tyler L Lantz
- Department of Biology, University of Oregon, Eugene, OR 97403
- Institute of Molecular Biology, University of Oregon, Eugene, OR 97403
| | - Yana Zavros
- Department of Pharmacology and System Physiology, University of Cincinnati, Cincinnati, OH 45221
| | - Robert J Coffey
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
- Nashville VA Medical Center, US Department of Veterans Affairs, Nashville, TN 37212
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232
- Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232
| | - James R Goldenring
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
- Nashville VA Medical Center, US Department of Veterans Affairs, Nashville, TN 37212
- Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, TN 37232
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232
- Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232
| | - Anne E Zemper
- Department of Biology, University of Oregon, Eugene, OR 97403
- Institute of Molecular Biology, University of Oregon, Eugene, OR 97403
| | - Richard M Peek
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232;
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232
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27
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Uotani T, Murakami K, Uchida T, Tanaka S, Nagashima H, Zeng XL, Akada J, Estes MK, Graham DY, Yamaoka Y. Changes of tight junction and interleukin-8 expression using a human gastroid monolayer model of Helicobacter pylori infection. Helicobacter 2019; 24:e12583. [PMID: 30950121 PMCID: PMC6918952 DOI: 10.1111/hel.12583] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Revised: 01/31/2019] [Accepted: 02/09/2019] [Indexed: 01/04/2023]
Abstract
BACKGROUND Lack of a model that mirrors Helicobacter pylori-induced gastric mucosal inflammation has hampered investigation of early host-bacterial interactions. We used an ex vivo model of human stomach, gastric epithelial organoid monolayers (gastroid monolayers) to investigate interactions of H pylori infection and the apical junctional complex and interleukin-8 (IL-8) expression. METHOD Morphology of human antral mucosal gastroid monolayers was evaluated using histology, immunohistochemical (IHC) staining, and transmission electron microscopy (TEM). Functional and gross changes in the apical junctional complexes were assessed using transepithelial electrical resistance (TEER), cytotoxicity assays, and confocal laser scanning microscopy. IL-8 expression was evaluated by real-time quantitative PCR and ELISA. RESULTS When evaluated by IHC and TEM, the morphology of gastroid monolayers closely resembled in vivo human stomach. Following inoculation of H pylori, TEER transiently declined (up to 51%) in an H pylori density-dependent manner. TEER recovered by 48 hours post-infection and remained normal despite continued presence and replication of H pylori. Confocal scanning microscopy showed minimal disruption of zonula occludens-1 or E-cadherin structure. IL-8 production was unchanged by infection with either CagA-positive or CagA-negative H pylori and JNK and MEK inhibitors did not suppress IL-8 production, whereas p38 and IKK inhibitor significantly did. CONCLUSION Human gastroid monolayers provide a model for experimental H pylori infection more consistent with in vivo human infections than seen with typical gastric epithelial cell lines. This ex vivo system should lead to better understanding of H pylori host-pathogen interactions.
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Affiliation(s)
- Takahiro Uotani
- Department of Gastroenterology and Hepatology, Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas,Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu, Japan
| | - Kosuke Murakami
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas
| | - Tomohisa Uchida
- Department of Molecular Pathology, Oita University Faculty of Medicine, Yufu, Japan
| | - Shingo Tanaka
- Department of Gastroenterology and Hepatology, Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas,Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu, Japan
| | | | - Xi-Lei Zeng
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas
| | - Junko Akada
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu, Japan
| | - Mary K. Estes
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas
| | - David Y. Graham
- Department of Gastroenterology and Hepatology, Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
| | - Yoshio Yamaoka
- Department of Gastroenterology and Hepatology, Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas,Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu, Japan
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28
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Tsugawa H, Kato C, Mori H, Matsuzaki J, Kameyama K, Saya H, Hatakeyama M, Suematsu M, Suzuki H. Cancer Stem-Cell Marker CD44v9-Positive Cells Arise From Helicobacter pylori-Infected CAPZA1-Overexpressing Cells. Cell Mol Gastroenterol Hepatol 2019; 8:319-334. [PMID: 31146068 PMCID: PMC6713896 DOI: 10.1016/j.jcmgh.2019.05.008] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 05/15/2019] [Accepted: 05/21/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS CD44 variant 9 (CD44v9)-positive cancer stem-like cells strongly contribute to the development and recurrence of gastric cancer. However, the origin of CD44v9-positive cells is uncertain. METHODS CD44v9, β-catenin, and epithelial splicing regulatory protein 1 signals were assessed by real-time reverse-transcription polymerase chain reaction, immunoblot analysis, or immunofluorescence microscopy. Capping actin protein of muscle Z-line α subunit 1 (CAPZA1) expression was assessed by immunoblot analysis or immunohistochemical analysis of Mongolian gerbils' gastric mucosa or human biopsy specimens. Levels of oxidative stress were assessed by measuring malondialdehyde and protein carbonylation. Histone H3 acetylation levels in the CAPZA1 proximal promoter region were measured by using chromatin immunoprecipitation analysis with an antibody against the acetylated histone H3 in human gastric carcinoma cell line (AGS) cells. RESULTS CD44v9 is expressed in CAPZA1-overexpressing cells in human gastric cancer tissues. CAPZA1 overexpression enhanced expression of β-catenin, which is a transcription factor for CD44, and epithelial splicing regulatory protein 1, which increases alternative splicing of CD44 to generate CD44v9. CAPZA1-overexpressing cells after cytotoxin-associated gene A accumulation showed CD44v9 expression by inducing nuclear accumulation of β-catenin, concomitant with the enhancement of expression of Sal-like protein 4 and Krüppel-like factor 5, which encode reprogramming factors. Oxidative stress increased the CAPZA1 expression in AGS cells through the enhancement of histone H3 acetylation of CAPZA1 promoter. CAPZA1 expression was increased depending on oxidative stress in H pylori-infected gastric mucosa. CONCLUSIONS CD44v9 expression is evoked from CAPZA1-overexpressing cells after accumulation of cytotoxin-associated gene A. Our findings provide important insights into the mechanisms underlying the development of CD44v9-positive cells.
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Affiliation(s)
- Hitoshi Tsugawa
- Department of Biochemistry, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Chihiro Kato
- Medical Education Center, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Hideki Mori
- Division of Gastroenterology and Hepatology, National Hospital Organization Tokyo Medical Center, Meguro-ku, Tokyo, Japan
| | - Juntaro Matsuzaki
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan
| | - Kaori Kameyama
- Department of Pathology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Hideyuki Saya
- Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Masanori Hatakeyama
- Division of Microbiology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Makoto Suematsu
- Department of Biochemistry, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Hidekazu Suzuki
- Department of Gastroenterology and Hepatology, Tokai University School of Medicine, Isehara, Kanagawa, Japan,Correspondence Address correspondence to: Hidekazu Suzuki, MD, PhD, FACG, AGAF, RFF, Department of Gastroenterology and Hepatology, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan. fax: +81(463)93-7134.
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29
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Pozdeev OK, Pozdeeva AO, Valeeva YV, Gulyaev PE, Savinova AN. Mechanisms of interacting <i>Helicobacter pylori</i> with gastric mucosal epithelium. II. A reaction of gastric epithelium on <i>Helicobacter pylori</i> colonization and persistence. RUSSIAN JOURNAL OF INFECTION AND IMMUNITY 2019; 9:253-261. [DOI: 10.15789/2220-7619-2019-2-253-261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Gastric and duodenal recurrent inflammatory diseases have a high prevalence, but the role played by microbes in its development remained unclear. However, the data published in 1983 by Marshall and Warren about isolating Helicobacter pylori from the stomach mucosa of the patient with gastritis and proposing relevant cultivation methods was the turning point in investigating etiology of the upper digestive tract inflammatory disorders. Moreover, it was shown that the majority of H. pylori spp. are found within the gastric lumen upon colonization, whereas around 20% of them are attached to the epithelial cells in the stomach. In addition, effects of interacting H. pylori with gastric epithelium and activation of some defense mechanisms due to bacterial colonization and spreading were analyzed. It was found that along with triggering pro-inflammatory response induced by proteins VacA as well as phosphorylated/unphosphorylated CagA, wherein the latter is able to induce a set of protective reactions H. pylori disrupts intercellular contacts, affects epithelial cell polarity and proliferation, and activates SHP-2 phosphatase resulting in emerging diverse types of cellular responses. The activation mechanisms for the mitogen-activated protein kinase (MAPK) pathway were discussed. The ability of H. pylori to regulate apoptosis, particularly via its suppression, by expressing ERK kinase and protein MCL1 facilitating bacterial survival in the gastric mucosa as well as beneficial effects related to bacterial circulation on gastric epithelial cell survival elicited by anti-apoptotic factors were also examined. Of note, persistence of H. pylori are mainly determined by activating transcriptional factors including NF-B, NFAT, SRF, T-cell lymphoid enhancing factor (TCF/LEF), regulating activity of MCL1 protein, in turn, being one of the main anti-apoptotic factors, as well as induced production of the migration inhibitory factor (MIF). The role of VacA cytotoxin in triggering epithelial cell apoptosis via caspase-mediated pathways was also considered. Infection with H. pylori is accompanied by release of proinflammatory cytokine cocktail detected both in vitro and in vivo. In particular, bacterial urease activating transcriptional factor NF-B was shown to play a crucial role in inducing cytokine production. Moreover, such signaling pathways may be activated after H. pylori is attached to the cognate receptor in the gastric epithelial surface by interacting with CD74 and MHC class II molecules. Finally, a role for various CD4+ T cell subsets, particularly type 17 T helper cells (Th17) in inducing immune response against H. pylori antigens in gastric mucosa was revealed were also discussed.
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30
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Tsugawa H, Mori H, Matsuzaki J, Sato A, Saito Y, Imoto M, Suematsu M, Suzuki H. CAPZA1 determines the risk of gastric carcinogenesis by inhibiting Helicobacter pylori CagA-degraded autophagy. Autophagy 2019; 15:242-258. [PMID: 30176157 PMCID: PMC6333452 DOI: 10.1080/15548627.2018.1515530] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Revised: 06/18/2018] [Accepted: 08/21/2018] [Indexed: 01/04/2023] Open
Abstract
Helicobacter pylori-derived CagA, a type IV secretion system effector, plays a role as an oncogenic driver in gastric epithelial cells. However, upon delivery into gastric epithelial cells, CagA is usually degraded by macroautophagy/autophagy. Hence, the induction of autophagy in H. pylori-infected epithelial cells is an important host-protective ability against gastric carcinogenesis. However, the mechanisms by which autophagosome-lysosome fusion is regulated, are unknown. Here, we report that enhancement of LAMP1 (lysosomal associated membrane protein 1) expression is necessary for autolysosome formation. LAMP1 expression is induced by nuclear translocated LRP1 (LDL receptor related protein 1) intracellular domain (LRP1-ICD) binding to the proximal LAMP1 promoter region. Nuclear translocation of LRP1-ICD is enhanced by H. pylori infection. In contrast, CAPZA1 (capping actin protein of muscle Z-line alpha subunit 1) inhibits LAMP1 expression via binding to LRP1-ICD in the nuclei. The binding of CAPZA1 to LRP1-ICD prevents LRP1-ICD binding to the LAMP1 proximal promoter. Thus, in CAPZA1-overexpressing gastric epithelial cells infected with H. pylori, autolysosome formation is inhibited and CagA escapes autophagic degradation. These findings identify CAPZA1 as a novel negative regulator of autolysosome formation and suggest that deregulation of CAPZA1 expression leads to increased risk of gastric carcinogenesis. Abbreviations: CagA: cytotoxin-associated gene A; CAPZA1: capping actin protein of muscle Z-line alpha subunit 1; ChIP: chromatin immunoprecipitation; GTF2I: general transcription factor IIi; HDAC: histone deacetylase; LAMP1: lysosomal associated membrane protein 1; LRP1: LDL receptor related protein 1; LRP1-ICD: CagA intracellular domain; qPCR: quantitative polymerase chain reaction; VacA: vacuolating cytotoxin.
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Affiliation(s)
- Hitoshi Tsugawa
- Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan
| | - Hideki Mori
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Juntaro Matsuzaki
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan
| | - Akira Sato
- Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan
| | - Yoshimasa Saito
- Division of Pharmacotherapeutics, Keio University Faculty of Pharmacy, Tokyo, Japan
| | - Masaya Imoto
- Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Kohoku-ku, Yokohama, Japan
| | - Makoto Suematsu
- Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan
| | - Hidekazu Suzuki
- Fellowship Training Center and Medical Education Center, Keio University School of Medicine, Tokyo, Japan
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31
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O'Rourke F, Kempf VAJ. Interaction of bacteria and stem cells in health and disease. FEMS Microbiol Rev 2019; 43:162-180. [DOI: 10.1093/femsre/fuz003] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Accepted: 01/11/2019] [Indexed: 12/11/2022] Open
Affiliation(s)
- Fiona O'Rourke
- Institut für Medizinische Mikrobiologie und Krankenhaushygiene, University Hospital, Goethe University, Paul-Ehrlich-Str. 40, D-60596 Frankfurt am Main, Germany
| | - Volkhard A J Kempf
- Institut für Medizinische Mikrobiologie und Krankenhaushygiene, University Hospital, Goethe University, Paul-Ehrlich-Str. 40, D-60596 Frankfurt am Main, Germany
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Krzysiek‐Maczka G, Targosz A, Szczyrk U, Strzałka M, Sliwowski Z, Brzozowski T, Czyz J, Ptak‐Belowska A. Role of Helicobacter pylori infection in cancer-associated fibroblast-induced epithelial-mesenchymal transition in vitro. Helicobacter 2018; 23:e12538. [PMID: 30246423 PMCID: PMC6282800 DOI: 10.1111/hel.12538] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Revised: 07/18/2018] [Accepted: 07/23/2018] [Indexed: 01/19/2023]
Abstract
BACKGROUND Major human gastrointestinal pathogen Helicobacter pylori (H. pylori) colonizes the gastric mucosa causing inflammation and severe complications including cancer, but the involvement of fibroblasts in the pathogenesis of these disorders in H. pylori-infected stomach has been little studied. Normal stroma contains few fibroblasts, especially myofibroblasts. Their number rapidly increases in the reactive stroma surrounding inflammatory region and neoplastic tissue; however, the interaction between H. pylori and fibroblasts remains unknown. We determined the effect of coincubation of normal rat gastric fibroblasts with alive H. pylori (cagA+vacA+) and H. pylori (cagA-vacA-) strains on the differentiation of these fibroblasts into cells possessing characteristics of cancer-associated fibroblasts (CAFs) able to induce epithelial-mesenchymal transition (EMT) of normal rat gastric epithelial cells (RGM-1). MATERIALS AND METHODS The panel of CAFs markers mRNA was analyzed in H. pylori (cagA+vacA+)-infected fibroblasts by RT-PCR. After insert coculture of differentiated fibroblasts with RGM-1 cells from 24 up to 48, 72, and 96 hours, the mRNA expression for EMT-associated genes was analyzed by RT-PCR. RESULTS The mRNA expression for CAFs markers was significantly increased after 72 hours of infection with H. pylori (cagA+vacA+) but not H. pylori (cagA-vacA-) strain. Following coculture with CAFs, RGM-1 cells showed significant decrease in E-cadherin mRNA, and the parallel increase in the expression of Twist and Snail transcription factors mRNA was observed along with the overexpression of mRNAs for TGFβR, HGFR, FGFR, N-cadherin, vimentin, α-SMA, VEGF, and integrin-β1. CONCLUSION Helicobacter pylori (cagA+vacA+) strain induces differentiation of normal fibroblasts into CAFs, likely to initiate the EMT process in RGM-1 epithelial cell line.
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Affiliation(s)
- Gracjana Krzysiek‐Maczka
- Department of PhysiologyThe Faculty of MedicineJagiellonian University Medical CollegeCracowPoland
| | - Aneta Targosz
- Department of PhysiologyThe Faculty of MedicineJagiellonian University Medical CollegeCracowPoland
| | - Urszula Szczyrk
- Department of PhysiologyThe Faculty of MedicineJagiellonian University Medical CollegeCracowPoland
| | - Malgorzata Strzałka
- Department of PhysiologyThe Faculty of MedicineJagiellonian University Medical CollegeCracowPoland
| | - Zbigniew Sliwowski
- Department of PhysiologyThe Faculty of MedicineJagiellonian University Medical CollegeCracowPoland
| | - Tomasz Brzozowski
- Department of PhysiologyThe Faculty of MedicineJagiellonian University Medical CollegeCracowPoland
| | - Jarosław Czyz
- Department of Cell BiologyThe Faculty of Biochemistry, Biophysics and BiotechnologyJagiellonian UniversityCracowPoland
| | - Agata Ptak‐Belowska
- Department of PhysiologyThe Faculty of MedicineJagiellonian University Medical CollegeCracowPoland
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Zhang B, Zhang X, Jin M, Hu L, Zang M, Qiu W, Wang S, Liu B, Liu S, Guo D. CagA increases DNA methylation and decreases PTEN expression in human gastric cancer. Mol Med Rep 2018; 19:309-319. [PMID: 30431097 PMCID: PMC6297774 DOI: 10.3892/mmr.2018.9654] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2018] [Accepted: 09/28/2018] [Indexed: 01/15/2023] Open
Abstract
Gastric cancer is one of the leading causes of cancer-associated mortality worldwide. Cytotoxin-associated gene A (CagA) has been reported to be associated with gastric diseases. Phosphatase and tensin homolog (PTEN) and tet methylcytosine dioxygenase 1 (Tet1) are important tumor-suppressor genes. The present study aimed to investigate the underlying functions of CagA in human gastric cancer, and to explore the associations between CagA, PTEN and Tet1 in gastric cancer. For that purpose, CagA overexpression and Tet1 interference recombinant lentiviral plasmids were constructed. Quantitative polymerase chain reaction (qPCR) was utilized to screen gene expression in HGC-27 human gastric cancer cells overexpressing CagA. qPCR and western blotting were used to detect gene and protein expression, respectively. In addition, the methylation status of PTEN was detected by methylation-specific PCR. The expression levels of PTEN, Tet1, apolipoprotein B mRNA editing enzyme catalytic subunit (APOBEC)3A, APOBEC3C and APOBEC3F were significantly decreased in the CagA overexpression group compared with in the negative control group in HGC-27 cells. Compared with in the negative control group, the mRNA and protein expression levels of PTEN were markedly decreased in cells with Tet1 interference. The decreased expression of PTEN was associated with increased methylation levels in the cells. In addition, the protein expression levels of PTEN were significantly decreased in HGC-27 cells when CagA was overexpressed. The expression levels of PTEN and Tet1 were also markedly decreased in CagA+ gastric cancer tissues compared with in non-cancerous tissues. The decreased expression of PTEN in CagA+ gastric cancer tissues was associated with increased methylation levels. In conclusion, overexpression of CagA significantly decreased the expression of PTEN, Tet1, APOBEC3A, APOBEC3C and APOBEC3F in human gastric cancer. In addition, CagA increased DNA methylation and decreased PTEN expression, which was reversed by Tet1 overexpression. The present study may facilitate future therapeutic approaches targeting human gastric cancer.
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Affiliation(s)
- Baogui Zhang
- Department of Gastrointestinal Surgery, Affiliated Hospital of Jining Medical University, Jining, Shandong 272000, P.R. China
| | - Xiaobei Zhang
- Department of Central Laboratory, Affiliated Hospital of Jining Medical University, Jining, Shandong 272000, P.R. China
| | - Meng Jin
- Department of Gastrointestinal Surgery, Affiliated Hospital of Jining Medical University, Jining, Shandong 272000, P.R. China
| | - Lei Hu
- Department of General Surgery Affiliated Provincial Hospital of Anhui Medical University, Hefei, Anhui 230001, P.R. China
| | - Mingde Zang
- Department of Gastric Cancer Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
| | - Weilong Qiu
- Department of Gastrointestinal Surgery, Affiliated Hospital of Jining Medical University, Jining, Shandong 272000, P.R. China
| | - Shouqi Wang
- Department of Gastrointestinal Surgery, Affiliated Hospital of Jining Medical University, Jining, Shandong 272000, P.R. China
| | - Bingya Liu
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China
| | - Shiqi Liu
- Department of Gastrointestinal Surgery, Affiliated Hospital of Jining Medical University, Jining, Shandong 272000, P.R. China
| | - Dongli Guo
- Department of Gastrointestinal Surgery, Affiliated Hospital of Jining Medical University, Jining, Shandong 272000, P.R. China
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Structural Analysis of Variability and Interaction of the N-terminal of the Oncogenic Effector CagA of Helicobacter pylori with Phosphatidylserine. Int J Mol Sci 2018; 19:ijms19103273. [PMID: 30360352 PMCID: PMC6214045 DOI: 10.3390/ijms19103273] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Revised: 09/13/2018] [Accepted: 09/14/2018] [Indexed: 01/01/2023] Open
Abstract
Helicobacter pylori cytotoxin-associated gene A protein (CagA) has been associated with the increase in virulence and risk of cancer. It has been demonstrated that CagA’s translocation is dependent on its interaction with phosphatidylserine. We evaluated the variability of the N-terminal CagA in 127 sequences reported in NCBI, by referring to molecular interaction forces with the phosphatidylserine and the docking of three mutations chosen from variations in specific positions. The major sites of conservation of the residues involved in CagA–Phosphatidylserine interaction were 617, 621 and 626 which had no amino acid variation. Position 636 had the lowest conservation score; mutations in this position were evaluated to observe the differences in intermolecular forces for the CagA–Phosphatidylserine complex. We evaluated the docking of three mutations: K636A, K636R and K636N. The crystal and mutation models presented a ΔG of −8.919907, −8.665261, −8.701923, −8.515097 Kcal/mol, respectively, while mutations K636A, K636R, K636N and the crystal structure presented 0, 3, 4 and 1 H-bonds, respectively. Likewise, the bulk effect of the ΔG and amount of H-bonds was estimated in all of the docking models. The type of mutation affected both the ΔG (χ2(1)=93.82, p-value <2.2×10−16) and the H-bonds (χ2(1)=91.93, p-value <2.2×10−16). Overall, 76.9% of the strains that exhibit the K636N mutation produced a severe pathology. The average H-bond count diminished when comparing the mutations with the crystal structure of all the docking models, which means that other molecular forces are involved in the CagA–Phosphatidylserine complex interaction.
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35
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Takahashi Y, Yamamichi N, Inada KI, Shiogama K, Sakurai K, Takeuchi C, Mizutani Y, Tsutsumi Y, Koike K. Nectin1 expression is frequently decreased in gastric cancers. Pathol Int 2018; 68:557-562. [PMID: 30221498 DOI: 10.1111/pin.12721] [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] [Received: 03/28/2018] [Accepted: 08/21/2018] [Indexed: 01/01/2023]
Abstract
Gastric cancer (GC) is rich in many different histological types, but how the histological pattern is defined remains to be proved. The relation between GC histological types and the expression of nectin1, which is one of the cell adhesion molecules that composes adherens junction, has not been reported. According to a publicly available database of 406 GC patients, the median overall survival of Nectin1 high expression patients was 55.4 months and that of low expression patients was 25.6 months (P = 0.0246). Using surgically or endoscopically resected GC samples, nectin1 expression was analyzed by immunohistochemistry. Nectin1 expressed at adherens junction in all the normal epithelial cells. However, nectin1 expressed not at adherens junction but at apical membrane in epithelial cells in intestinal metaplasia. The expression pattern of nectin1 in intestinal type GC resembled to intestinal metaplasia. In order to analyze the difference in nectin1 expression between GC histological types, a total of 116 intestinal type GC and 33 diffuse type GC. The expression of necitin1 in diffuse type GC (3.0%) was remarkably decreased compared to that in intestinal type GC (65.5%) (P < 0.0001). In conclusion, this is the first report showing an association between nectin1 expression and histological subtypes of GC.
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Affiliation(s)
- Yu Takahashi
- Department of Gastroenterology, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
| | - Nobutake Yamamichi
- Department of Gastroenterology, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
| | - Ken-Ichi Inada
- Department of Diagnostic Pathology II, Fujita Health University, Nagoya-city, Aichi, Japan
| | - Kazuya Shiogama
- Department of Clinical Examination, Graduate School of Health Sciences, Fujita Health University, Toyoake-city, Aichi, Japan
| | - Kouhei Sakurai
- Department of Diagnostic Pathology II, Fujita Health University, Nagoya-city, Aichi, Japan
| | - Chihiro Takeuchi
- Department of Gastroenterology, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
| | - Yasuyoshi Mizutani
- Department of Molecular Oncology, Fujita Health University School of Medicine, Toyoake-city, Aichi, Japan
| | | | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
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Lim SH, Methé BA, Knoll BM, Morris A, Obaro SK. Invasive non-typhoidal Salmonella in sickle cell disease in Africa: is increased gut permeability the missing link? J Transl Med 2018; 16:239. [PMID: 30165857 PMCID: PMC6116559 DOI: 10.1186/s12967-018-1622-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Accepted: 08/25/2018] [Indexed: 02/07/2023] Open
Abstract
Non-typhoidal Salmonella usually induces self-limiting gastroenteritis. However, in many parts of Africa, especially in individuals who are malnourished, infected with malaria, or have sickle cell disease, the organism causes serious and potentially fatal systemic infections. Since the portal of entry of non-typhoidal Salmonella into the systemic circulation is by way of the intestine, we argue that an increased gut permeability plays a vital role in the initiation of invasive non-typhoidal Salmonella in these patients. Here, we will appraise the evidence supporting a breach in the intestinal barrier and propose the mechanisms for the increased risks for invasive non-typhoidal Salmonella infections in these individuals.
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Affiliation(s)
- Seah H Lim
- Division of Hematology and Oncology, New York Medical College, Hawthorne, NY, USA. .,Westchester Medical Center Cancer Institute, 19 Bradhurst Avenue, Suite 2575S, Hawthorne, NY, 10532, USA.
| | - Barbara A Methé
- Center for Microbiome in Medicine, University of Pittsburgh School of Medicine, Pittsburgh, USA
| | - Bettina M Knoll
- Division of Infectious Diseases, New York Medical College, Hawthorne, NY, USA
| | - Alison Morris
- Center for Microbiome in Medicine, University of Pittsburgh School of Medicine, Pittsburgh, USA
| | - Stephen K Obaro
- Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE, USA
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Ansari S, Gantuya B, Tuan VP, Yamaoka Y. Diffuse Gastric Cancer: A Summary of Analogous Contributing Factors for Its Molecular Pathogenicity. Int J Mol Sci 2018; 19:ijms19082424. [PMID: 30115886 PMCID: PMC6121269 DOI: 10.3390/ijms19082424] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Revised: 08/08/2018] [Accepted: 08/14/2018] [Indexed: 12/16/2022] Open
Abstract
Gastric cancer is the third leading cause of cancer-related deaths and ranks as the fifth most common cancer worldwide. Incidence and mortality differ depending on the geographical region and gastric cancer ranks first in East Asian countries. Although genetic factors, gastric environment, and Helicobacter pylori infection have been associated with the pathogenicity and development of intestinal-type gastric cancer that follows the Correa’s cascade, the pathogenicity of diffuse-type gastric cancer remains mostly unknown and undefined. However, genetic abnormalities in the cell adherence factors, such as E-cadherin and cellular activities that cause impaired cell integrity and physiology, have been documented as contributing factors. In recent years, H. pylori infection has been also associated with the development of diffuse-type gastric cancer. Therefore, in this report, we discuss the host factors as well as the bacterial factors that have been reported as associated factors contributing to the development of diffuse-type gastric cancer.
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Affiliation(s)
- Shamshul Ansari
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu-City, Oita 879-5593, Japan.
| | - Boldbaatar Gantuya
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu-City, Oita 879-5593, Japan.
- Department of Internal Medicine, Gastroenterology unit, Mongolian National University of Medical Sciences, Ulaanbaatar-14210, Mongolia.
| | - Vo Phuoc Tuan
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu-City, Oita 879-5593, Japan.
- Department of Endoscopy, Cho Ray Hospital, Ho Chi Minh, Vietnam.
| | - Yoshio Yamaoka
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu-City, Oita 879-5593, Japan.
- Department of Medicine, Gastroenterology and Hepatology Section, Baylor College of Medicine, Houston, TX 77030, USA.
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Hayashi T, Senda M, Suzuki N, Nishikawa H, Ben C, Tang C, Nagase L, Inoue K, Senda T, Hatakeyama M. Differential Mechanisms for SHP2 Binding and Activation Are Exploited by Geographically Distinct Helicobacter pylori CagA Oncoproteins. Cell Rep 2018; 20:2876-2890. [PMID: 28930683 DOI: 10.1016/j.celrep.2017.08.080] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Revised: 06/26/2017] [Accepted: 08/23/2017] [Indexed: 12/28/2022] Open
Abstract
Helicobacter pylori East Asian CagA is more closely associated with gastric cancer than Western CagA. Here we show that, upon tyrosine phosphorylation, the East Asian CagA-specific EPIYA-D segment binds to the N-SH2 domain of pro-oncogenic SHP2 phosphatase two orders of magnitude greater than Western CagA-specific EPIYA-C. This high-affinity binding is achieved via cryptic interaction between Phe at the +5 position from phosphotyrosine in EPIYA-D and a hollow on the N-SH2 phosphopeptide-binding floor. Also, duplication of EPIYA-C in Western CagA, which increases gastric cancer risk, enables divalent high-affinity binding with SHP2 via N-SH2 and C-SH2. These strong CagA bindings enforce enzymatic activation of SHP2, which endows cells with neoplastic traits. Mechanistically, N-SH2 in SHP2 is in an equilibrium between stimulatory "relaxed" and inhibitory "squeezed" states, which is fixed upon high-affinity CagA binding to the "relaxed" state that stimulates SHP2. Accordingly, East Asian CagA and Western CagA exploit distinct mechanisms for SHP2 deregulation.
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Affiliation(s)
- Takeru Hayashi
- Department of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
| | - Miki Senda
- Structural Biology Research Center, Photon Factory, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Tsukuba 305-0801, Japan
| | - Nobuhiro Suzuki
- Structural Biology Research Center, Photon Factory, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Tsukuba 305-0801, Japan
| | - Hiroko Nishikawa
- Department of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; Max Planck-The University of Tokyo Center for Integrative Inflammology, Tokyo 113-0033, Japan
| | - Chi Ben
- Department of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
| | - Chao Tang
- Department of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
| | - Lisa Nagase
- Structural Biology Research Center, Photon Factory, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Tsukuba 305-0801, Japan
| | - Kaori Inoue
- Department of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
| | - Toshiya Senda
- Structural Biology Research Center, Photon Factory, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Tsukuba 305-0801, Japan; Department of Materials Structure Science, School of High Energy Accelerator Science, The Graduate University of Advanced Studies, Tsukuba 305-0801, Japan.
| | - Masanori Hatakeyama
- Department of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; Max Planck-The University of Tokyo Center for Integrative Inflammology, Tokyo 113-0033, Japan.
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Bridge DR, Blum FC, Jang S, Kim J, Cha JH, Merrell DS. Creation and Initial Characterization of Isogenic Helicobacter pylori CagA EPIYA Variants Reveals Differential Activation of Host Cell Signaling Pathways. Sci Rep 2017; 7:11057. [PMID: 28887533 PMCID: PMC5591203 DOI: 10.1038/s41598-017-11382-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Accepted: 08/23/2017] [Indexed: 12/18/2022] Open
Abstract
The polymorphic CagA toxin is associated with Helicobacter pylori-induced disease. Previous data generated using non-isogenic strains and transfection models suggest that variation surrounding the C-terminal Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs as well as the number of EPIYA motifs influence disease outcome. To investigate potential CagA-mediated effects on host cell signaling, we constructed and characterized a large panel of isogenic H. pylori strains that differ primarily in the CagA EPIYA region. The number of EPIYA-C motifs or the presence of an EPIYA-D motif impacted early changes in host cell elongation; however, the degree of elongation was comparable across all strains at later time points. In contrast, the strain carrying the EPIYA-D motif induced more IL-8 secretion than any other EPIYA type, and a single EPIYA-C motif induced comparable IL-8 secretion as isolates carrying multiple EPIYA-C alleles. Similar levels of ERK1/2 activation were induced by all strains carrying a functional CagA allele. Together, our data suggest that polymorphism in the CagA C-terminus is responsible for differential alterations in some, but not all, host cell signaling pathways. Notably, our results differ from non-isogenic strain studies, thus highlighting the importance of using isogenic strains to study the role of CagA toxin polymorphism in gastric cancer development.
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Affiliation(s)
- Dacie R Bridge
- Uniformed Services University of the Health Sciences, F. Edward Hébert School of Medicine, Department of Microbiology and Immunology, Bethesda, Maryland, 20814, USA
- University of Maryland School of Medicine, Center for Vaccine Development, Division of Geographic Medicine, Department of Medicine, Baltimore Maryland, 21201, USA
| | - Faith C Blum
- Uniformed Services University of the Health Sciences, F. Edward Hébert School of Medicine, Department of Microbiology and Immunology, Bethesda, Maryland, 20814, USA
| | - Sungil Jang
- Department of Oral Biology, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, South Korea
| | - Jinmoon Kim
- Department of Oral Biology, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, South Korea
- Department of Applied Life Science, BK21 Plus Project, Yonsei University College of Dentistry, Seoul, South Korea
| | - Jeong-Heon Cha
- Department of Oral Biology, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, South Korea
- Department of Applied Life Science, BK21 Plus Project, Yonsei University College of Dentistry, Seoul, South Korea
- Microbiology & Molecular Biology, Key Laboratory of Oral Medicine, Guangzhou Institute of Oral Disease, Stomatology Hospital of Guangzhou Medical University, Guangzhou, China
| | - D Scott Merrell
- Uniformed Services University of the Health Sciences, F. Edward Hébert School of Medicine, Department of Microbiology and Immunology, Bethesda, Maryland, 20814, USA.
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Tapia R, Kralicek SE, Hecht GA. EPEC effector EspF promotes Crumbs3 endocytosis and disrupts epithelial cell polarity. Cell Microbiol 2017; 19. [PMID: 28618099 DOI: 10.1111/cmi.12757] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Revised: 05/19/2017] [Accepted: 06/09/2017] [Indexed: 12/12/2022]
Abstract
Enteropathogenic Escherichia coli (EPEC) uses a type III secretion system to inject effector proteins into host intestinal epithelial cells causing diarrhoea. EPEC infection redistributes basolateral proteins β1-integrin and Na+ /K+ ATPase to the apical membrane of host cells. The Crumbs (Crb) polarity complex (Crb3/Pals1/Patj) is essential for epithelial cell polarisation and tight junction (TJ) assembly. Here, we demonstrate that EPEC displaces Crb3 and Pals1 from the apical membrane to the cytoplasm of cultured intestinal epithelial cells and colonocytes of infected mice. In vitro studies show that EspF, but not Map, alters Crb3, whereas both effectors modulate Pals1. EspF perturbs polarity formation in cyst morphogenesis assays and induces endocytosis and apical redistribution of Na+ /K+ ATPase. EspF binds to sorting nexin 9 (SNX9) causing membrane remodelling in host cells. Infection with ΔespF/pespFD3, a mutant strain that ablates EspF binding to SNX9, or inhibition of dynamin, attenuates Crb3 endocytosis caused by EPEC. In addition, infection with ΔespF/pespFD3 has no impact on Na+ /K+ ATPase endocytosis. These data support the hypothesis that EPEC perturbs apical-basal polarity in an EspF-dependent manner, which would contribute to EPEC-associated diarrhoea by disruption of TJ and altering the crucial positioning of membrane transporters involved in the absorption of ions and solutes.
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Affiliation(s)
- Rocio Tapia
- Department of Medicine and Division of Gastroenterology and Nutrition, Loyola University Chicago, Chicago, IL, USA
| | - Sarah E Kralicek
- Department of Medicine and Division of Gastroenterology and Nutrition, Loyola University Chicago, Chicago, IL, USA
| | - Gail A Hecht
- Department of Medicine and Division of Gastroenterology and Nutrition, Loyola University Chicago, Chicago, IL, USA.,Department of Microbiology and Immunology, Loyola University Chicago, Maywood, IL, USA.,Edward Hines Jr. VA Hospital, Hines, IL, USA
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Abstract
Helicobacter pylori is the most common bacterial infection worldwide, and virtually all infected persons develop co-existing gastritis. H. pylori is able to send and receive signals from the gastric mucosa, which enables both host and microbe to engage in a dynamic equilibrium. In order to persist within the human host, H. pylori has adopted dichotomous strategies to both induce inflammation as a means of liberating nutrients while simultaneously tempering the immune response to augment its survival. Toll-like receptors (TLRs) and Nod proteins are innate immune receptors that are present in epithelial cells and represent the first line of defense against pathogens. To ensure persistence, H. pylori manipulates TLR-mediated defenses using strategies that include rendering its LPS and flagellin to be non-stimulatory to TLR4 and TLR5, respectively; translocating peptidoglycan into host cells to induce NOD1-mediated anti-inflammatory responses; and translocating DNA into host cells to induce TLR9 activation.
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Structural Insights into Helicobacter pylori Cag Protein Interactions with Host Cell Factors. Curr Top Microbiol Immunol 2017; 400:129-147. [PMID: 28124152 DOI: 10.1007/978-3-319-50520-6_6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The most virulent strains of Helicobacter pylori carry a genomic island (cagPAI) containing a set of 27-31 genes. The encoded proteins assemble a syringe-like apparatus to inject the cytotoxin-associated gene A (CagA) protein into gastric cells. This molecular device belongs to the type IV secretion system (T4SS) family albeit with unique characteristics. The cagPAI-encoded T4SS and its effector protein CagA have an intricate relationship with the host cell, with multiple interactions that only start to be deciphered from a structural point of view. On the one hand, the major roles of the interactions between CagL and CagA (and perhaps CagI and CagY) and host cell factors are to facilitate H. pylori adhesion and to mediate the injection of the CagA oncoprotein. On the other hand, CagA interactions with host cell partners interfere with cellular pathways to subvert cell defences and to promote H. pylori infection. Although a clear mechanism for CagA translocation is still lacking, the structural definition of CagA and CagL domains involved in interactions with signalling proteins are progressively coming to light. In this chapter, we will focus on the structural aspects of Cag protein interactions with host cell molecules, critical molecular events precluding H. pylori-mediated gastric cancer development.
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Tapia R, Kralicek SE, Hecht GA. Modulation of epithelial cell polarity by bacterial pathogens. Ann N Y Acad Sci 2017. [PMID: 28628193 DOI: 10.1111/nyas.13388] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Epithelial cells constitute a physical barrier that aids in protecting the host from microbial pathogens. Polarized epithelial cells contain distinct apical and basolateral membrane domains separated by intercellular junctions, including tight junctions (TJs), which contribute to the maintenance of apical-basal polarity. Polarity complexes also contribute to the establishment of TJ formation. Several pathogens perturb epithelial TJ barrier function and structure in addition to causing a loss of apical-basal polarity. Here, we review the impact of pathogenic bacteria on the disruption of cell-cell junctions and epithelial polarity.
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Affiliation(s)
- Rocio Tapia
- Division of Gastroenterology and Nutrition, Department of Medicine, Loyola University Chicago, Maywood, Illinois
| | - Sarah E Kralicek
- Division of Gastroenterology and Nutrition, Department of Medicine, Loyola University Chicago, Maywood, Illinois
| | - Gail A Hecht
- Division of Gastroenterology and Nutrition, Department of Medicine, Loyola University Chicago, Maywood, Illinois.,Department of Microbiology and Immunology, Loyola University Chicago, Maywood, Illinois.,Edward Hines Jr. VA Hospital, Hines, Illinois
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Ruch TR, Engel JN. Targeting the Mucosal Barrier: How Pathogens Modulate the Cellular Polarity Network. Cold Spring Harb Perspect Biol 2017; 9:cshperspect.a027953. [PMID: 28193722 DOI: 10.1101/cshperspect.a027953] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The mucosal barrier is composed of polarized epithelial cells with distinct apical and basolateral surfaces separated by tight junctions and serves as both a physical and immunological barrier to incoming pathogens. Specialized polarity proteins are critical for establishment and maintenance of polarity. Many human pathogens have evolved virulence mechanisms that target the polarity network to enhance binding, create replication niches, move through the barrier by transcytosis, or bypass the barrier by disrupting cell-cell junctions. This review summarizes recent advances and compares and contrasts how three important human pathogens that colonize mucosal surfaces, Pseudomonas aeruginosa, Helicobacter pylori, and Neisseria meningitidis, subvert the host cell polarization machinery during infection.
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Affiliation(s)
- Travis R Ruch
- Department of Medicine, University of California, San Francisco, San Francisco, California 94143
| | - Joanne N Engel
- Department of Medicine, University of California, San Francisco, San Francisco, California 94143.,Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, California 94143
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Li Q, Liu J, Gong Y, Yuan Y. Association of CagA EPIYA-D or EPIYA-C phosphorylation sites with peptic ulcer and gastric cancer risks: A meta-analysis. Medicine (Baltimore) 2017; 96:e6620. [PMID: 28445260 PMCID: PMC5413225 DOI: 10.1097/md.0000000000006620] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Increasingly, studies have focused on the relationship between Helicobacter pylori (H pylori) cytotoxin associated gene A protein (CagA) Glu-Pro-Ile-Tyr-Ala (EPIYA)-D motifs or multiple EPIYA-C phosphorylation sites and peptic ulcer disease (PUD) or gastric cancer (GC) risk. However, the conclusions have been inconsistent. The aim of this meta-analysis was to evaluate whether 1 CagA EPIYA-D motif or multiple EPIYA-C phosphorylation sites were associated with PUD or GC risk. MATERIALS AND METHODS A literature search was performed in PubMed, Web of Science, Wanfang Data, Excerpt Medica Database, and the Chinese National Knowledge Infrastructure database to identify eligible research. We analyzed the odds ratios (OR) and 95% confidence intervals (CI) to assess the strength of association. RESULTS Compared with 1 EPIYA-C motif in Asian populations, 1 EPIYA-D site was associated with an increased GC risk (OR=1.91, 95% CI=1.19-3.07, P = .008). However, 1 EPIYA-D motif was not significantly associated with PUD (OR = 0.90, 95% CI = 0.46-1.76, P = .764), gastric ulcer (GU) (OR = 0.85, 95% CI = 0.27-2.63, P = .771), or duodenal ulcer (DU) (OR = 0.89, 95% CI = 0.25-3.16, P = .859) risk. Compared with no more than 1 EPIYA-C motif, multiple motifs were associated with increased PUD (OR = 2.33, 95% CI = 1.29-4.20, P = .005) and DU (OR = 2.32, 95% CI = 1.08-5.00, P = .031) risk in Asia and GC risk in the United States and Europe (OR = 3.28, 95% CI = 2.32-4.64, P < .001). Multiple EPIYA-C sites were not associated with GU risk (OR = 4.54, 95% CI = 0.95-21.83, P = .059). There was no publication bias identified in these comparisons. CONCLUSIONS In Asia, 1 EPIYA-D motif was significantly associated with increased GC risk. Multiple EPIYA-C motifs were associated with increased PUD and DU risk, particularly in Asia. In the United States and Europe, multiple EPIYA-C motifs were associated with increased GC risk. Therefore, detection of polymorphic CagA EPIYA motifs may improve clinical prediction of disease risk.
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Helicobacter pylori, Cancer, and the Gastric Microbiota. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 908:393-408. [PMID: 27573782 DOI: 10.1007/978-3-319-41388-4_19] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Gastric adenocarcinoma is one of the leading causes of cancer-related death worldwide and Helicobacter pylori infection is the strongest known risk factor for this disease. Although the stomach was once thought to be a sterile environment, it is now known to house many bacterial species leading to a complex interplay between H. pylori and other residents of the gastric microbiota. In addition to the role of H. pylori virulence factors, host genetic polymorphisms, and diet, it is now becoming clear that components of the gastrointestinal microbiota may also influence H. pylori-induced pathogenesis. In this chapter, we discuss emerging data regarding the gastric microbiota in humans and animal models and alterations that occur to the composition of the gastric microbiota in the presence of H. pylori infection that may augment the risk of developing gastric cancer.
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Backert S, Schmidt TP, Harrer A, Wessler S. Exploiting the Gastric Epithelial Barrier: Helicobacter pylori's Attack on Tight and Adherens Junctions. Curr Top Microbiol Immunol 2017; 400:195-226. [PMID: 28124155 DOI: 10.1007/978-3-319-50520-6_9] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Highly organized intercellular tight and adherens junctions are crucial structural components for establishing and maintenance of epithelial barrier functions, which control the microbiota and protect against intruding pathogens in humans. Alterations in these complexes represent key events in the development and progression of multiple infectious diseases as well as various cancers. The gastric pathogen Helicobacter pylori exerts an amazing set of strategies to manipulate these epithelial cell-to-cell junctions, which are implicated in changing cell polarity, migration and invasive growth as well as pro-inflammatory and proliferative responses. This chapter focuses on the H. pylori pathogenicity factors VacA, CagA, HtrA and urease, and how they can induce host cell signaling involved in altering cell-to-cell permeability. We propose a stepwise model for how H. pylori targets components of tight and adherens junctions in order to disrupt the gastric epithelial cell layer, giving fresh insights into the pathogenesis of this important bacterium.
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Affiliation(s)
- Steffen Backert
- Division of Microbiology, Department of Biology, Friedrich Alexander University Erlangen-Nuremberg, Staudtstr. 5, 91058, Erlangen, Germany.
| | - Thomas P Schmidt
- Division of Microbiology, Department of Molecular Biology, Paris-Lodron University of Salzburg, Billroth Str. 11, 5020, Salzburg, Austria
| | - Aileen Harrer
- Division of Microbiology, Department of Biology, Friedrich Alexander University Erlangen-Nuremberg, Staudtstr. 5, 91058, Erlangen, Germany
| | - Silja Wessler
- Division of Microbiology, Department of Molecular Biology, Paris-Lodron University of Salzburg, Billroth Str. 11, 5020, Salzburg, Austria.
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Rivas-Ortiz CI, Lopez-Vidal Y, Arredondo-Hernandez LJR, Castillo-Rojas G. Genetic Alterations in Gastric Cancer Associated with Helicobacter pylori Infection. Front Med (Lausanne) 2017; 4:47. [PMID: 28512631 PMCID: PMC5411440 DOI: 10.3389/fmed.2017.00047] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Accepted: 04/07/2017] [Indexed: 12/11/2022] Open
Abstract
Gastric cancer is a world health problem and depicts the fourth leading mortality cause from malignancy in Mexico. Causation of gastric cancer is not only due to the combined effects of environmental factors and genetic variants. Recent molecular studies have transgressed a number of genes involved in gastric carcinogenesis. The aim of this review is to understand the recent basics of gene expression in the development of the process of gastric carcinogenesis. Genetic variants, polymorphisms, desoxyribonucleic acid methylation, and genes involved in mediating inflammation have been associated with the development of gastric carcinogenesis. Recently, these genes (interleukin 10, Il-17, mucin 1, β-catenin, CDX1, SMAD4, SERPINE1, hypoxia-inducible factor 1 subunit alpha, GSK3β, CDH17, matrix metalloproteinase 7, RUNX3, RASSF1A, TFF1, HAI-2, and COX-2) have been studied in association with oncogenic activation or inactivation of tumor suppressor genes. All these mechanisms have been investigated to elucidate the process of gastric carcinogenesis, as well as their potential use as biomarkers and/or molecular targets to treatment of disease.
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Affiliation(s)
- Claudia I. Rivas-Ortiz
- Programa de Inmunología Molecular Microbiana, Departamento de Microbiología y Parasitología, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | - Yolanda Lopez-Vidal
- Programa de Inmunología Molecular Microbiana, Departamento de Microbiología y Parasitología, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | | | - Gonzalo Castillo-Rojas
- Programa de Inmunología Molecular Microbiana, Departamento de Microbiología y Parasitología, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
- *Correspondence: Gonzalo Castillo-Rojas,
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HATAKEYAMA M. Structure and function of Helicobacter pylori CagA, the first-identified bacterial protein involved in human cancer. PROCEEDINGS OF THE JAPAN ACADEMY. SERIES B, PHYSICAL AND BIOLOGICAL SCIENCES 2017; 93:196-219. [PMID: 28413197 PMCID: PMC5489429 DOI: 10.2183/pjab.93.013] [Citation(s) in RCA: 144] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/14/2023]
Abstract
Chronic infection with Helicobacter pylori cagA-positive strains is the strongest risk factor of gastric cancer. The cagA gene-encoded CagA protein is delivered into gastric epithelial cells via bacterial type IV secretion, where it undergoes tyrosine phosphorylation at the Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs. Delivered CagA then acts as a non-physiological scaffold/hub protein by interacting with multiple host signaling molecules, most notably the pro-oncogenic phosphatase SHP2 and the polarity-regulating kinase PAR1/MARK, in both tyrosine phosphorylation-dependent and -independent manners. CagA-mediated manipulation of intracellular signaling promotes neoplastic transformation of gastric epithelial cells. Transgenic expression of CagA in experimental animals has confirmed the oncogenic potential of the bacterial protein. Structural polymorphism of CagA influences its scaffold function, which may underlie the geographic difference in the incidence of gastric cancer. Since CagA is no longer required for the maintenance of established gastric cancer cells, studying the role of CagA during neoplastic transformation will provide an excellent opportunity to understand molecular processes underlying "Hit-and-Run" carcinogenesis.
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Affiliation(s)
- Masanori HATAKEYAMA
- Department of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Correspondence should be addressed: M. Hatakeyama, Division of Microbiology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan (e-mail: )
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