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Clyne M, Ó Cróinín T. Pathogenicity and virulence of Helicobacter pylori: A paradigm of chronic infection. Virulence 2025; 16:2438735. [PMID: 39725863 DOI: 10.1080/21505594.2024.2438735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 11/18/2024] [Accepted: 12/02/2024] [Indexed: 12/28/2024] Open
Abstract
Infection with Helicobacter pylori is one of the most common infections of mankind. Infection typically occurs in childhood and persists for the lifetime of the host unless eradicated with antimicrobials. The organism colonizes the stomach and causes gastritis. Most infected individuals are asymptomatic, but infection also causes gastric and duodenal ulceration, and gastric cancer. H. pylori possesses an arsenal of virulence factors, including a potent urease enzyme for protection from acid, flagella that mediate motility, an abundance of outer membrane proteins that can mediate attachment, several immunomodulatory proteins, and an ability to adapt to specific conditions in individual human stomachs. The presence of a type 4 secretion system that injects effector molecules into gastric cells and subverts host cell signalling is associated with virulence. In this review we discuss the interplay of H. pylori colonization and virulence factors with host and environmental factors to determine disease outcome in infected individuals.
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Affiliation(s)
- Marguerite Clyne
- School of Medicine, University College Dublin, Dublin, Ireland
- The Conway Institute of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
| | - Tadhg Ó Cróinín
- The Conway Institute of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
- School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
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Gaggioli MR, Jones AG, Panagi I, Washington EJ, Loney RE, Muench JH, Foster MW, Brennan RG, Thurston TLM, Ko DC. A single amino acid in the Salmonella effector SarA/SteE triggers supraphysiological activation of STAT3 for anti-inflammatory gene expression. Cell Rep 2025; 44:115530. [PMID: 40188438 PMCID: PMC12014907 DOI: 10.1016/j.celrep.2025.115530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 02/25/2025] [Accepted: 03/17/2025] [Indexed: 04/08/2025] Open
Abstract
Salmonella causes ∼1 million cases of gastroenteritis annually in the United States. Critical to virulence are secreted effectors that reprogram host functions. We previously discovered the effector SarA facilitates phosphorylation of STAT3, inducing expression of the anti-inflammatory cytokine interleukin-10 (IL-10). This STAT3 activation requires a region of homology with the host cytokine receptor gp130. Here, we demonstrate that a single amino acid difference is critical for the anti-inflammatory bias of SarA-STAT3 signaling. An isoleucine at pY+1 of the YxxQ motif in SarA (which binds the STAT3 SH2 domain) causes increased STAT3 recruitment and phosphorylation, biasing toward anti-inflammatory targets. This isoleucine renders SarA a better substrate for tyrosine phosphorylation by GSK-3. GSK-3 is canonically a serine/threonine kinase that nonetheless undergoes tyrosine autophosphorylation at a motif with isoleucine at the pY+1 position. Our results provide a molecular basis for how a Salmonella effector achieves supraphysiological levels of STAT3 activation to control host genes.
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Affiliation(s)
- Margaret R Gaggioli
- Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA
| | - Angela G Jones
- Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA
| | - Ioanna Panagi
- Department of Infectious Disease, Centre for Bacterial Resistance Biology, Imperial College London, London, UK
| | - Erica J Washington
- Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA; Department of Biochemistry, School of Medicine, Duke University, Durham, NC 27710, USA
| | - Rachel E Loney
- Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA
| | | | - Matthew W Foster
- Duke Proteomics and Metabolomics Core Facility, School of Medicine, Duke University, Durham, NC 27710, USA
| | - Richard G Brennan
- Department of Biochemistry, School of Medicine, Duke University, Durham, NC 27710, USA
| | - Teresa L M Thurston
- Department of Infectious Disease, Centre for Bacterial Resistance Biology, Imperial College London, London, UK
| | - Dennis C Ko
- Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA; Division of Infectious Diseases, Department of Medicine, School of Medicine, Duke University, Durham, NC 27710, USA.
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Ziogou A, Giannakodimos A, Giannakodimos I, Schizas D, Charalampakis N. Effect of Helicobacter Pylori infection on immunotherapy for gastrointestinal cancer: a narrative review. Immunotherapy 2025:1-14. [PMID: 40087147 DOI: 10.1080/1750743x.2025.2479410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 03/11/2025] [Indexed: 03/16/2025] Open
Abstract
Immunotherapy for gastrointestinal cancers has elicited considerable amount of attention as a viable therapeutic option for several cancer types. Gut microbiome as a whole plays a critical role in shaping immune responses and influencing cancer progression. Recent evidence suggests that Helicobacter pylori (H. pylori), may influence immunotherapy efficacy by modulating the tumor microenvironment. Infection with H. pylori is common as it affects approximately 50% of the global population and remains the leading risk factor for gastric cancer. Interestingly, recent clinical and preclinical data has associated H. pylori with colorectal cancer carcinogenesis. Gut microbiome appears to be a modulator of the relationship between the immune system, gastrointestinal cancer development and existing therapies. Infection with H. pylori may affect immunotherapy results in both gastroesophageal and colorectal cancer; favorable results were noticed in H. pylori positive patients with gastric cancer, while in colorectal cancer patients the pathogen seemed to impede immunotherapy's action. This article aims to review current data on the role of H. pylori in triggering gastric inflammation and cancer, as well as its potential involvement in colorectal cancer development. Additionally, it seeks to highlight the impact of H. pylori infection on the response to immunotherapy in gastrointestinal cancers.
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Affiliation(s)
- Afroditi Ziogou
- Department of Medical Oncology, Metaxa Cancer Hospital of Piraeus, Piraeus, Greece
| | | | - Ilias Giannakodimos
- Departement of Urology, Attikon University Hospital of Athens, Athens, Greece
| | - Dimitrios Schizas
- First Department of Surgery, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece
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Tan Y, Matsuzaki J, Saito Y, Suzuki H. Environmental factors in gastric carcinogenesis and preventive intervention strategies. Genes Environ 2025; 47:5. [PMID: 40045434 PMCID: PMC11881338 DOI: 10.1186/s41021-025-00328-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2024] [Accepted: 01/28/2025] [Indexed: 03/09/2025] Open
Abstract
Gastric cancer, a significant global health concern, arises from a complex interplay of genetic and environmental factors. Helicobacter pylori (H. pylori) infection is a major risk factor that can be mitigated through eradication strategies. Epstein-Barr virus (EBV) infection causes a distinct subtype of gastric cancer called EBV-associated gastric cancer. The gastric microbiome, a dynamic ecosystem, is also involved in carcinogenesis, particularly dysbiosis and specific bacterial species such as Streptococcus anginosus. Long-term use of proton pump inhibitors and potassium-competitive acid blockers also increases the risk of gastric cancer, whereas non-steroidal anti-inflammatory drugs including aspirin may have a protective effect. Smoking significantly increases the risk, and cessation can reduce it. Dietary factors such as high intake of salt, processed meats, and red meat may increase the risk, whereas a diet rich in fruits and vegetables may be protective. Extracellular vesicles, which are small membrane-bound structures released by cells, modulate the tumor microenvironment and may serve as biomarkers for risk stratification and as therapeutic targets in gastric cancer. This review highlights the multifaceted etiology of gastric cancer and its risk factors and emphasizes the importance of a multi-pronged approach to prevention including H. pylori eradication and modification of lifestyle factors, as well as the potential of microbiome-based and EV-based interventions. Further research is needed to refine risk stratification and to develop personalized prevention strategies.
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Affiliation(s)
- Yuzhi Tan
- Division of Pharmacotherapeutics, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512, Japan
| | - Juntaro Matsuzaki
- Division of Pharmacotherapeutics, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512, Japan
| | - Yoshimasa Saito
- Division of Pharmacotherapeutics, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512, Japan
| | - Hidekazu Suzuki
- Department of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University School of Medicine, 143 Shimokasuya, Isehara, 259-1193, Kanagawa, Japan.
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Elger W, Tegtmeyer N, Rohde M, Linz B, Hirsch C, Backert S. Cultivation and molecular characterization of viable Helicobacter pylori from the root canal of 170 deciduous teeth of children. Cell Commun Signal 2024; 22:578. [PMID: 39627817 PMCID: PMC11613870 DOI: 10.1186/s12964-024-01948-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 11/16/2024] [Indexed: 12/08/2024] Open
Abstract
BACKGROUND Helicobacter pylori is a persistent pathogen in the human stomach. However, the proposed transmission route via the oral cavity is not understood and under intense debate. While dozens of studies have shown by PCR that H. pylori DNA is frequently present in the oral cavity, data on the growth and characterization of viable H. pylori from this compartment are very scarce, and it is unclear whether the bacteria can survive in the oral cavity for longer time periods or even colonize it. METHODS Selective growth methods, scanning electron microscopy, urease assay, Western blotting, PCR, and gene sequencing were applied to identify and examine viable H. pylori in decayed milk teeth. RESULTS Here, we studied viable H. pylori in the plaque and root canals of 170 endodontically infected deciduous teeth that were extracted from 54 children. While H. pylori DNA was detected in several plaque and many root canal samples by PCR, live bacteria could only be cultivated from 28 root canals, but not from plaque. These 28 isolates have been identified as H. pylori by PCR and sequencing of vacA, cagA and htrA genes, phylogenetic analyses, protein expression of major H. pylori virulence factors, and by signal transduction events during infection of human cell lines. CONCLUSIONS Thus, the microaerobic environment in the root canals of endodontically infected teeth may represent a protected and transient reservoir for live H. pylori, especially in individuals with poor dental hygiene, which could serve as a potential source for re-infection of the stomach after antibiotic therapy or for transmission to other individuals.
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Affiliation(s)
- Wieland Elger
- Department of Paediatric Dentistry, University School of Dental Medicine, University of Leipzig, Leipzig, Germany
| | - Nicole Tegtmeyer
- Division of Microbiology, Department Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Manfred Rohde
- Central Facility for Microscopy, Helmholtz Centre for Infection Research, Brunswick, Germany
| | - Bodo Linz
- Division of Microbiology, Department Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Christian Hirsch
- Department of Paediatric Dentistry, University School of Dental Medicine, University of Leipzig, Leipzig, Germany.
| | - Steffen Backert
- Division of Microbiology, Department Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
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Lusta KA, Churov AV, Beloyartsev DF, Golovyuk AL, Lee AA, Sukhorukov VN, Orekhov AN. The two coin sides of bacterial extracellular membrane nanovesicles: atherosclerosis trigger or remedy. DISCOVER NANO 2024; 19:179. [PMID: 39532781 PMCID: PMC11557815 DOI: 10.1186/s11671-024-04149-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Accepted: 11/04/2024] [Indexed: 11/16/2024]
Abstract
Among the numerous driving forces that cause the atherosclerotic cardiovascular disease (ASCVD), pathogenic bacterial extracellular membrane nanovesicles (BEMNs) containing toxins and virulence factors appear to be the key trigger of inflammation and atherogenesis, the major processes involved in the pathogenesis of ASCVD. Since BEMNs are the carriers of nanosized biomolecules to distant sites, they are now being considered as a novel drug delivery system. Nowadays, many therapeutic strategies are used to treat ASCVD. However, the conventional anti-atherosclerotic therapies are not effective enough. This primarily due to the inefficiency of non-targeted drug delivery systems to tissue affected areas, which, in turn, leads to numerous side effects, as well as faulty pharmacokinetics. In this regard, nanomedicine methods using nanoparticles (NPs) as targeted drug delivery vehicles proved to be extremely useful. Bioengineered BEMNs equipped with disease-specific ligand moieties and loaded with corresponding drugs represent a promising tool in nanomedicine, which can be used as a novel drug delivery system for a successful therapy of ASCVD. In this review, we outline the involvement of pathogenic BEMNs in the triggering of ASCVD, the conventional therapeutic strategies for the treatment of ASCVD, and the recent trends in nanomedicine using BEMNs and NPs as a vehicle for targeted drug delivery.
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Affiliation(s)
- Konstantin A Lusta
- Institute for Atherosclerosis Research, Ltd, Osennyaya Street 4-1-207, Moscow, Russia, 121609.
| | - Alexey V Churov
- Institute on Aging Research, Russian Gerontology Clinical Research Center, Pirogov Russian National Research Medical University, Moscow, Russia, 129226
- Institute of General Pathology and Pathophysiology, 8 Baltiiskaya Street, Moscow, Russia, 125315
| | - Dmitry F Beloyartsev
- Vascular Surgery Department, A.V. Vishnevsky National Medical Research Center of Surgery, 27 Bolshaya Serpukhovskaya Street, Moscow, Russia, 117997
| | - Alexander L Golovyuk
- Vascular Surgery Department, A.V. Vishnevsky National Medical Research Center of Surgery, 27 Bolshaya Serpukhovskaya Street, Moscow, Russia, 117997
| | - Arthur A Lee
- Insitute of Human Morphology, Petrovsky Russian National Center of Surgery, 2 Abrikosovsky Lane, Moscow, Russia, 119991
| | - Vasily N Sukhorukov
- Insitute of Human Morphology, Petrovsky Russian National Center of Surgery, 2 Abrikosovsky Lane, Moscow, Russia, 119991
- Institute of General Pathology and Pathophysiology, 8 Baltiiskaya Street, Moscow, Russia, 125315
| | - Alexander N Orekhov
- Insitute of Human Morphology, Petrovsky Russian National Center of Surgery, 2 Abrikosovsky Lane, Moscow, Russia, 119991
- Institute of General Pathology and Pathophysiology, 8 Baltiiskaya Street, Moscow, Russia, 125315
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Ji X, Sun Z, Wu H, Zhang J, Liu S, Cao X, Wang B, Wang F, Zhang Y, Li B, Feng J, Zhao H. More powerful dysregulation of Helicobacter pylori East Asian-type CagA on intracellular signalings. BMC Microbiol 2024; 24:467. [PMID: 39528935 PMCID: PMC11552142 DOI: 10.1186/s12866-024-03619-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Accepted: 11/04/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Chronic infection by Helicobacter pylori strains expressing cytotoxin-associated gene A (CagA) are the strongest risk factor for gastric cancer. CagA can be classified into East Asian-type and Western-type (CagAE and CagAW), with CagAE being more closely associated with gastric cancer. This study aimed to investigate the impact of CagAE on intracellular signaling pathways to explain its high oncogenicity. RESULTS Mutant H. pylori strains expressing either CagAE or CagAW were generated by transforming CagAE/W-expression plasmid into CagA-deleted G27 strain (G27ΔCagA). In human gastric epithelial cells (GES-1) infection, CagAE induced more severe cytopathic changes, including higher interleukin-8 (IL-8) secretion, reduced cell viability, more pronounced "hummingbird phenotype" alterations, and increased cell migration and invasion compared to CagAW. Transcriptome analysis revealed that CagAE had a stronger effect on the up-regulation of key intracellular processes, including tumor necrosis factor-ɑ (TNF-ɑ) signal pathway via nuclear factor kappa-B (NF-κB), inflammatory response, interferon-γ (IFN-γ) response, hypoxia, ultraviolet (UV) response, and Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) signaling. A significant upregulation of hypoxia-related genes was a notable feature of CagAE. GES-1 cells infected with CagAE exhibited more severe intracellular hypoxia and higher levels of reactive oxygen species (ROS) than those infected with CagAW. Inhibition of hypoxia-inducible factor-1α (HIF-1α), which blocks hypoxia signaling, mitigated CagAE-induced cell migration, emphasizing the role of hypoxia in mediating CagAE effects. CONCLUSIONS The study provides transcriptome evidence of CagA-associated intracellular regulation during H. pylori infection, demonstrating that CagAE exerts stronger effects on intracellular signaling than CagAW. These findings offer insights into the heightened carcinogenic potential of CagAE in H. pylori-induced gastric cancer.
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Affiliation(s)
- Xiaofei Ji
- Binzhou Medical University, Yantai, China
| | - Zekun Sun
- Binzhou Medical University, Yantai, China
| | - Hao Wu
- Binzhou Medical University, Yantai, China
- Department of Blood Transfusion, Jining First People's Hospital, Jining, China
| | | | | | | | - Bin Wang
- Binzhou Medical University, Yantai, China
| | | | - Ying Zhang
- Binzhou Medical University, Yantai, China
| | - Boqing Li
- Binzhou Medical University, Yantai, China
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Xie R, You N, Chen WY, Zhu P, Wang P, Lv YP, Yue GY, Xu XL, Wu JB, Xu JY, Liu SX, Lü MH, Yang SQ, Cheng P, Mao FY, Teng YS, Peng LS, Zhang JY, Liao YL, Yang SM, Zhao YL, Chen W, Zou QM, Zhuang Y. Helicobacter pylori-Induced Angiopoietin-Like 4 Promotes Gastric Bacterial Colonization and Gastritis. RESEARCH (WASHINGTON, D.C.) 2024; 7:0409. [PMID: 39022746 PMCID: PMC11254415 DOI: 10.34133/research.0409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 05/22/2024] [Indexed: 07/20/2024]
Abstract
Helicobacter pylori infection is characterized as progressive processes of bacterial persistence and chronic gastritis with features of infiltration of mononuclear cells more than granulocytes in gastric mucosa. Angiopoietin-like 4 (ANGPTL4) is considered a double-edged sword in inflammation-associated diseases, but its function and clinical relevance in H. pylori-associated pathology are unknown. Here, we demonstrate both pro-colonization and pro-inflammation roles of ANGPTL4 in H. pylori infection. Increased ANGPTL4 in the infected gastric mucosa was produced from gastric epithelial cells (GECs) synergistically induced by H. pylori and IL-17A in a cagA-dependent manner. Human gastric ANGPTL4 correlated with H. pylori colonization and the severity of gastritis, and mouse ANGPTL4 from non-bone marrow-derived cells promoted bacteria colonization and inflammation. Importantly, H. pylori colonization and inflammation were attenuated in Il17a -/-, Angptl4 -/-, and Il17a -/- Angptl4 -/- mice. Mechanistically, ANGPTL4 bound to integrin αV (ITGAV) on GECs to suppress CXCL1 production by inhibiting ERK, leading to decreased gastric influx of neutrophils, thereby promoting H. pylori colonization; ANGPTL4 also bound to ITGAV on monocytes to promote CCL5 production by activating PI3K-AKT-NF-κB, resulting in increased gastric influx of regulatory CD4+ T cells (Tregs) via CCL5-CCR4-dependent migration. In turn, ANGPTL4 induced Treg proliferation by binding to ITGAV to activate PI3K-AKT-NF-κB, promoting H. pylori-associated gastritis. Overall, we propose a model in which ANGPTL4 collectively ensures H. pylori persistence and promotes gastritis. Efforts to inhibit ANGPTL4-associated pathway may prove valuable strategies in treating H. pylori infection.
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Affiliation(s)
- Rui Xie
- Department ofEndoscopy and Digestive System, Guizhou Provincial People’s Hospital, Guiyang, China
| | - Nan You
- Department of Hepatobiliary Surgery, XinQiao Hospital,
Third Military Medical University, Chongqing, China
| | - Wan-Yan Chen
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine,
Third Military Medical University, Chongqing, China
| | - Peng Zhu
- Department of Gastroenterology, Suining First People’s Hospital, Suining, Sichuan, China
| | - Pan Wang
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine,
Third Military Medical University, Chongqing, China
| | - Yi-Pin Lv
- Department of Infection, The General Hospital of Western Theater Command, Chengdu, Sichuan, China
| | - Geng-Yu Yue
- Department ofEndoscopy and Digestive System, Guizhou Provincial People’s Hospital, Guiyang, China
| | - Xiao-Lin Xu
- Department ofEndoscopy and Digestive System, Guizhou Provincial People’s Hospital, Guiyang, China
| | - Jiang-Bo Wu
- Department ofEndoscopy and Digestive System, Guizhou Provincial People’s Hospital, Guiyang, China
| | - Jing-Yu Xu
- Department ofEndoscopy and Digestive System, Guizhou Provincial People’s Hospital, Guiyang, China
| | - Si-Xu Liu
- Department of Gastroenterology,
Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Mu-Han Lü
- Department of Gastroenterology,
Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Sheng-Qian Yang
- Chongqing Engineering Research Center for Pharmacodynamics Evaluation, Department of Pharmaceutics, College of Pharmacy and Laboratory Medicine,
Third Military Medical University, Chongqing, China
| | - Ping Cheng
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine,
Third Military Medical University, Chongqing, China
| | - Fang-Yuan Mao
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine,
Third Military Medical University, Chongqing, China
| | - Yong-Sheng Teng
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine,
Third Military Medical University, Chongqing, China
| | - Liu-Sheng Peng
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine,
Third Military Medical University, Chongqing, China
| | - Jin-Yu Zhang
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine,
Third Military Medical University, Chongqing, China
| | - Ya-Ling Liao
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine,
Third Military Medical University, Chongqing, China
| | - Shi-Ming Yang
- Department of Gastroenterology, XinQiao Hospital,
Third Military Medical University, Chongqing, China
| | - Yong-Liang Zhao
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital,
Third Military Medical University, Chongqing, China
| | - Weisan Chen
- La Trobe Institute of Molecular Science,
La Trobe University, Bundoora, Victoria 3085, Australia
| | - Quan-Ming Zou
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine,
Third Military Medical University, Chongqing, China
| | - Yuan Zhuang
- Department ofEndoscopy and Digestive System, Guizhou Provincial People’s Hospital, Guiyang, China
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine,
Third Military Medical University, Chongqing, China
- Department of Gastroenterology,
Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
- State Key Laboratory of Trauma and Chemical Poisoning, Chongqing, China
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9
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Mishra Y, Ranjan A, Mishra V, Chattaraj A, Aljabali AAA, El-Tanani M, Hromić-Jahjefendić A, Uversky VN, Tambuwala MM. The role of the gut microbiome in gastrointestinal cancers. Cell Signal 2024; 115:111013. [PMID: 38113978 DOI: 10.1016/j.cellsig.2023.111013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 12/06/2023] [Accepted: 12/13/2023] [Indexed: 12/21/2023]
Abstract
The gut microbiota present in the human digestive system is incredibly varied and is home to trillions of microorganisms. The gut microbiome is shaped at birth, while numerous genetic, dietary, and environmental variables primarily influence the microbiome composition. The importance of gut microbiota on host health is becoming more widely acknowledged. Digestion, intestinal permeability, and immunological and metabolism responses can all be affected by changes in the composition and function of the gut microbiota. There is mounting evidence that the microbial population's complex traits are important biomarkers and indicators of patient outcomes in cancer and its therapies. Numerous studies have demonstrated that changed commensal gut microorganisms contribute to the development and spread of cancer through various routes. Despite the ongoing controversy surrounding the gut microbiome and gastrointestinal cancer, accumulating evidence points to a potentially far more intricate connection than a simple cause-and-effect relationship. SIMPLE SUMMARY: Due to their high frequency and fatality rate, gastrointestinal cancers are regarded as a severe public health issue with complex medical and economic burdens. The gut microbiota may directly or indirectly interact with existing therapies like immunotherapy and chemotherapy, affecting how well a treatment works. The gut microbiome influences the immune response's activity, function, and development. Generally, certain gut bacteria impact the antitumor actions during cancer by creating particular metabolites or triggering T-cell responses. Yet, certain bacterial species have been found to promote cellular proliferation and metastasis in cancer, and comprehending these interactions in the context of cancer may help identify possible treatment targets. Notwithstanding the improvements in the field, additional research is still required to comprehend the underlying processes, examine the effects on existing therapies, and pinpoint certain bacteria and immune cells that can cause this interaction.
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Affiliation(s)
- Yachana Mishra
- School of Bioengineering and Biosciences, Lovely Professional University, Phagwara 144411, Punjab, India
| | - Abhigyan Ranjan
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara 144411, Punjab, India
| | - Vijay Mishra
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara 144411, Punjab, India
| | - Aditi Chattaraj
- School of Bioengineering and Biosciences, Lovely Professional University, Phagwara 144411, Punjab, India
| | - Alaa A A Aljabali
- Department of Pharmaceutical Sciences, Yarmouk University, Irbid, Jordan
| | - Mohamed El-Tanani
- College of Pharmacy, Ras Alkhama Medical and Health Sciences University, United Arab Emirates
| | - Altijana Hromić-Jahjefendić
- Department of Genetics and Bioengineering, Faculty of Engineering and Natural Sciences, International University of Sarajevo, Hrasnicka cesta 15, Sarajevo 71000, Bosnia and Herzegovina
| | - Vladimir N Uversky
- Department of Molecular Medicine and USF Health Byrd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
| | - Murtaza M Tambuwala
- Lincoln Medical School, University of Lincoln, Brayford Pool, Lincoln LN6 7TS, England, United Kingdom.
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10
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Gaggioli MR, Jones AG, Panagi I, Washington EJ, Loney RE, Muench JH, Brennan RG, Thurston TLM, Ko DC. A single amino acid in the Salmonella effector SarA/SteE triggers supraphysiological activation of STAT3 for anti-inflammatory target gene expression. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.02.14.580367. [PMID: 38405869 PMCID: PMC10888966 DOI: 10.1101/2024.02.14.580367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/27/2024]
Abstract
Non-typhoidal Salmonella enterica cause an estimated 1 million cases of gastroenteritis annually in the United States. These serovars use secreted protein effectors to mimic and reprogram host cellular functions. We previously discovered that the secreted effector SarA (Salmonella anti-inflammatory response activator; also known as SteE) was required for increased intracellular replication of S. Typhimurium and production of the anti-inflammatory cytokine interleukin-10 (IL-10). SarA facilitates phosphorylation of STAT3 through a region of homology with the host cytokine receptor gp130. Here, we demonstrate that a single amino acid difference between SarA and gp130 is critical for the anti-inflammatory bias of SarA-STAT3 signaling. An isoleucine at the pY+1 position of the YxxQ motif in SarA (which binds the SH2 domain in STAT3) causes increased STAT3 phosphorylation and expression of anti-inflammatory target genes. This isoleucine, completely conserved in ~4000 Salmonella isolates, renders SarA a better substrate for tyrosine phosphorylation by GSK-3. GSK-3 is canonically a serine/threonine kinase that nonetheless undergoes tyrosine autophosphorylation at a motif that has an invariant isoleucine at the pY+1 position. Our results provide a molecular basis for how a Salmonella secreted effector achieves supraphysiological levels of STAT3 activation to control host genes during infection.
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Affiliation(s)
- Margaret R. Gaggioli
- Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA
| | - Angela G. Jones
- Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA
| | - Ioanna Panagi
- Department of Infectious Disease, Centre for Bacterial Resistance Biology, Imperial College London, London, UK
| | - Erica J. Washington
- Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA
- Department of Biochemistry, School of Medicine, Duke University, Durham, NC 27710, USA
| | - Rachel E. Loney
- Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA
| | | | - Richard G. Brennan
- Department of Biochemistry, School of Medicine, Duke University, Durham, NC 27710, USA
| | - Teresa L. M. Thurston
- Department of Infectious Disease, Centre for Bacterial Resistance Biology, Imperial College London, London, UK
| | - Dennis C. Ko
- Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA
- Division of Infectious Diseases, Department of Medicine, School of Medicine, Duke University, Durham, NC 27710, USA
- Lead contact
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11
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González-Stegmaier R, Aguila-Torres P, Villarroel-Espíndola F. Historical and Molecular Perspectives on the Presence of Helicobacter pylori in Latin America: A Niche to Improve Gastric Cancer Risk Assessment. Int J Mol Sci 2024; 25:1761. [PMID: 38339039 PMCID: PMC10855479 DOI: 10.3390/ijms25031761] [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: 01/16/2024] [Revised: 01/26/2024] [Accepted: 01/30/2024] [Indexed: 02/12/2024] Open
Abstract
Helicobacter pylori (H. pylori) is responsible for causing chronic gastritis, which can cause peptic ulcer and premalignant lesions such as atrophic gastritis, intestinal metaplasia, and dysplasia, with the risk of developing gastric cancer. Recent data describe that H. pylori colonizes the gastric mucosa of more than 50% of the world's population; however, this bacterium has been described as infecting the human population since its prehistory. This review focuses on the populations and subpopulations of H. pylori, differentiated by the polymorphisms present in their constitutive and virulence genes. These genes have spread and associated with different human populations, showing variability depending on their geographical distribution, and have evolved together with the human being. The predominant genotypes worldwide, Latin America and Chile, are described to understand the genetic diversity and pathogenicity of H. pylori in different populations and geographic regions. The high similarity in the sequence of virulence genes between H. pylori strains present in Peruvian and Spanish natives in Latin America suggests a European influence. The presence of cagA-positive strains and vacA s1 m1 allelic variants is observed with greater prevalence in Chilean patients with more severe gastrointestinal diseases and is associated with its geographical distribution. These findings highlight the importance of understanding the genetic diversity of H. pylori in different regions of the world for a more accurate assessment of the risk of associated diseases and their potential impact on health.
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Affiliation(s)
- Roxana González-Stegmaier
- Traslational Medicine Laboratory, Instituto Oncológico Fundación Arturo López Pérez, Santiago 7500000, Chile;
| | - Patricia Aguila-Torres
- Laboratorio de Microbiología Molecular, Escuela de Tecnología Médica, Universidad Austral de Chile, Puerto Montt 5480000, Chile;
| | - Franz Villarroel-Espíndola
- Traslational Medicine Laboratory, Instituto Oncológico Fundación Arturo López Pérez, Santiago 7500000, Chile;
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12
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Baral B, Kandpal M, Ray A, Jana A, Yadav DS, Sachin K, Mishra A, Baig MS, Jha HC. Helicobacter pylori and Epstein-Barr virus infection in cell polarity alterations. Folia Microbiol (Praha) 2024; 69:41-57. [PMID: 37672163 DOI: 10.1007/s12223-023-01091-7] [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: 02/19/2023] [Accepted: 08/28/2023] [Indexed: 09/07/2023]
Abstract
The asymmetrical distribution of the cellular organelles inside the cell is maintained by a group of cell polarity proteins. The maintenance of polarity is one of the vital host defense mechanisms against pathogens, and the loss of it contributes to infection facilitation and cancer progression. Studies have suggested that infection of viruses and bacteria alters cell polarity. Helicobacter pylori and Epstein-Barr virus are group I carcinogens involved in the progression of multiple clinical conditions besides gastric cancer (GC) and Burkitt's lymphoma, respectively. Moreover, the coinfection of both these pathogens contributes to a highly aggressive form of GC. H. pylori and EBV target the host cell polarity complexes for their pathogenesis. H. pylori-associated proteins like CagA, VacA OipA, and urease were shown to imbalance the cellular homeostasis by altering the cell polarity. Similarly, EBV-associated genes LMP1, LMP2A, LMP2B, EBNA3C, and EBNA1 also contribute to altered cell asymmetry. This review summarized all the possible mechanisms involved in cell polarity deformation in H. pylori and EBV-infected epithelial cells. We have also discussed deregulated molecular pathways like NF-κB, TGF-β/SMAD, and β-catenin in H. pylori, EBV, and their coinfection that further modulate PAR, SCRIB, or CRB polarity complexes in epithelial cells.
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Affiliation(s)
- Budhadev Baral
- Infection Bioengineering Group, Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore, Madhya Pradesh, 453552, India
| | - Meenakshi Kandpal
- Infection Bioengineering Group, Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore, Madhya Pradesh, 453552, India
| | - Anushka Ray
- Infection Bioengineering Group, Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore, Madhya Pradesh, 453552, India
| | - Ankit Jana
- Infection Bioengineering Group, Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore, Madhya Pradesh, 453552, India
| | - Dhirendra Singh Yadav
- Central Forensic Science Laboratory, Pune, DFSS, Ministry of Home Affairs, Govt. of India, Talegaon MIDC Phase-1, Near JCB Factory, Pune, Maharashtra, 410506, India
| | - Kumar Sachin
- Himalayan School of Biosciences, Swami Rama Himalayan University, Swami Ram Nagar, Jolly Grant, Dehradun, Uttarakhand, 248 016, India
| | - Amit Mishra
- Department of Bioscience & Bioengineering, Indian Institute of Technology Jodhpur, NH 65 Nagaur Road, Karwar, Jodhpur District, Rajasthan, 342037, India
| | - Mirza S Baig
- Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore, Madhya Pradesh, 453552, India
| | - Hem Chandra Jha
- Infection Bioengineering Group, Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore, Madhya Pradesh, 453552, India.
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13
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Engelsberger V, Gerhard M, Mejías-Luque R. Effects of Helicobacter pylori infection on intestinal microbiota, immunity and colorectal cancer risk. Front Cell Infect Microbiol 2024; 14:1339750. [PMID: 38343887 PMCID: PMC10853882 DOI: 10.3389/fcimb.2024.1339750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 01/10/2024] [Indexed: 02/15/2024] Open
Abstract
Infecting about half of the world´s population, Helicobacter pylori is one of the most prevalent bacterial infections worldwide and the strongest known risk factor for gastric cancer. Although H. pylori colonizes exclusively the gastric epithelium, the infection has also been associated with various extragastric diseases, including colorectal cancer (CRC). Epidemiological studies reported an almost two-fold increased risk for infected individuals to develop CRC, but only recently, direct causal and functional links between the chronic infection and CRC have been revealed. Besides modulating the host intestinal immune response, H. pylori is thought to increase CRC risk by inducing gut microbiota alterations. It is known that H. pylori infection not only impacts the gastric microbiota at the site of infection but also leads to changes in bacterial colonization in the distal large intestine. Considering that the gut microbiome plays a driving role in CRC, H. pylori infection emerges as a key factor responsible for promoting changes in microbiome signatures that could contribute to tumor development. Within this review, we want to focus on the interplay between H. pylori infection, changes in the intestinal microbiota, and intestinal immunity. In addition, the effects of H. pylori antibiotic eradication therapy will be discussed.
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Affiliation(s)
| | | | - Raquel Mejías-Luque
- Institute for Medical Microbiology, Immunology and Hygiene, TUM School of Medicine and Health, Department Preclinical Medicine, Technical University of Munich, Munich, Germany
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14
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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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15
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OKAMOTO M, MIURA A, ITO R, KAMADA T, MIZUKAMI Y, KAWAMOTO K. G-protein-coupled estrogen receptor prevents nuclear factor-kappa B promoter activation by Helicobacter pylori cytotoxin-associated gene A in gastric cancer cells. J Vet Med Sci 2023; 85:1348-1354. [PMID: 37952974 PMCID: PMC10788165 DOI: 10.1292/jvms.23-0054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Accepted: 10/20/2023] [Indexed: 11/14/2023] Open
Abstract
Helicobacter pylori is a well-known pathogen that causes chronic gastritis, leading to the development of gastric cancer. This bacterium has also been detected in dogs, and symptoms similar to those in humans have been reported. The cytotoxin-associated gene A (CagA) is involved in pathogenesis through aberrant activation of host signal transduction, including the nuclear factor-kappa B (NF-κB) pathway. We have previously shown the anti-inflammatory effect of the G-protein-coupled estrogen receptor (GPER) via inhibiting of NF-κB activation in several cells. Therefore, here, we investigated the effect of GPER on CagA-mediated NF-κB promoter activity and showed that CagA overexpression in gastric cancer cells activated the NF-κB reporter and induced interleukin 8 (il-8) expression, both of which were inhibited by the GPER agonist.
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Affiliation(s)
- Mariko OKAMOTO
- Laboratory of Immunology and Infection Control, Department
of Veterinary Medicine, School of Veterinary Medicine, Azabu University, Kanagawa,
Japan
| | - Atsushi MIURA
- Laboratory of Immunology and Infection Control, Department
of Veterinary Medicine, School of Veterinary Medicine, Azabu University, Kanagawa,
Japan
| | - Ryota ITO
- Laboratory of Immunology and Infection Control, Department
of Veterinary Medicine, School of Veterinary Medicine, Azabu University, Kanagawa,
Japan
| | - Toshiki KAMADA
- Laboratory of Immunology and Infection Control, Department
of Veterinary Medicine, School of Veterinary Medicine, Azabu University, Kanagawa,
Japan
| | - Yoichi MIZUKAMI
- Institute of Gene Research, Yamaguchi University Science
Research Center, Yamaguchi, Japan
| | - Keiko KAWAMOTO
- Laboratory of Immunology and Infection Control, Department
of Veterinary Medicine, School of Veterinary Medicine, Azabu University, Kanagawa,
Japan
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16
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Cheng S, Li H, Chi J, Zhao W, Lin J, Liu X, Xu C. FTO-mediated m 6A modification promotes malignant transformation of gastric mucosal epithelial cells in chronic Cag A + Helicobacter pylori infection. J Cancer Res Clin Oncol 2023; 149:7327-7340. [PMID: 36918410 PMCID: PMC10374804 DOI: 10.1007/s00432-023-04684-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Accepted: 03/05/2023] [Indexed: 03/16/2023]
Abstract
OBJECTIVES Cag A+ Helicobacter pylori chronic infection cause malignant transformation of the human gastric mucosa. N6-methyladenosine (m6A) modifications are the most common and abundant mRNA modifications and one of the pathways affecting tumorigenicity and tumor progression. However, the role of m6A modification in the process of chronic H. pylori infection leading to malignant transformation of gastric mucosa is unclear. METHODS In this study, we used Cag A- and Cag A+H. pylori chronic infection to establish cellular models in GES-1 cells and analyzed the cellular morphology, proliferation, apoptosis, invasiveness and tumorigenicity of gastric mucosal epithelial cells. The m6A expression levels of GES-1 cells after chronic infection with Cag A- and Cag A+H. pylori were examined, and modifying effect of FTO (the fat mass and obesity-associated protein) on CD44 was verified by MeRIP-qPCR. Finally, the FTO expression changes and m6A expression levels were further validated in clinical gastric cancer tissues. RESULTS Chronic Cag A+H. pylori-infected GES-1 cells exhibit altered cell morphology, apoptosis inhibition, abnormal proliferation, enhanced migration, colony formation, and increased stem cell-like properties. Meanwhile, FTO and CD44 expression was enhanced, and FTO may induce malignant transformation of gastric mucosa by regulating CD44 mRNA m6A methylation modifications. CONCLUSIONS We verified the effect of chronic stimulation of Cag A+H. pylori on malignant transformation of gastric mucosal epithelium. revealing the possibility of FTO in promoting malignant transformation of gastric mucosa by modifying CD44 mRNA methylation, suggesting that FTO expression is a potential molecule for malignant transformation of gastric mucosal epithelial cells.
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Affiliation(s)
- Sha Cheng
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, 410013, Hunan, China
| | - Huan Li
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, 410013, Hunan, China
| | - Jingshu Chi
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, 410013, Hunan, China
| | - Wenfang Zhao
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, 410013, Hunan, China
| | - Jiahui Lin
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, 410013, Hunan, China
| | - Xiaoming Liu
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, 410013, Hunan, China
| | - Canxia Xu
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, 410013, Hunan, China.
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17
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Karayiannis I, Martinez-Gonzalez B, Kontizas E, Kokkota AV, Petraki K, Mentis A, Kollia P, Sgouras DN. Induction of MMP-3 and MMP-9 expression during Helicobacter pylori infection via MAPK signaling pathways. Helicobacter 2023; 28:e12987. [PMID: 37139985 DOI: 10.1111/hel.12987] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 03/22/2023] [Accepted: 04/19/2023] [Indexed: 05/05/2023]
Abstract
BACKGROUND AND AIMS Helicobacter pylori (H. pylori)-induced gastric pathology involves remodeling of extracellular matrix mediated by aberrant activity of matrix metalloproteinases (MMPs). We have previously shown that in vitro H. pylori infection leads to MMP-3 and MMP-9 overexpression, associated with phosphorylation of bacterial oncoprotein CagA. We extended these findings in an in vivo model of H. pylori infection and further assessed the involvement of MAPK pathways in MMP expression. MATERIALS AND METHODS C57BL/6 mice were infected with H. pylori strains HPARE, HPARE ΔCagA, and SS1, for 6 and 9 months. Transcriptional expression of Mmp-3 and Mmp-9 was evaluated via qPCR while respective protein levels in the gastric mucosa were determined immunohistochemically. Epithelial cell lines AGS and GES-1 were infected with H. pylori strain P12 in the presence of chemical inhibitors of JNK, ERK1/2, and p38 pathways, for 24 h. mRNA and protein expression of MMP-3 and MMP-9 were determined via qPCR and Western blot, respectively. RESULTS We observed transcriptional activation of Mmp-3 and Mmp-9 as well as aberrant MMP-3 and MMP-9 protein expression in murine gastric tissue following H. pylori infection. CagA expression was associated with MMP upregulation, particularly during the early time points of infection. We found that inhibition of ERK1/2 resulted in reduced mRNA and protein expression of MMP-3 and MMP-9 during H. pylori infection, in both cell lines. Expressed protein levels of both MMPs were also found reduced in the presence of JNK pathway inhibitors in both cell lines. However, p38 inhibition resulted in a more complex effect, probably attributed to the accumulation of phospho-p38 and increased phospho-ERK1/2 activity due to crosstalk between MAPK pathways. CONCLUSIONS H. pylori colonization leads to the upregulation of MMP-3 and MMP-9 in vivo, which primarily involves ERK1/2 and JNK pathways. Therefore, their inhibition may potentially offer a protective effect against gastric carcinogenesis and metastasis.
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Affiliation(s)
- Ioannis Karayiannis
- Laboratory of Medical Microbiology, Hellenic Pasteur Institute, Athens, Greece
- Department of Genetics and Biotechnology, Faculty of Biology, School of Physical Sciences, University of Athens, Athens, Greece
| | | | | | | | | | - Andreas Mentis
- Laboratory of Medical Microbiology, Hellenic Pasteur Institute, Athens, Greece
| | - Panagoula Kollia
- Department of Genetics and Biotechnology, Faculty of Biology, School of Physical Sciences, University of Athens, Athens, Greece
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18
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Xi Y, Zhang XL, Luo QX, Gan HN, Liu YS, Shao SH, Mao XH. Helicobacter pylori regulates stomach diseases by activating cell pathways and DNA methylation of host cells. Front Cell Dev Biol 2023; 11:1187638. [PMID: 37215092 PMCID: PMC10192871 DOI: 10.3389/fcell.2023.1187638] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Accepted: 04/25/2023] [Indexed: 05/24/2023] Open
Abstract
One of the most prevalent malignant tumors of the digestive tract is gastric cancer (GC). Age, high salt intake, Helicobacter pylori (H. pylori) infection, and a diet deficient in fruits and vegetables are risk factors for the illness. A significant risk factor for gastric cancer is infection with H. pylori. Infecting gastric epithelial cells with virulence agents secreted by H. pylori can cause methylation of tumor genes or carcinogenic signaling pathways to be activated. Regulate downstream genes' aberrant expression, albeit the precise mechanism by which this happens is unclear. Oncogene, oncosuppressor, and other gene modifications, as well as a number of different gene change types, are all directly associated to the carcinogenesis of gastric cancer. In this review, we describe comprehensive H. pylori and its virulence factors, as well as the activation of the NF-κB, MAPK, JAK/STAT signaling pathways, and DNA methylation following infection with host cells via virulence factors, resulting in abnormal gene expression. As a result, host-related proteins are regulated, and gastric cancer progression is influenced. This review provides insight into the H. pylori infection, summarizes a series of relevant papers, discusses the complex signaling pathways underlying molecular mechanisms, and proposes new approach to immunotherapy of this important disease.
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Affiliation(s)
- Yue Xi
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Xiao-Li Zhang
- Department of Clinical Laboratory, The Affiliated Yixing Hospital of Jiangsu University, Wuxi, China
| | - Qing-Xin Luo
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Hai-Ning Gan
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Yu-Shi Liu
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Shi-He Shao
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Xu-Hua Mao
- Department of Clinical Laboratory, The Affiliated Yixing Hospital of Jiangsu University, Wuxi, China
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19
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Giammanco A, Anzalone R, Serra N, Graceffa G, Vieni S, Scibetta N, Rea T, Capra G, Fasciana T. Helicobacter pylori and Epstein-Barr Virus Co-Infection in Gastric Disease: What Is the Correlation with p53 Mutation, Genes Methylation and Microsatellite Instability in a Cohort of Sicilian Population? Int J Mol Sci 2023; 24:ijms24098104. [PMID: 37175810 PMCID: PMC10179236 DOI: 10.3390/ijms24098104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 04/06/2023] [Accepted: 04/10/2023] [Indexed: 05/15/2023] Open
Abstract
Genetic predisposition, environmental factors, and infectious agents interact in the development of gastric diseases. Helicobacter pylori (Hp) and Epstein-Barr virus (EBV) infection has recently been shown to be correlated with these diseases. A cross-sectional study was performed on 100 hospitalized Italian patients with and without gastric diseases. The patients were stratified into four groups. Significant methylation status differences among CDH1, DAPK, COX2, hMLH1 and CDKN2A were observed for coinfected (Hp-EBV group) patients; particularly, a significant presence of COX2 (p = 0.0179) was observed. For microsatellite instability, minor stability was described in the Hp-HBV group (69.23%, p = 0.0456). Finally, for p53 mutation in the EBV group, exon 6 was, significantly, most frequent in comparison to others (p = 0.0124), and in the Hp-EBV group exon 8 was, significantly, most frequent in comparison to others (p < 0.0001). A significant positive relationship was found between patients with infection (Hp, EBV or both) and p53 mutation (rho = 0.383, p = 0.0001), methylation status (rho = 0.432, p < 0.0001) and microsatellite instability (rho = 0.285, p = 0.004). Finally, we observed among infection and methylation status, microsatellite instability, and p53 mutation a significant positive relationship only between infection and methylation status (OR = 3.78, p = 0.0075) and infection and p53 mutation (OR = 6.21, p = 0.0082). According to our analysis, gastric disease in the Sicilian population has different pathways depending on the presence of various factors, including infectious agents such as Hp and EBV and genetic factors of the subject.
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Affiliation(s)
- Anna Giammanco
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, 90127 Palermo, Italy
| | - Rita Anzalone
- Department of Surgical Oncological and Oral Sciences, University of Palermo, 90133 Palermo, Italy
| | - Nicola Serra
- Department of Public Health, University Federico II of Naples, 80138 Napoli, Italy
| | - Giuseppa Graceffa
- Department of Surgical Oncological and Oral Sciences, University of Palermo, 90133 Palermo, Italy
| | - Salvatore Vieni
- Department of Surgical Oncological and Oral Sciences, University of Palermo, 90133 Palermo, Italy
| | - Nunzia Scibetta
- Anatomopathology Unit, Arnas Civico Di Cristina Benfratelli Hospital, 90127 Palermo, Italy
| | - Teresa Rea
- Public Health Department, Federico II University Hospital, 80131 Naples, Italy
| | - Giuseppina Capra
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, 90127 Palermo, Italy
| | - Teresa Fasciana
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, 90127 Palermo, Italy
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20
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Cao Z, An L, Han Y, Jiao S, Zhou Z. The Hippo signaling pathway in gastric cancer. Acta Biochim Biophys Sin (Shanghai) 2023. [PMID: 36924251 DOI: 10.3724/abbs.2023038] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/09/2023] Open
Abstract
Gastric cancer (GC) is an aggressive malignant disease which still lacks effective early diagnosis markers and targeted therapies, representing the fourth-leading cause of cancer-associated death worldwide. The Hippo signaling pathway plays crucial roles in organ size control and tissue homeostasis under physiological conditions, yet its aberrations have been closely associated with several hallmarks of cancer. The last decade witnessed a burst of investigations dissecting how Hippo dysregulation contributes to tumorigenesis, highlighting the therapeutic potential of targeting this pathway for tumor intervention. In this review, we systemically document studies on the Hippo pathway in the contexts of gastric tumor initiation, progression, metastasis, acquired drug resistance, and the emerging development of Hippo-targeting strategies. By summarizing major open questions in this field, we aim to inspire further in-depth understanding of Hippo signaling in GC development, as well as the translational implications of targeting Hippo for GC treatment.
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Affiliation(s)
- Zhifa Cao
- Department of Stomatology, Shanghai Tenth People's Hospital, Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, Shanghai 200072, China.,CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Liwei An
- Department of Stomatology, Shanghai Tenth People's Hospital, Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, Shanghai 200072, China
| | - Yi Han
- Department of Stomatology, Shanghai Tenth People's Hospital, Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, Shanghai 200072, China
| | - Shi Jiao
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200438, China
| | - Zhaocai Zhou
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200438, China.,Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing 211166, China
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21
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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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22
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Hatakeyama M. Impact of the Helicobacter pylori Oncoprotein CagA in Gastric Carcinogenesis. Curr Top Microbiol Immunol 2023; 444:239-257. [PMID: 38231221 DOI: 10.1007/978-3-031-47331-9_9] [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 CagA is the first and only bacterial oncoprotein etiologically associated with human cancer. Upon delivery into gastric epithelial cells via bacterial type IV secretion, CagA acts as a pathogenic/pro-oncogenic scaffold that interacts with and functionally perturbs multiple host proteins such as pro-oncogenic SHP2 phosphatase and polarity-regulating kinase PAR1b/MARK2. Although H. pylori infection is established during early childhood, gastric cancer generally develops in elderly individuals, indicating that oncogenic CagA activity is effectively counteracted at a younger age. Moreover, the eradication of cagA-positive H. pylori cannot cure established gastric cancer, indicating that H. pylori CagA-triggered gastric carcinogenesis proceeds via a hit-and-run mechanism. In addition to its direct oncogenic action, CagA induces BRCAness, a cellular status characterized by replication fork destabilization and loss of error-free homologous recombination-mediated DNA double-strand breaks (DSBs) by inhibiting cytoplasmic-to-nuclear localization of the BRCA1 tumor suppressor. This causes genomic instability that leads to the accumulation of excess mutations in the host cell genome, which may underlie hit-and-run gastric carcinogenesis. The close connection between CagA and BRCAness was corroborated by a recent large-scale case-control study that revealed that the risk of gastric cancer in individuals carrying pathogenic variants of genes that induce BRCAness (such as BRCA1 and BRCA2) dramatically increases upon infection with cagA-positive H. pylori. Accordingly, CagA-mediated BRCAness plays a crucial role in the development of gastric cancer in conjunction with the direct oncogenic action of CagA.
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Affiliation(s)
- Masanori Hatakeyama
- Institute of Microbial Chemistry, Laboratory of Microbial Carcinogenesis, Microbial Chemistry Research Foundation, 3-14-23 Kamiosaki, Shinagawa-Ku, Tokyo, 141-0021, Japan.
- Institute for Genetic Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-Ku, Sapporo, 060-0815, Japan.
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23
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Yamaoka Y, Saruuljavkhlan B, Alfaray RI, Linz B. Pathogenomics of Helicobacter pylori. Curr Top Microbiol Immunol 2023; 444:117-155. [PMID: 38231217 DOI: 10.1007/978-3-031-47331-9_5] [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
The human stomach bacterium Helicobacter pylori, the causative agent of gastritis, ulcers and adenocarcinoma, possesses very high genetic diversity. H. pylori has been associated with anatomically modern humans since their origins over 100,000 years ago and has co-evolved with its human host ever since. Predominantly intrafamilial and local transmission, along with genetic isolation, genetic drift, and selection have facilitated the development of distinct bacterial populations that are characteristic for large geographical areas. H. pylori utilizes a large arsenal of virulence and colonization factors to mediate the interaction with its host. Those include various adhesins, the vacuolating cytotoxin VacA, urease, serine protease HtrA, the cytotoxin-associated genes pathogenicity island (cagPAI)-encoded type-IV secretion system and its effector protein CagA, all of which contribute to disease development. While many pathogenicity-related factors are present in all strains, some belong to the auxiliary genome and are associated with specific phylogeographic populations. H. pylori is naturally competent for DNA uptake and recombination, and its genome evolution is driven by extraordinarily high recombination and mutation rates that are by far exceeding those in other bacteria. Comparative genome analyses revealed that adaptation of H. pylori to individual hosts is associated with strong selection for particular protein variants that facilitate immune evasion, especially in surface-exposed and in secreted virulence factors. Recent studies identified single-nucleotide polymorphisms (SNPs) in H. pylori that are associated with the development of severe gastric disease, including gastric cancer. Here, we review the current knowledge about the pathogenomics of H. pylori.
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Affiliation(s)
- Yoshio Yamaoka
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, 1-1, Idaigaoka, Hasama-machi, Yufu Oita, 879-5593, Japan
- Department of Medicine, Gastroenterology and Hepatology Section, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Batsaikhan Saruuljavkhlan
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, 1-1, Idaigaoka, Hasama-machi, Yufu Oita, 879-5593, Japan
| | - Ricky Indra Alfaray
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, 1-1, Idaigaoka, Hasama-machi, Yufu Oita, 879-5593, Japan
- Helicobacter pylori and Microbiota Study Group, Universitas Airlangga, Surabaya, 60286, East Java, Indonesia
| | - Bodo Linz
- Division of Microbiology, Department Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Staudtstr. 5, 91058, Erlangen, Germany.
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24
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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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25
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Wang H, Zhao M, Shi F, Zheng S, Xiong L, Zheng L. A review of signal pathway induced by virulent protein CagA of Helicobacter pylori. Front Cell Infect Microbiol 2023; 13:1062803. [PMID: 37124036 PMCID: PMC10140366 DOI: 10.3389/fcimb.2023.1062803] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 03/24/2023] [Indexed: 05/02/2023] Open
Abstract
Gastric cancer (GC), a common and high-mortality disease, still occupies an important position in current cancer research, and Helicobacter pylori (H. pylori) infection as its important risk factor has been a hot and challenging research area. Among the numerous pathogenic factors of H. pylori, the virulence protein CagA has been widely studied as the only bacterial-derived oncoprotein. It was found that CagA entering into gastric epithelial cells (GECs) can induce the dysregulation of multiple cellular pathways such as MAPK signaling pathway, PI3K/Akt signaling pathway, NF-κB signaling pathway, Wnt/β-catenin signaling pathway, JAK-STAT signaling pathway, Hippo signaling pathway through phosphorylation and non-phosphorylation. These disordered pathways cause pathological changes in morphology, adhesion, polarity, proliferation, movement, and other processes of GECs, which eventually promotes the occurrence of GC. With the deepening of H. pylori-related research, the research on CagA-induced abnormal signaling pathway has been updated and deepened to some extent, so the key signaling pathways activated by CagA are used as the main stem to sort out the pathogenesis of CagA in this paper, aiming to provide new strategies for the H. pylori infection and treatment of GC in the future.
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Affiliation(s)
- Haiqiang Wang
- Department of Internal Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Mei Zhao
- Graduate School of Heilongjiang University of Chinese Medicine, Harbin, China
| | - Fan Shi
- Graduate School of Heilongjiang University of Chinese Medicine, Harbin, China
| | - Shudan Zheng
- Graduate School of Heilongjiang University of Chinese Medicine, Harbin, China
| | - Li Xiong
- Graduate School of Heilongjiang University of Chinese Medicine, Harbin, China
| | - Lihong Zheng
- Department of Internal Medicine, Fourth Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
- *Correspondence: Lihong Zheng,
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26
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Ferreira RM, Figueiredo J, Pinto-Ribeiro I, Gullo I, Sgouras DN, Carreto L, Castro P, Santos MA, Carneiro F, Seruca R, Figueiredo C. Activation of Laminin γ2 by Helicobacter pylori Promotes Invasion and Survival of Gastric Cancer Cells With E-Cadherin Defects. J Infect Dis 2022; 226:2226-2237. [PMID: 36173814 DOI: 10.1093/infdis/jiac397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 09/22/2022] [Accepted: 09/26/2022] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Helicobacter pylori infection induces cellular phenotypes relevant for cancer progression, namely cell motility and invasion. We hypothesized that the extracellular matrix (ECM) could be involved in these deleterious effects. METHODS Microarrays were used to uncover ECM interactors in cells infected with H. pylori. LAMC2, encoding laminin γ2, was selected as a candidate gene and its expression was assessed in vitro and in vivo. The role of LAMC2 was investigated by small interference RNA (siRNA) combined with a set of functional assays. Laminin γ2 and E-cadherin expression patterns were evaluated in gastric cancer cases. RESULTS Laminin γ2 was found significantly overexpressed in gastric cancer cells infected with H. pylori. This finding was validated in vitro by infection with clinical isolates and in vivo by using gastric biopsies of infected and noninfected individuals. We showed that laminin γ2 overexpression is dependent on the bacterial type IV secretion system and on the CagA. Functionally, laminin γ2 promotes cell invasion and resistance to apoptosis, through modulation of Src, JNK, and AKT activity. These effects were abrogated in cells with functional E-cadherin. CONCLUSIONS These data highlight laminin γ2 and its downstream effectors as potential therapeutic targets, and the value of H. pylori eradication to delay gastric cancer onset and progression.
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Affiliation(s)
- Rui M Ferreira
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.,Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
| | - Joana Figueiredo
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.,Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal.,Department of Pathology, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Ines Pinto-Ribeiro
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.,Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
| | - Irene Gullo
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.,Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal.,Department of Pathology, Faculty of Medicine, University of Porto, Porto, Portugal.,Department of Pathology, Centro Hospitalar Universitário São João, Porto, Portugal
| | | | - Laura Carreto
- Department of Biology, University of Aveiro, Aveiro, Portugal.,Centre of Environmental and Marine Studies, University of Aveiro, Aveiro, Portugal
| | - Patricia Castro
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.,Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
| | - Manuel A Santos
- Institute of Biomedicine, University of Aveiro, Aveiro, Portugal.,Multidisciplinary Institute of Ageing, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Fatima Carneiro
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.,Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal.,Department of Pathology, Faculty of Medicine, University of Porto, Porto, Portugal.,Department of Pathology, Centro Hospitalar Universitário São João, Porto, Portugal
| | - Raquel Seruca
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.,Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal.,Department of Pathology, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Ceu Figueiredo
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.,Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal.,Department of Pathology, Faculty of Medicine, University of Porto, Porto, Portugal
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27
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Reyes VE. Helicobacter pylori Immune Response in Children Versus Adults. MEDICAL RESEARCH ARCHIVES 2022; 10:3370. [PMID: 37936946 PMCID: PMC10629867 DOI: 10.18103/mra.v10i12.3370] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/09/2023]
Abstract
H. pylori is perhaps the most prevalent human pathogen worldwide and infects almost half of the world's population. Despite the decreasing prevalence of infection overall, it is significant in developing countries. Most infections are acquired in childhood and persist for a lifetime unless treated. Children are often asymptomatic and often develop a tolerogenic immune response that includes T regulatory cells and their products, immunosuppressive cytokines, such as interleukin (IL)-10, and transforming growth factor-β (TGF-β). This contrasts to the gastric immune response seen in H. pylori-infected adults, where the response is mainly inflammatory, with predominant Th1 and Th17 cells, as well as, inflammatory cytokines, such as TNF-α, IFN-γ, IL-1, IL-6, IL-8, and IL-17. Therefore, compared to adults, infected children generally have limited gastric inflammation and peptic ulcer disease. H. pylori surreptitiously subverts immune defenses to persist in the human gastric mucosa for decades. The chronic infection might result in clinically significant diseases in adults, such as peptic ulcer disease, gastric adenocarcinoma, and mucosa-associated lymphoid tissue lymphoma. This review compares the infection in children and adults and highlights the H. pylori virulence mechanisms responsible for the pathogenesis and immune evasion.
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Affiliation(s)
- Victor E. Reyes
- Department of Pediatrics, Department of Microbiology and Immunology, University of Texas Medical Branch, 301 University Blvd. Galveston, TX 77555-0372 USA
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28
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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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Abstract
Until recently, bacteria have been studied in terms of their roles in infectious diseases and mainly by using isolation and culture methods. However, in practice, many bacteria existing on the earth are difficult to isolate and culture, and thus only a limited number of them have been studied to date. On the other hand, in 2005, the next-generation sequencing technology became generally available, and since then genomic analysis of bacterial flora has become widespread. As a result, it has been revealed that the lower respiratory tract, which was previously thought to be sterile, in fact has bacterial flora (a microbiome) with a high level of biodiversity. In addition, it has been found that various diseases develop and worsen depending on the balance of the bacterial flora, and in recent years, a relationship has been established between various disorders. Recent research on cancer-associated microbial communities has elucidated the reciprocal interactions among bacteria, tumors and immune cells, the bacterial pathways associated with induction of oncogenesis, and their translational significance. Nevertheless, despite the increasing evidence showing that dysbiosis is associated with lung oncogenesis, the detailed mechanisms remain to be fully elucidated. Microorganisms seem to trigger tumor initiation and progression, presumably through the production of bacterio-toxins and other pro-inflammatory factors. The purpose of this review is to present a context for the basic mechanisms and molecular functions of the airway microbiome in oncogenesis, in an effort to prevent cancer by strategies utilizing the airway microbiota, as well as summarizing the mechanisms wherein the microbiome acts as a modulator of immunotherapies in lung cancer.
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30
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Abstract
Like most solid tumours, the microenvironment of epithelial-derived gastric adenocarcinoma (GAC) consists of a variety of stromal cell types, including fibroblasts, and neuronal, endothelial and immune cells. In this article, we review the role of the immune microenvironment in the progression of chronic inflammation to GAC, primarily the immune microenvironment driven by the gram-negative bacterial species Helicobacter pylori. The infection-driven nature of most GACs has renewed awareness of the immune microenvironment and its effect on tumour development and progression. About 75-90% of GACs are associated with prior H. pylori infection and 5-10% with Epstein-Barr virus infection. Although 50% of the world's population is infected with H. pylori, only 1-3% will progress to GAC, with progression the result of a combination of the H. pylori strain, host susceptibility and composition of the chronic inflammatory response. Other environmental risk factors include exposure to a high-salt diet and nitrates. Genetically, chromosome instability occurs in ~50% of GACs and 21% of GACs are microsatellite instability-high tumours. Here, we review the timeline and pathogenesis of the events triggered by H. pylori that can create an immunosuppressive microenvironment by modulating the host's innate and adaptive immune responses, and subsequently favour GAC development.
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31
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Guo K, Duan J, Lu J, Xiao L, Han L, Zeng S, Tang X, Li W, Huang L, Zhang Y. TNF-α-inducing protein of Helicobacter pylori promotes EMT and cancer stem-like cells properties via activation of Wnt/β-catenin signaling pathway in gastric cancer cells. Pathog Dis 2022; 80:6626024. [PMID: 35776950 DOI: 10.1093/femspd/ftac025] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 06/20/2022] [Accepted: 06/28/2022] [Indexed: 11/13/2022] Open
Abstract
Tumor necrosis factor-α-inducing protein (Tipα) is a newly identified toxin, which promotes the inflammation and carcinogenesis caused by Helicobacter pylori (H. pylori). However, its mechanism of pathogenesis is still unclear. To investigate the carcinogenic mechanisms of Tipα, SGC7901 cells and SGC7901-derived cancer stem-like cells (CSCs) were stimulated by recombinant Tipα protein with or without Wnt/β-catenin signaling inhibitor XAV939. qRT-PCR and Western blotting were employed to detect expression of epithelial-mesenchymal transition (EMT), CSCs markers, and downstream target genes of this signaling pathway. The cell migration ability was measured by wound healing assay and transwell assay. Our results indicated that Tipα promoted CSC properties of SGC7901 spheroids, including increased expression of CSC specific surface markers CD44, Oct4, Nanog, and an increased capacity for self-renewal. Tipα activated Wnt/β-catenin signaling in both SGC7901 cells or CSCs. Furthermore, Tipα induced the EMT and increased the expressions of downstream target genes of this signaling, including c-myc, cyclin D1, and CD44. However, XAV939 pretreatment inhibited Tipα-induced EMT and CSC properties in SGC7901 cells or CSCs. These results suggest that Tipα promotes EMT and CSC-like properties in gastric cancer cells through activation of Wnt/β-catenin signaling pathway, thereby accelerating the progression of gastric cancer.
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Affiliation(s)
- Kaiyun Guo
- Institute of Pathogenic Biology, Hengyang Medical College, University of South China; Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control; Hunan Province Innovative Training Base for Postgraduates, University of South China and Nanyue Biopharmaceutical Co. Ltd., Hengyang 421001, Hunan, China
| | - Jie Duan
- Institute of Pathogenic Biology, Hengyang Medical College, University of South China; Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control; Hunan Province Innovative Training Base for Postgraduates, University of South China and Nanyue Biopharmaceutical Co. Ltd., Hengyang 421001, Hunan, China
| | - Jingwen Lu
- Institute of Pathogenic Biology, Hengyang Medical College, University of South China; Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control; Hunan Province Innovative Training Base for Postgraduates, University of South China and Nanyue Biopharmaceutical Co. Ltd., Hengyang 421001, Hunan, China
| | - Lingqiao Xiao
- Institute of Pathogenic Biology, Hengyang Medical College, University of South China; Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control; Hunan Province Innovative Training Base for Postgraduates, University of South China and Nanyue Biopharmaceutical Co. Ltd., Hengyang 421001, Hunan, China
| | - Liang Han
- Institute of Pathogenic Biology, Hengyang Medical College, University of South China; Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control; Hunan Province Innovative Training Base for Postgraduates, University of South China and Nanyue Biopharmaceutical Co. Ltd., Hengyang 421001, Hunan, China
| | - Shasha Zeng
- Institute of Pathogenic Biology, Hengyang Medical College, University of South China; Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control; Hunan Province Innovative Training Base for Postgraduates, University of South China and Nanyue Biopharmaceutical Co. Ltd., Hengyang 421001, Hunan, China
| | - Xin Tang
- School of Nursing, University of South China, Hengyang 421001, Hunan, China
| | - Wenjing Li
- Institute of Pathogenic Biology, Hengyang Medical College, University of South China; Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control; Hunan Province Innovative Training Base for Postgraduates, University of South China and Nanyue Biopharmaceutical Co. Ltd., Hengyang 421001, Hunan, China
| | - Lijun Huang
- Institute of Pathogenic Biology, Hengyang Medical College, University of South China; Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control; Hunan Province Innovative Training Base for Postgraduates, University of South China and Nanyue Biopharmaceutical Co. Ltd., Hengyang 421001, Hunan, China
| | - Yan Zhang
- Institute of Pathogenic Biology, Hengyang Medical College, University of South China; Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control; Hunan Province Innovative Training Base for Postgraduates, University of South China and Nanyue Biopharmaceutical Co. Ltd., Hengyang 421001, Hunan, China
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32
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Noto JM, Piazuelo MB, Shah SC, Romero-Gallo J, Hart JL, Di C, Carmichael JD, Delgado AG, Halvorson AE, Greevy RA, Wroblewski LE, Sharma A, Newton AB, Allaman MM, Wilson KT, Washington MK, Calcutt MW, Schey KL, Cummings BP, Flynn CR, Zackular JP, Peek RM. Iron deficiency linked to altered bile acid metabolism promotes Helicobacter pylori-induced inflammation-driven gastric carcinogenesis. J Clin Invest 2022; 132:e147822. [PMID: 35316215 PMCID: PMC9106351 DOI: 10.1172/jci147822] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 03/16/2022] [Indexed: 12/24/2022] Open
Abstract
Gastric carcinogenesis is mediated by complex interactions among Helicobacter pylori, host, and environmental factors. Here, we demonstrate that H. pylori augmented gastric injury in INS-GAS mice under iron-deficient conditions. Mechanistically, these phenotypes were not driven by alterations in the gastric microbiota; however, discovery-based and targeted metabolomics revealed that bile acids were significantly altered in H. pylori-infected mice with iron deficiency, with significant upregulation of deoxycholic acid (DCA), a carcinogenic bile acid. The severity of gastric injury was further augmented when H. pylori-infected mice were treated with DCA, and, in vitro, DCA increased translocation of the H. pylori oncoprotein CagA into host cells. Conversely, bile acid sequestration attenuated H. pylori-induced injury under conditions of iron deficiency. To translate these findings to human populations, we evaluated the association between bile acid sequestrant use and gastric cancer risk in a large human cohort. Among 416,885 individuals, a significant dose-dependent reduction in risk was associated with cumulative bile acid sequestrant use. Further, expression of the bile acid receptor transmembrane G protein-coupled bile acid receptor 5 (TGR5) paralleled the severity of carcinogenic lesions in humans. These data demonstrate that increased H. pylori-induced injury within the context of iron deficiency is tightly linked to altered bile acid metabolism, which may promote gastric carcinogenesis.
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Affiliation(s)
- Jennifer M Noto
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - M Blanca Piazuelo
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Shailja C Shah
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Judith Romero-Gallo
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | | | - Chao Di
- Division of Protective Immunity, and
- Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - James D Carmichael
- Department of Biochemistry, Mass Spectrometry Research Center Laboratory, Vanderbilt University, Nashville, Tennessee, USA
| | - Alberto G Delgado
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Alese E Halvorson
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Robert A Greevy
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Lydia E Wroblewski
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Ayushi Sharma
- Creighton University School of Medicine, Omaha, Nebraska, USA
| | | | - Margaret M Allaman
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Keith T Wilson
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee, USA
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - M Kay Washington
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - M Wade Calcutt
- Department of Biochemistry, Mass Spectrometry Research Center Laboratory, Vanderbilt University, Nashville, Tennessee, USA
| | - Kevin L Schey
- Department of Biochemistry, Mass Spectrometry Research Center Laboratory, Vanderbilt University, Nashville, Tennessee, USA
| | - Bethany P Cummings
- Department of Surgery, University of California, Davis, Davis, California, USA
| | - Charles R Flynn
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Joseph P Zackular
- Division of Protective Immunity, and
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Richard M Peek
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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Prasad SK, Bhat S, Shashank D, C R A, R S, Rachtanapun P, Devegowda D, Santhekadur PK, Sommano SR. Bacteria-Mediated Oncogenesis and the Underlying Molecular Intricacies: What We Know So Far. Front Oncol 2022; 12:836004. [PMID: 35480118 PMCID: PMC9036991 DOI: 10.3389/fonc.2022.836004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 02/22/2022] [Indexed: 01/10/2023] Open
Abstract
Cancers are known to have multifactorial etiology. Certain bacteria and viruses are proven carcinogens. Lately, there has been in-depth research investigating carcinogenic capabilities of some bacteria. Reports indicate that chronic inflammation and harmful bacterial metabolites to be strong promoters of neoplasticity. Helicobacter pylori-induced gastric adenocarcinoma is the best illustration of the chronic inflammation paradigm of oncogenesis. Chronic inflammation, which produces excessive reactive oxygen species (ROS) is hypothesized to cause cancerous cell proliferation. Other possible bacteria-dependent mechanisms and virulence factors have also been suspected of playing a vital role in the bacteria-induced-cancer(s). Numerous attempts have been made to explore and establish the possible relationship between the two. With the growing concerns on anti-microbial resistance and over-dependence of mankind on antibiotics to treat bacterial infections, it must be deemed critical to understand and identify carcinogenic bacteria, to establish their role in causing cancer.
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Affiliation(s)
- Shashanka K Prasad
- Department of Biotechnology and Bioinformatics, Faculty of Life Sciences, Jagadguru Sri Shivarathreeshwara (JSS) Academy of Higher Education and Research (JSSAHER), Mysuru, India
| | - Smitha Bhat
- Department of Biotechnology and Bioinformatics, Faculty of Life Sciences, Jagadguru Sri Shivarathreeshwara (JSS) Academy of Higher Education and Research (JSSAHER), Mysuru, India
| | - Dharini Shashank
- Department of General Surgery, Adichunchanagiri Institute of Medical Sciences, Mandya, India
| | - Akshatha C R
- Department of Medical Oncology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
| | - Sindhu R
- Department of Microbiology, Faculty of Life Sciences, Jagadguru Sri Shivarathreeshwara (JSS) Academy of Higher Education and Research (JSSAHER), Mysuru, India
| | - Pornchai Rachtanapun
- School of Agro-Industry, Faculty of Agro-Industry, Chiang Mai University, Chiang Mai, Thailand
- Cluster of Agro Bio-Circular-Green Industry (Agro BCG), Chiang Mai University, Chiang Mai, Thailand
| | - Devananda Devegowda
- Centre of Excellence in Molecular Biology and Regenerative Medicine (CEMR), Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education and Research (JSSAHER), Mysuru, India
| | - Prasanna K Santhekadur
- Centre of Excellence in Molecular Biology and Regenerative Medicine (CEMR), Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education and Research (JSSAHER), Mysuru, India
| | - Sarana Rose Sommano
- Cluster of Agro Bio-Circular-Green Industry (Agro BCG), Chiang Mai University, Chiang Mai, Thailand
- Department of Plant and Soil Sciences, Faculty of Agriculture, Chiang Mai University, Chiang Mai, Thailand
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34
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Gobert AP, Wilson KT. Induction and Regulation of the Innate Immune Response in Helicobacter pylori Infection. Cell Mol Gastroenterol Hepatol 2022; 13:1347-1363. [PMID: 35124288 PMCID: PMC8933844 DOI: 10.1016/j.jcmgh.2022.01.022] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 01/25/2022] [Accepted: 01/25/2022] [Indexed: 12/30/2022]
Abstract
Gastric cancer (GC) is the fifth most common cancer and the fourth most common cause of cancer-related death worldwide. The intestinal type of GC progresses from acute to chronic gastritis, multifocal atrophic gastritis, intestinal metaplasia, dysplasia, and carcinoma. Infection of the stomach by Helicobacter pylori, a Gram-negative bacterium that infects approximately 50% of the world's population, is the causal determinant that initiates the gastric inflammation and then disease progression. In this context, the induction of the innate immune response of gastric epithelial cells and myeloid cells by H. pylori effectors plays a critical role in the outcome of the infection. However, only 1% to 3% of infected patients develop gastric adenocarcinoma, emphasizing that other mechanisms regulate the localized non-specific response, including the gastric microbiota and genetic factors. This review summarizes studies describing the factors that induce and regulate the mucosal innate immune response during H. pylori infection.
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Affiliation(s)
- Alain P Gobert
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Nashville, Tennessee; Center for Mucosal Inflammation and Cancer, Nashville, Tennessee; Program in Cancer Biology, Nashville, Tennessee.
| | - Keith T Wilson
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Nashville, Tennessee; Center for Mucosal Inflammation and Cancer, Nashville, Tennessee; Program in Cancer Biology, Nashville, Tennessee; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee; Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee.
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Abstract
The intimate involvement of pathogens with the heightened risk for developing certain cancers is an area of research that has captured a great deal of attention over the last 10 years. One firmly established paradigm that highlights this aspect of disease progression is in the instance of Helicobacter pylori infection and the contribution it makes in elevating the risk for developing gastric cancer. Whilst the molecular mechanisms that pinpoint the contribution that this microorganism inflicts towards host cells during gastric cancer initiation have come into greater focus, another picture that has also emerged is one that implicates the host's immune system, and the chronic inflammation that can arise therefrom, as being a central contributory factor in disease progression. Consequently, when taken with the underlying role that the extracellular matrix plays in the development of most cancers, and how this dynamic can be modulated by proteases expressed from the tumor or inflammatory cells, a complex and detailed relationship shared between the individual cellular components and their surroundings is coming into focus. In this review article, we draw attention to the emerging role played by the cathepsin proteases in modulating the stage-specific progression of Helicobacter pylori-initiated gastric cancer and the underlying immune response, while highlighting the therapeutic significance of this dynamic and how it may be amenable for novel intervention strategies within a basic research or clinical setting.
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López-Gómez M, García de Santiago B, Delgado-López PD, Malmierca E, González-Olmedo J, Gómez-Raposo C, Sandoval C, Ruiz-Seco P, Escribano N, Gómez-Cerezo JF, Casado E. Gastrointestinal tumors and infectious agents: A wide field to explore. World J Meta-Anal 2021; 9:505-521. [DOI: 10.13105/wjma.v9.i6.505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 08/26/2021] [Accepted: 12/23/2021] [Indexed: 02/06/2023] Open
Abstract
Infection is currently one of the main contributors to carcinogenesis. In fact, the International Agency for Research on Cancer has categorized eleven biological agents as group I carcinogens. It is estimated that around 16% of the 12.7 million new cancers diagnosed in 2008 were attributable to infectious agents. Although underdeveloped regions carry the highest incidence rates, about 7.4% of infection-related cancer cases occur in developed areas. Physicians are increasingly aware of the potential carcinogenic role of common virus like the Human Papilloma virus in cervical cancer, or the hepatitis B and C viruses in hepatocarcinoma. However, the carcinogenic role of several other infectious agents is less recognized. Given that gastrointestinal malignancies carry an overall poor prognosis, a better understanding of the carcinogenic mechanisms triggered by infectious agents is key to decrease the rate of cancer related deaths. Preventive measures directed to such infections would ideally impact survival. In this paper we review the main pathogenic mechanisms related to the development of gastrointestinal malignancies induced by infectious microorganisms and other pathogens which are currently under investigation.
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Affiliation(s)
- Miriam López-Gómez
- Medical Oncology Department. Precision Oncology Laboratory, Infanta Sofía University Hospital, San Sebastián de los Reyes 28231, Madrid, Spain
| | - Belén García de Santiago
- Pharmacy Department, Infanta Sofia University Hospital, San Sebastián de los Reyes 28703, Madrid, Spain
| | | | - Eduardo Malmierca
- Internal Medicine Department, Infanta Sofía University Hospital, San Sebastián de los Reyes 28703, Madrid, Spain
| | - Jesús González-Olmedo
- Medical Oncology Department, Infanta Sofia University Hospital, San Sebastián de los Reyes 28703, Madrid, Spain
| | - César Gómez-Raposo
- Medical Oncology Department, Infanta Sofia University Hospital, San Sebastián de los Reyes 28703, Madrid, Spain
| | - Carmen Sandoval
- Medical Oncology Department, Infanta Sofia University Hospital, San Sebastián de los Reyes 28703, Madrid, Spain
| | - Pilar Ruiz-Seco
- Internal Medicine Department, Infanta Sofía University Hospital, San Sebastián de los Reyes 28703, Madrid, Spain
| | - Nora Escribano
- Intensive Care Unit, Jiménez Díaz Foundation, Madrid 28040, Madrid, Spain
| | - Jorge Francisco Gómez-Cerezo
- Internal Medicine Department, Infanta Sofía University Hospital, San Sebastián de los Reyes 28703, Madrid, Spain
| | - Enrique Casado
- Medical Oncology Department, Infanta Sofia University Hospital, San Sebastián de los Reyes 28703, Madrid, Spain
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Li F, Zhu H, Tao K, Xia Y, Liu M, Wang Y, Sun Y, Cao T, Chai J, Ni F, Shi B, Xu H. Mucosal microbial microenvironment in early gastric neoplasia and non-neoplastic gastric disease. J Gastroenterol Hepatol 2021; 36:3092-3101. [PMID: 34089623 DOI: 10.1111/jgh.15565] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/31/2021] [Accepted: 06/02/2021] [Indexed: 01/06/2023]
Abstract
BACKGROUND AND AIM The biological characterization of microbial environment in early gastric cancer (EGC), other than Helicobacter pylori, is limited. This study aimed to explore the microbial microenvironment in chronic gastritis (CG), fundic gland polyps (FGPs), low-grade intraepithelial neoplasia (LGIN), and EGC. METHODS 16S-rRNA gene sequencing and bioinformatic analysis were performed on 63 individuals with 252 mucosal biopsies or endoscopic submucosal dissection margin samples from endoscopy. RESULTS The microbiota in gastric LGIN functions analogously to EGC in terms of functional prediction. Neoplastic lesions showed a significant difference to CG or FGPs in beta diversity of the microbiota. Bacteria genera including Paracoccus, Blautia, Barnesiella, Lactobacillus, Thauera, Collinsella were significantly enriched in gastric neoplastic mucosa (LGIN and EGC) compared with non-neoplastic tissues (CG and FGPs). While Pseudomonas and Kingella were depleted in neoplastic tissues. FGPs showed a distinctive microbial network system that negatively interacted with Helicobacter. CONCLUSIONS In terms of the mucosal microbial microenvironment, gastric LGIN and EGC showed no significant difference as early neoplastic lesions. We observed a coordinated microbial microenvironment that correlated negatively with Helicobacter.
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Affiliation(s)
- Fudong Li
- Department of Gastroenterology and Endoscopy Center, The First Hospital of Jilin University, Changchun, China
| | - He Zhu
- Department of Gastroenterology and Endoscopy Center, The First Hospital of Jilin University, Changchun, China
| | - Ke Tao
- Department of Gastroenterology and Endoscopy Center, The First Hospital of Jilin University, Changchun, China
| | - Yan Xia
- Department of Gastroenterology and Endoscopy Center, The First Hospital of Jilin University, Changchun, China
| | - Mingqing Liu
- Department of Gastroenterology and Endoscopy Center, The First Hospital of Jilin University, Changchun, China
| | - Yu Wang
- Department of Gastroenterology and Endoscopy Center, The First Hospital of Jilin University, Changchun, China
| | - Yu Sun
- Department of Gastroenterology and Endoscopy Center, The First Hospital of Jilin University, Changchun, China
| | - Tingting Cao
- Department of Gastroenterology and Endoscopy Center, The First Hospital of Jilin University, Changchun, China
| | - Jiannan Chai
- Department of Clinical Laboratory, The First Hospital of Jilin University, Changchun, China
| | - Fengming Ni
- Department of Gastroenterology and Endoscopy Center, The First Hospital of Jilin University, Changchun, China
| | - Bing Shi
- Department of Gastroenterology and Endoscopy Center, The First Hospital of Jilin University, Changchun, China
| | - Hong Xu
- Department of Gastroenterology and Endoscopy Center, The First Hospital of Jilin University, Changchun, China
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Diechler S, Chichirau BE, Posselt G, Sgouras DN, Wessler S. Helicobacter pylori CagA EPIYA Motif Variations Affect Metabolic Activity in B Cells. Toxins (Basel) 2021; 13:toxins13090592. [PMID: 34564597 PMCID: PMC8473296 DOI: 10.3390/toxins13090592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 08/21/2021] [Accepted: 08/22/2021] [Indexed: 11/18/2022] Open
Abstract
Background: Helicobacter pylori (Hp) colonizes the human stomach and can induce gastric cancer and mucosa-associated lymphoid tissue (MALT) lymphoma. Clinical observations suggest a role for the Hp virulence factor cytotoxin-associated gene A (CagA) in pathogenesis. The pathogenic activity of CagA is partly regulated by tyrosine phosphorylation of C-terminal Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs in host cells. However, CagA differs considerably in EPIYA motifs, whose functions have been well characterized in epithelial cells. Since CagA is fragmented in immune cells, different CagA variants may exhibit undetected functions in B cells. Methods: B cells were infected with Hp isolates and isogenic mutants expressing different CagA EPIYA variants. CagA translocation and tyrosine phosphorylation were investigated by Western blotting. Apoptosis was analyzed by flow cytometry and metabolic activity was detected by an MTT assay. Results: Isogenic CagA EPIYA variants are equally well translocated into B cells, followed by tyrosine phosphorylation and cleavage. B cell apoptosis was induced in a CagA-independent manner. However, variants containing at least one EPIYA-C motif affected metabolic activity independently of phosphorylation or multiplication of EPIYA-C motifs. Conclusions: The diverse structure of CagA regulates B cell physiology, whereas B cell survival is independent of CagA.
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Affiliation(s)
- Sebastian Diechler
- Division of Microbiology, Department of Biosciences, Paris-Lodron University of Salzburg, 5020 Salzburg, Austria; (S.D.); (B.E.C.); (G.P.)
| | - Bianca E. Chichirau
- Division of Microbiology, Department of Biosciences, Paris-Lodron University of Salzburg, 5020 Salzburg, Austria; (S.D.); (B.E.C.); (G.P.)
| | - Gernot Posselt
- Division of Microbiology, Department of Biosciences, Paris-Lodron University of Salzburg, 5020 Salzburg, Austria; (S.D.); (B.E.C.); (G.P.)
| | - Dionyssios N. Sgouras
- Laboratory of Medical Microbiology, Hellenic Pasteur Institute, 127 Vas. Sofias Avenue, 115 21 Athens, Greece;
| | - Silja Wessler
- Division of Microbiology, Department of Biosciences, Paris-Lodron University of Salzburg, 5020 Salzburg, Austria; (S.D.); (B.E.C.); (G.P.)
- Cancer Cluster Salzburg, Allergy-Cancer-BioNano Research Centre, Paris-Lodron University of Salzburg, 5020 Salzburg, Austria
- Correspondence: ; Tel.: +43-662-8044-7210
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Helicobacter pylori CagA Induces Cortactin Y-470 Phosphorylation-Dependent Gastric Epithelial Cell Scattering via Abl, Vav2 and Rac1 Activation. Cancers (Basel) 2021; 13:cancers13164241. [PMID: 34439396 PMCID: PMC8391897 DOI: 10.3390/cancers13164241] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 08/10/2021] [Accepted: 08/15/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Various microbial pathogens target the actin-binding protein cortactin to promote their own uptake, proliferation and spread, and exhibit proposed roles in human cancerogenesis. We aimed to study the molecular mechanisms of how the gastric pathogen Helicobacter pylori hijacks cortactin phosphorylation via tyrosine kinase Abl to trigger cancer-related signal transduction events. We discovered that cortactin phosphorylated at Y-470 recruits the signaling factor Vav2 to activate the small Rho GTPase Rac1, and finally, a cancer cell motility phenotype. We also demonstrate that phosphorylation of cortactin at Y-470 can be completely inhibited by the well-known Abl inhibitor imatinib. Imatinib is an established oral chemotherapy medication, employed for efficient systemic treatment of various cancers. These results reveal a comprehensive novel pathway for how precisely H. pylori manipulates host signaling in gastric disease development, and may pave the way for new opportunities of treatment of the outcome of infections with this pathogen, i.e., through using imatinib. Abstract The pathogen Helicobacter pylori is the first reported bacterial type-1 carcinogen playing a role in the development of human malignancies, including gastric adenocarcinoma. Cancer cell motility is an important process in this scenario, however, the molecular mechanisms are still not fully understood. Here, we demonstrate that H. pylori subverts the actin-binding protein cortactin through its type-IV secretion system and injected oncoprotein CagA, e.g., by inducing tyrosine phosphorylation of cortactin at Y-470, which triggers gastric epithelial cell scattering and motility. During infection of AGS cells, cortactin was discovered to undergo tyrosine dephosphorylation at residues Y-421 and Y-486, which is mediated through inactivation of Src kinase. However, H. pylori also profoundly activates tyrosine kinase Abl, which simultaneously phosphorylates cortactin at Y-470. Phosphorylated cortactin interacts with the SH2-domain of Vav2, a guanine nucleotide exchange factor for the Rho-family of GTPases. The cortactin/Vav2 complex then stimulates a previously unrecognized activation cascade including the small GTPase Rac1, to effect actin rearrangements and cell scattering. We hypothesize that injected CagA targets cortactin to locally open the gastric epithelium in order to get access to certain nutrients. This may disturb the cellular barrier functions, likely contributing to the induction of cell motility, which is important in gastric cancer development.
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Taxauer K, Hamway Y, Ralser A, Dietl A, Mink K, Vieth M, Singer BB, Gerhard M, Mejías-Luque R. Engagement of CEACAM1 by Helicobacterpylori HopQ Is Important for the Activation of Non-Canonical NF-κB in Gastric Epithelial Cells. Microorganisms 2021; 9:1748. [PMID: 34442827 PMCID: PMC8400456 DOI: 10.3390/microorganisms9081748] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 08/04/2021] [Accepted: 08/10/2021] [Indexed: 01/01/2023] Open
Abstract
The gastric pathogen Helicobacter pylori infects half of the world's population and is a major risk factor for gastric cancer development. In order to attach to human gastric epithelial cells and inject the oncoprotein CagA into host cells, H. pylori utilizes the outer membrane protein HopQ that binds to the cell surface protein CEACAM, which can be expressed on the gastric mucosa. Once bound, H. pylori activates a number of signaling pathways, including canonical and non-canonical NF-κB. We investigated whether HopQ-CEACAM interaction is involved in activating the non-canonical NF-κB signaling pathway. Different gastric cancer cells were infected with the H. pylori wild type, or HopQ mutant strains, and the activation of non-canonical NF-κB was related to CEACAM expression levels. The correlation between CEACAM levels and the activation of non-canonical NF-κB was confirmed in human gastric tissue samples. Taken together, our findings show that the HopQ-CEACAM interaction is important for activation of the non-canonical NF-κB pathway in gastric epithelial cells.
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Affiliation(s)
- Karin Taxauer
- Institute for Medical Microbiology, Immunology and Hygiene, Technical University Munich, 81675 Munich, Germany; (K.T.); (Y.H.); (A.R.); (A.D.); (K.M.); (M.G.)
| | - Youssef Hamway
- Institute for Medical Microbiology, Immunology and Hygiene, Technical University Munich, 81675 Munich, Germany; (K.T.); (Y.H.); (A.R.); (A.D.); (K.M.); (M.G.)
| | - Anna Ralser
- Institute for Medical Microbiology, Immunology and Hygiene, Technical University Munich, 81675 Munich, Germany; (K.T.); (Y.H.); (A.R.); (A.D.); (K.M.); (M.G.)
| | - Alisa Dietl
- Institute for Medical Microbiology, Immunology and Hygiene, Technical University Munich, 81675 Munich, Germany; (K.T.); (Y.H.); (A.R.); (A.D.); (K.M.); (M.G.)
| | - Karin Mink
- Institute for Medical Microbiology, Immunology and Hygiene, Technical University Munich, 81675 Munich, Germany; (K.T.); (Y.H.); (A.R.); (A.D.); (K.M.); (M.G.)
| | - Michael Vieth
- Institute of Pathology, Friedrich-Alexander University Erlangen-Nuremberg, Klinikum Bayreuth, 95445 Bayreuth, Germany;
| | - Bernhard B. Singer
- Institute of Anatomy, Medical Faculty, University of Duisburg-Essen, 45147 Essen, Germany;
| | - Markus Gerhard
- Institute for Medical Microbiology, Immunology and Hygiene, Technical University Munich, 81675 Munich, Germany; (K.T.); (Y.H.); (A.R.); (A.D.); (K.M.); (M.G.)
| | - Raquel Mejías-Luque
- Institute for Medical Microbiology, Immunology and Hygiene, Technical University Munich, 81675 Munich, Germany; (K.T.); (Y.H.); (A.R.); (A.D.); (K.M.); (M.G.)
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Sharafutdinov I, Backert S, Tegtmeyer N. The Helicobacter pylori type IV secretion system upregulates epithelial cortactin expression by a CagA- and JNK-dependent pathway. Cell Microbiol 2021; 23:e13376. [PMID: 34197673 DOI: 10.1111/cmi.13376] [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: 04/03/2021] [Revised: 06/18/2021] [Accepted: 06/28/2021] [Indexed: 12/11/2022]
Abstract
Cortactin represents an important actin-binding factor, which controls actin-cytoskeletal remodelling in host cells. In this way, cortactin has been shown to exhibit crucial functions both for cell movement and tumour cell invasion. In addition, the cortactin gene cttn is amplified in various cancer types of humans. Helicobacter pylori is the causative agent of multiple gastric diseases and represents a significant risk factor for the development of gastric adenocarcinoma. It has been repeatedly shown that H. pylori manipulates cancer-related signal transduction events in infected gastric epithelial cells such as the phosphorylation status of cortactin. In fact, H. pylori modifies the activity of cortactin's binding partners to stimulate changes in the actin-cytoskeleton, cell adhesion and motility. Here we show that H. pylori infection of cultured AGS and Caco-2 cells for 24-48 hr leads to the overexpression of cortactin by 2-3 fold at the protein level. We demonstrate that this activity requires the integrity of the type IV secretion system (T4SS) encoded by the cag pathogenicity island (cagPAI) as well as the translocated effector protein CagA. We further show that ectopic expression of CagA is sufficient to stimulate cortactin overexpression. Furthermore, phosphorylation of CagA at the EPIYA-repeat region is not required, suggesting that this CagA activity proceeds in a phosphorylation-independent fashion. Inhibitor studies further demonstrate that the involved signalling pathway comprises the mitogen-activated protein kinase JNK (c-Jun N-terminal kinase), but not ERK1/2 or p38. Taken together, using H. pylori as a model system, this study discovered a previously unrecognised cortactin activation cascade by a microbial pathogen. We suggest that H. pylori targets cortactin to manipulate the cellular architecture and epithelial barrier functions that can impact gastric cancer development. TAKE AWAYS: Helicobacter pylori infection induces overexpression of cortactin at the protein level Cortactin upregulation requires the T4SS and effector protein CagA Ectopic expression of CagA is sufficient to stimulate cortactin overexpression Overexpression of cortactin proceeds CagA phosphorylation-independent The involved host cell signalling pathway comprises the MAP kinase JNK.
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Affiliation(s)
- Irshad Sharafutdinov
- Department of Biology, Division of Microbiology, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, 91058, Germany
| | - Steffen Backert
- Department of Biology, Division of Microbiology, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, 91058, Germany
| | - Nicole Tegtmeyer
- Department of Biology, Division of Microbiology, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, 91058, Germany
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Knorr J, Sharafutdinov I, Fiedler F, Soltan Esmaeili D, Rohde M, Rottner K, Backert S, Tegtmeyer N. Cortactin Is Required for Efficient FAK, Src and Abl Tyrosine Kinase Activation and Phosphorylation of Helicobacter pylori CagA. Int J Mol Sci 2021; 22:ijms22116045. [PMID: 34205064 PMCID: PMC8199859 DOI: 10.3390/ijms22116045] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 05/28/2021] [Accepted: 06/01/2021] [Indexed: 12/11/2022] Open
Abstract
Cortactin is a well-known regulatory protein of the host actin cytoskeleton and represents an attractive target of microbial pathogens like Helicobacter pylori. H. pylori manipulates cortactin's phosphorylation status by type-IV secretion-dependent injection of its virulence protein CagA. Multiple host tyrosine kinases, like FAK, Src, and Abl, are activated during infection, but the pathway(s) involved is (are) not yet fully established. Among them, Src and Abl target CagA and stimulate tyrosine phosphorylation of the latter at its EPIYA-motifs. To investigate the role of cortactin in more detail, we generated a CRISPR/Cas9 knockout of cortactin in AGS gastric epithelial cells. Surprisingly, we found that FAK, Src, and Abl kinase activities were dramatically downregulated associated with widely diminished CagA phosphorylation in cortactin knockout cells compared to the parental control. Together, we report here a yet unrecognized cortactin-dependent signaling pathway involving FAK, Src, and Abl activation, and controlling efficient phosphorylation of injected CagA during infection. Thus, the cortactin status could serve as a potential new biomarker of gastric cancer development.
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Affiliation(s)
- Jakob Knorr
- Department of Biology, Division of Microbiology, Friedrich-Alexander University of Erlangen-Nuremberg, 91058 Erlangen, Germany; (J.K.); (I.S.); (F.F.); (D.S.E.); (S.B.)
| | - Irshad Sharafutdinov
- Department of Biology, Division of Microbiology, Friedrich-Alexander University of Erlangen-Nuremberg, 91058 Erlangen, Germany; (J.K.); (I.S.); (F.F.); (D.S.E.); (S.B.)
| | - Florian Fiedler
- Department of Biology, Division of Microbiology, Friedrich-Alexander University of Erlangen-Nuremberg, 91058 Erlangen, Germany; (J.K.); (I.S.); (F.F.); (D.S.E.); (S.B.)
| | - Delara Soltan Esmaeili
- Department of Biology, Division of Microbiology, Friedrich-Alexander University of Erlangen-Nuremberg, 91058 Erlangen, Germany; (J.K.); (I.S.); (F.F.); (D.S.E.); (S.B.)
| | - Manfred Rohde
- Central Facility for Microscopy, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany;
| | - Klemens Rottner
- Department of Cell Biology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany;
- Division of Molecular Cell Biology, Zoological Institute, Technische Universität Braunschweig, 38106 Braunschweig, Germany
| | - Steffen Backert
- Department of Biology, Division of Microbiology, Friedrich-Alexander University of Erlangen-Nuremberg, 91058 Erlangen, Germany; (J.K.); (I.S.); (F.F.); (D.S.E.); (S.B.)
| | - Nicole Tegtmeyer
- Department of Biology, Division of Microbiology, Friedrich-Alexander University of Erlangen-Nuremberg, 91058 Erlangen, Germany; (J.K.); (I.S.); (F.F.); (D.S.E.); (S.B.)
- Correspondence:
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Shen X, Zhang W, Peng C, Yan J, Chen P, Jiang C, Yuan Y, Chen D, Zhu W, Yao M. In vitro anti-bacterial activity and network pharmacology analysis of Sanguisorba officinalis L. against Helicobacter pylori infection. Chin Med 2021; 16:33. [PMID: 33865425 PMCID: PMC8052767 DOI: 10.1186/s13020-021-00442-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 04/08/2021] [Indexed: 12/11/2022] Open
Abstract
Background Helicobacter pylori (H. pylori) infection has become an international public health problem, and antibiotic-based triple or quadruple therapy is currently the mainstay of treatment. However, the effectiveness of these therapies decreases due to resistance to multiple commonly used antibiotics. Sanguisorba officinalis L. (S. officinalis), a traditional Chinese medicine clinically used for hemostasis and treatment of diarrhea, has various pharmacological activities. In this study, in vitro antimicrobial activity was used for the preliminary evaluation of S. officinalis against H. pylori. And a pharmacology analysis approach was also utilized to elucidate its underlying mechanisms against H. pylori infection. Methods Micro-broth dilution method, agar dilution method, checkerboard assay, scanning electron microscopy (SEM), and transmission electron microscopy (TEM) were used for the assessment of anti-bacterial activity. Active ingredients screening, GO analysis, KEGG analysis, construction of PPI network, molecular docking, and RT-qPCR were used to elucidate the underlying pharmacological mechanisms of S. officinalis against H. pylori infection. Results The minimum inhibitory concentration (MIC) values of S. officinalis against multiple H. pylori strains including clinically isolated multi-drug resistant (MDR) strains were ranging from 160 to 320 µg/ml. These results showed that S. officinalis had additive interaction with four commonly used antibiotics and could exert antibacterial effect by changing the morphology of bacteria without developing drug resistance. Through network pharmacology analysis, 8 active ingredients in S. officinalis were screened out for subsequent studies. Among 222 putative targets of S. officinalis, 49 targets were identified as potential targets for treatment of H. pylori infection. And these 49 targets were significantly enriched in GO processes such as protein kinase B signaling, protein kinase activity, protein kinase binding, and KEGG pathways such as Pathways in cancer, MicroRNAs in cancer, and TNF signaling pathway. Protein-protein interaction analysis yielded 5 core targets (AKT1, VEGFA, EGFR, SRC, CCND1), which were validated by molecular docking and RT-qPCR. Conclusions Overall, this study confirmed the in vitro inhibitory activity of S. officinalis against H. pylori and explored the possible pharmacological mechanisms, laying the foundation for further research and clinical application. Supplementary Information The online version contains supplementary material available at 10.1186/s13020-021-00442-1.
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Affiliation(s)
- Xue Shen
- School of Pharmaceutical Science, Sun Yat-Sen University, Guangzhou, 510006, China
| | - Weijia Zhang
- School of Pharmaceutical Science, Sun Yat-Sen University, Guangzhou, 510006, China
| | - Chang Peng
- School of Pharmaceutical Science (Shenzhen), Sun Yat-Sen University, Guangzhou, 510006, China
| | - Jiahui Yan
- School of Pharmaceutical Science, Sun Yat-Sen University, Guangzhou, 510006, China
| | - Pengting Chen
- School of Pharmaceutical Science, Sun Yat-Sen University, Guangzhou, 510006, China
| | - Cheng Jiang
- School of Pharmaceutical Science (Shenzhen), Sun Yat-Sen University, Guangzhou, 510006, China
| | - Yuemei Yuan
- School of Ecology, Sun Yat-Sen University, Guangzhou, 510006, China
| | - Donglian Chen
- Qingyuan Hospital of Traditional Chinese Medicine, Qingyuan, 511500, China
| | - Weixing Zhu
- Qingyuan Hospital of Traditional Chinese Medicine, Qingyuan, 511500, China.
| | - Meicun Yao
- School of Pharmaceutical Science (Shenzhen), Sun Yat-Sen University, Guangzhou, 510006, China.
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Palrasu M, Zaika E, El-Rifai W, Que J, Zaika AI. Role of Bacterial and Viral Pathogens in Gastric Carcinogenesis. Cancers (Basel) 2021; 13:1878. [PMID: 33919876 PMCID: PMC8070847 DOI: 10.3390/cancers13081878] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 04/02/2021] [Accepted: 04/11/2021] [Indexed: 01/10/2023] Open
Abstract
Gastric cancer (GC) is one of the deadliest malignancies worldwide. In contrast to many other tumor types, gastric carcinogenesis is tightly linked to infectious events. Infections with Helicobacter pylori (H. pylori) bacterium and Epstein-Barr virus (EBV) are the two most investigated risk factors for GC. These pathogens infect more than half of the world's population. Fortunately, only a small fraction of infected individuals develops GC, suggesting high complexity of tumorigenic processes in the human stomach. Recent studies suggest that the multifaceted interplay between microbial, environmental, and host genetic factors underlies gastric tumorigenesis. Many aspects of these interactions still remain unclear. In this review, we update on recent discoveries, focusing on the roles of various gastric pathogens and gastric microbiome in tumorigenesis.
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Affiliation(s)
- Manikandan Palrasu
- Department of Surgery, University of Miami, Miami, FL 33136, USA; (M.P.); (E.Z.); (W.E.-R.)
| | - Elena Zaika
- Department of Surgery, University of Miami, Miami, FL 33136, USA; (M.P.); (E.Z.); (W.E.-R.)
| | - Wael El-Rifai
- Department of Surgery, University of Miami, Miami, FL 33136, USA; (M.P.); (E.Z.); (W.E.-R.)
- Department of Veterans Affairs, Miami VA Healthcare System, Miami, FL 33136, USA
| | - Jianwen Que
- Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA;
| | - Alexander I. Zaika
- Department of Surgery, University of Miami, Miami, FL 33136, USA; (M.P.); (E.Z.); (W.E.-R.)
- Department of Veterans Affairs, Miami VA Healthcare System, Miami, FL 33136, USA
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A bacterial small RNA regulates the adaptation of Helicobacter pylori to the host environment. Nat Commun 2021; 12:2085. [PMID: 33837194 PMCID: PMC8035401 DOI: 10.1038/s41467-021-22317-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Accepted: 03/10/2021] [Indexed: 12/15/2022] Open
Abstract
Long-term infection of the stomach with Helicobacter pylori can cause gastric cancer. However, the mechanisms by which the bacteria adapt to the stomach environment are poorly understood. Here, we show that a small non-coding RNA of H. pylori (HPnc4160, also known as IsoB or NikS) regulates the pathogen’s adaptation to the host environment as well as bacterial oncoprotein production. In a rodent model of H. pylori infection, the genomes of bacteria isolated from the stomach possess an increased number of T-repeats upstream of the HPnc4160-coding region, and this leads to reduced HPnc4160 expression. We use RNA-seq and iTRAQ analyses to identify eight targets of HPnc4160, including genes encoding outer membrane proteins and oncoprotein CagA. Mutant strains with HPnc4160 deficiency display increased colonization ability of the mouse stomach, in comparison with the wild-type strain. Furthermore, HPnc4160 expression is lower in clinical isolates from gastric cancer patients than in isolates derived from non-cancer patients, while the expression of HPnc4160’s targets is higher in the isolates from gastric cancer patients. Therefore, the small RNA HPnc4160 regulates H. pylori adaptation to the host environment and, potentially, gastric carcinogenesis. Long-term infection of the stomach with Helicobacter pylori can cause gastric cancer. Here, Kinoshita-Daitoku et al. show that a small non-coding RNA of H. pylori regulates bacterial adaptation to the stomach environment and bacterial oncoprotein production.
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Tong Y, Gao H, Qi Q, Liu X, Li J, Gao J, Li P, Wang Y, Du L, Wang C. High fat diet, gut microbiome and gastrointestinal cancer. Theranostics 2021; 11:5889-5910. [PMID: 33897888 PMCID: PMC8058730 DOI: 10.7150/thno.56157] [Citation(s) in RCA: 100] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 03/09/2021] [Indexed: 12/12/2022] Open
Abstract
Gastrointestinal cancer is currently one of the main causes of cancer death, with a large number of cases and a wide range of lesioned sites. A high fat diet, as a public health problem, has been shown to be correlated with various digestive system diseases and tumors, and can accelerate the occurrence of cancer due to inflammation and altered metabolism. The gut microbiome has been the focus of research in recent years, and associated with cell damage or tumor immune microenvironment changes via direct or extra-intestinal effects; this may facilitate the occurrence and development of gastrointestinal tumors. Based on research showing that both a high fat diet and gut microbes can promote the occurrence of gastrointestinal tumors, and that a high fat diet imbalances intestinal microbes, we propose that a high fat diet drives gastrointestinal tumors by changing the composition of intestinal microbes.
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Affiliation(s)
- Yao Tong
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Huiru Gao
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Qiuchen Qi
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Xiaoyan Liu
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Juan Li
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Jie Gao
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Peilong Li
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Yunshan Wang
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Lutao Du
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Chuanxin Wang
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
- Shandong Engineering & Technology Research Center for Tumor Marker Detection, Jinan, Shandong, China
- Shandong Provincial Clinical Medicine Research Center for Clinical Laboratory, Jinan, Shandong, China
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Tagoe EA, Awandare GA, Quaye O, Asmah RH, Archampong TN, Osman MA, Brown CA. Helicobacter Pylori Variants with ABC-Type Tyrosine Phosphorylation Motif in Gastric Biopsies of Ghanaian Patients. BIOMED RESEARCH INTERNATIONAL 2021; 2021:6616059. [PMID: 33860041 PMCID: PMC8026283 DOI: 10.1155/2021/6616059] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 03/17/2021] [Accepted: 03/22/2021] [Indexed: 11/17/2022]
Abstract
BACKGROUND Helicobacter pylori pathogenicity and disease severity are determined by the tyrosine phosphorylation motifs of CagA protein. This study is aimed at detecting the presence of H. pylori and identifying the CagA tyrosine phosphorylation motifs in Ghanaian patients. Material and Methods. A total of 94 archival genomic DNA samples from gastric biopsies were used for the study, and H. pylori was detected by amplifying the 16S rRNA gene. The 3'-end variable region of the cagA gene was amplified, and the entire 3'-end was sequenced and translated into amino acids. RESULTS H. pylori was detected in 53.2% (50/94) of the samples, and all the detected bacteria harboured the cagA gene. Two variants of the bacteria were identified based on the size of the amplified cagA gene: 207 bp and 285 bp. The 207 bp and 285 bp variants accounted for 74% and 22%, respectively, and 4% showed both fragments. Translated amino acid sequence of the cagA gene showed EPIYA-A, EPIYA-B, and EPIYA-C (ABC type) motifs, indicating the Western variant. The CagA protein C-terminal showed insertion of amino acids in the sequence flanking the EPIYA-A motif at the N-terminal and a complete deletion of the EPIYA-CC and EPIYA-CCC motifs together with the flanking sequences. CONCLUSIONS H. pylori identified were Western variant (ABC type) with unique amino acid insertions, suggesting unique variants in Ghanaian patients. Further investigation is however required to understand the role of the molecular diversity of the variant in gastric disease outcome.
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Affiliation(s)
- Emmanuel A. Tagoe
- West African Centre for Cell Biology of Infectious Pathogens (WACCBIP)/Department of Biochemistry, Cell and Molecular Biology, University of Ghana, Legon, Accra, Ghana
- Department of Medical Laboratory Sciences, University of Ghana, Korle Bu, Accra, Ghana
| | - Gordon A. Awandare
- West African Centre for Cell Biology of Infectious Pathogens (WACCBIP)/Department of Biochemistry, Cell and Molecular Biology, University of Ghana, Legon, Accra, Ghana
| | - Osbourne Quaye
- West African Centre for Cell Biology of Infectious Pathogens (WACCBIP)/Department of Biochemistry, Cell and Molecular Biology, University of Ghana, Legon, Accra, Ghana
| | - Richard H. Asmah
- Department of Medical Laboratory Sciences, University of Ghana, Korle Bu, Accra, Ghana
- Department of Biomedical Sciences, School of Basic and Biomedical Sciences, University of Allied Health Sciences, Ho, Ghana
| | - Timothy N. Archampong
- Department of Medicine, University of Ghana Medical School, University of Ghana, Korle Bu, Accra, Ghana
| | - Mahasin A. Osman
- Departments of Medicine, College of Medicine and Life Sciences, University of Toledo, OH 34614, USA
| | - Charles A. Brown
- Department of Medical Laboratory Sciences, University of Ghana, Korle Bu, Accra, Ghana
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Gastric Cancer: Advances in Carcinogenesis Research and New Therapeutic Strategies. Int J Mol Sci 2021; 22:ijms22073418. [PMID: 33810350 PMCID: PMC8037554 DOI: 10.3390/ijms22073418] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 03/17/2021] [Accepted: 03/22/2021] [Indexed: 12/16/2022] Open
Abstract
Gastric cancer’s bad incidence, prognosis, cellular and molecular heterogeneity amongst others make this disease a major health issue worldwide. Understanding this affliction is a priority for proper patients’ management and for the development of efficient therapeutical strategies. This review gives an overview of major scientific advances, made during the past 5-years, to improve the comprehension of gastric adenocarcinoma. A focus was made on the different actors of gastric carcinogenesis, including, Helicobacter pylori cancer stem cells, tumour microenvironment and microbiota. New and recent potential biomarkers were assessed as well as emerging therapeutical strategies involving cancer stem cells targeting as well as immunotherapy. Finally, recent experimental models to study this highly complex disease were discussed, highlighting the importance of gastric cancer understanding in the hard-fought struggle against cancer relapse, metastasis and bad prognosis.
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Mao FY, Lv YP, Hao CJ, Teng YS, Liu YG, Cheng P, Yang SM, Chen W, Liu T, Zou QM, Xie R, Xu JY, Zhuang Y. Helicobacter pylori-Induced Rev-erbα Fosters Gastric Bacteria Colonization by Impairing Host Innate and Adaptive Defense. Cell Mol Gastroenterol Hepatol 2021; 12:395-425. [PMID: 33676046 PMCID: PMC8255816 DOI: 10.1016/j.jcmgh.2021.02.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 02/25/2021] [Accepted: 02/25/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Rev-erbα represents a powerful transcriptional repressor involved in immunity. However, the regulation, function, and clinical relevance of Rev-erbα in Helicobacter pylori infection are presently unknown. METHODS Rev-erbα was examined in gastric samples from H pylori-infected patients and mice. Gastric epithelial cells (GECs) were isolated and infected with H pylori for Rev-erbα regulation assays. Gastric tissues from Rev-erbα-/- and wild-type (littermate control) mice or these mice adoptively transferred with CD4+ T cells from IFN-γ-/- and wild-type mice, bone marrow chimera mice and mice with in vivo pharmacological activation or inhibition of Rev-erbα were examined for bacteria colonization. GECs, CD45+CD11c-Ly6G-CD11b+CD68- myeloid cells and CD4+ T cells were isolated, stimulated and/or cultured for Rev-erbα function assays. RESULTS Rev-erbα was increased in gastric mucosa of H pylori-infected patients and mice. H pylori induced GECs to express Rev-erbα via the phosphorylated cagA that activated ERK signaling pathway to mediate NF-κB directly binding to Rev-erbα promoter, which resulted in increased bacteria colonization within gastric mucosa. Mechanistically, Rev-erbα in GECs not only directly suppressed Reg3b and β-defensin-1 expression, which resulted in impaired bactericidal effects against H pylori of these antibacterial proteins in vitro and in vivo; but also directly inhibited chemokine CCL21 expression, which led to decreased gastric influx of CD45+CD11c-Ly6G-CD11b+CD68- myeloid cells by CCL21-CCR7-dependent migration and, as a direct consequence, reduced bacterial clearing capacity of H pylori-specific Th1 cell response. CONCLUSIONS Overall, this study identifies a model involving Rev-erbα, which collectively ensures gastric bacterial persistence by suppressing host gene expression required for local innate and adaptive defense against H pylori.
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Affiliation(s)
- Fang-Yuan Mao
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
| | - Yi-Pin Lv
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
| | - Chuan-Jie Hao
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
| | - Yong-Sheng Teng
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
| | - Yu-Gang Liu
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
| | - Ping Cheng
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
| | - Shi-Ming Yang
- Department of Gastroenterology, XinQiao Hospital, Third Military Medical University, Chongqing, China
| | - Weisan Chen
- La Trobe Institute of Molecular Science, La Trobe University, Bundoora, Australia
| | - Tao Liu
- Department of Pharmacology, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
| | - Quan-Ming Zou
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
| | - Rui Xie
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Jing-Yu Xu
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Yuan Zhuang
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China,Department of Gastroenterology, the Affiliated Hospital of Southwest Medical University, Luzhou, China,Correspondence Address correspondence to: Yuan Zhuang, National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, No.30 Gaotanyan Street, Chongqing 400038, China.fax: (86)023-68752315.
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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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