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Peng Y, Lei X, Yang Q, Zhang G, He S, Wang M, Ling R, Zheng B, He J, Chen X, Li F, Zhou Q, Zhao L, Ye G, Li G. Helicobacter pylori CagA-mediated ether lipid biosynthesis promotes ferroptosis susceptibility in gastric cancer. Exp Mol Med 2024; 56:441-452. [PMID: 38383581 PMCID: PMC10907675 DOI: 10.1038/s12276-024-01167-5] [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: 07/28/2023] [Revised: 11/20/2023] [Accepted: 11/29/2023] [Indexed: 02/23/2024] Open
Abstract
Helicobacter pylori, particularly cytotoxin-associated gene A (CagA)-positive strains, plays a key role in the progression of gastric cancer (GC). Ferroptosis, associated with lethal lipid peroxidation, has emerged to play an important role in malignant and infectious diseases, but the role of CagA in ferroptosis in cancer cells has not been determined. Here, we report that CagA confers GC cells sensitivity to ferroptosis both in vitro and in vivo. Mechanistically, CagA promotes the synthesis of polyunsaturated ether phospholipids (PUFA-ePLs), which is mediated by increased expression of alkylglycerone phosphate synthase (AGPS) and 1-acylglycerol-3-phosphate O-acyltransferase 3 (AGPAT3), leading to susceptibility to ferroptosis. This susceptibility is mediated by activation of the MEK/ERK/SRF pathway. SRF is a crucial transcription factor that increases AGPS transcription by binding to the AGPS promoter region. Moreover, the results demonstrated that CagA-positive cells are more sensitive to apatinib than are CagA-negative cells, suggesting that detecting the H. pylori CagA status may aid patient stratification for treatment with apatinib.
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Affiliation(s)
- Yanmei Peng
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Xuetao Lei
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Qingbin Yang
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Guofan Zhang
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Sixiao He
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, 518172, China
| | - Minghao Wang
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Ruoyu Ling
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Boyang Zheng
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Jiayong He
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Xinhua Chen
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Fengping Li
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Qiming Zhou
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Liying Zhao
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China.
| | - Gengtai Ye
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China.
| | - Guoxin Li
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China.
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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: 6] [Impact Index Per Article: 1.5] [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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Blaser N, Backert S, Pachathundikandi SK. Immune Cell Signaling by Helicobacter pylori: Impact on Gastric Pathology. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1149:77-106. [PMID: 31049845 DOI: 10.1007/5584_2019_360] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Helicobacter pylori represents a highly successful colonizer of the human stomach. Infections with this Gram-negative bacterium can persist lifelong, and although in the majority of cases colonization is asymptomatic, it can trigger pathologies ranging from chronic gastritis and peptic ulceration to gastric cancer. The interaction of the bacteria with the human host modulates immune responses in different ways to enable bacterial survival and persistence. H. pylori uses various pathogenicity-associated factors such as VacA, NapA, CGT, GGT, lipopolysaccharide, peptidoglycan, heptose 1,7-bisphosphate, ADP-heptose, cholesterol glucosides, urease and a type IV secretion system for controlling immune signaling and cellular functions. It appears that H. pylori manipulates multiple extracellular immune receptors such as integrin-β2 (CD18), EGFR, CD74, CD300E, DC-SIGN, MINCLE, TRPM2, T-cell and Toll-like receptors as well as a number of intracellular receptors including NLRP3, NOD1, NOD2, TIFA and ALPK1. Consequently, downstream signaling pathways are hijacked, inducing tolerogenic dendritic cells, inhibiting effector T cell responses and changing the gastrointestinal microbiota. Here, we discuss in detail the interplay of bacterial factors with multiple immuno-regulatory cells and summarize the main immune evasion and persistence strategies employed by H. pylori.
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Affiliation(s)
- Nicole Blaser
- Department of Biology, Institute for Microbiology, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Steffen Backert
- Department of Biology, Institute for Microbiology, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Suneesh Kumar Pachathundikandi
- Department of Biology, Institute for Microbiology, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany.
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Shibata W, Sue S, Tsumura S, Ishii Y, Sato T, Kameta E, Sugimori M, Yamada H, Kaneko H, Sasaki T, Ishii T, Tamura T, Kondo M, Maeda S. Helicobacter-induced gastric inflammation alters the properties of gastric tissue stem/progenitor cells. BMC Gastroenterol 2017; 17:145. [PMID: 29212456 PMCID: PMC5719643 DOI: 10.1186/s12876-017-0706-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Accepted: 11/24/2017] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Although Helicobacter-induced gastric inflammation is the major predisposing factor for gastric carcinogenesis, the precise mechanism by which chronic gastritis causes gastric cancer remains unclear. Intestinal and spasmolytic polypeptide-expressing metaplasia (SPEM) is considered as precancerous lesions, changes in epithelial tissue stem/progenitor cells after chronic inflammation has not been clarified yet. In this study, we utilized three-dimensional gastric epithelial cell culture systems that could form organoids, mimicking gastric epithelial layer, and characterized the changes in epithelial cells after chronic Helicobacter felis infection. METHODS We used three mice model; 1) long-term H. felis infection, 2) H. felis eradication, and 3) MNU chemical carcinogenesis model. We performed cRNA microarray analysis after organoid culture, and analyzed the effects of chronic gastric inflammation on tissue stem cells, by the size of organoid, mRNA expression profile and immunohistochemical analysis. RESULTS The number of organoids cultured from gastric epithelial cells was significantly higher in organoids isolated from H. felis-infected mice compared with those from uninfected gastric mucosa. Based on the mRNA expression profile, we found that possible stem cell markers such as Cd44, Dclk1, and genes associated with the intestinal phenotype, such as Villin, were increased in organoids isolated from H. felis-infected mucosa compared with the control. The upregulation of these genes were cancelled after H. felis eradication. In a xenograft model, tumors were generated only from organoids cultured from carcinogen-treated gastric mucosa, not from H. felis infected mucosa or control organoids. CONCLUSIONS Our results suggested that, as a possible mechanism of gastric carcinogenesis, chronic inflammation induced by H. felis infection increased the number of tissue stem/progenitor cells and the expression of stem cell markers. These findings suggest that chronic inflammation may alter the direction of differentiation toward undifferentiated state and that drawbacks may enable cells to redifferentiate to intestinal metaplasia or neoplasia.
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Affiliation(s)
- Wataru Shibata
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
- Division of Translational Research, Advanced Medical Research Center, Yokohama City University, Yokohama, Japan
| | - Soichiro Sue
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Sachiko Tsumura
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
- School of Medicine, Yokohama City University, Yokohama, Japan
| | - Yasuaki Ishii
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Takeshi Sato
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Eri Kameta
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Makoto Sugimori
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Hiroaki Yamada
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Hiroaki Kaneko
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Tomohiko Sasaki
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Tomohiro Ishii
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Toshihide Tamura
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Masaaki Kondo
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Shin Maeda
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
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Kinoshita H, Hayakawa Y, Koike K. Metaplasia in the Stomach-Precursor of Gastric Cancer? Int J Mol Sci 2017; 18:ijms18102063. [PMID: 28953255 PMCID: PMC5666745 DOI: 10.3390/ijms18102063] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Revised: 09/23/2017] [Accepted: 09/25/2017] [Indexed: 02/07/2023] Open
Abstract
Despite a significant decrease in the incidence of gastric cancer in Western countries over the past century, gastric cancer is still one of the leading causes of cancer-related deaths worldwide. Most human gastric cancers develop after long-term Helicobacter pylori infection via the Correa pathway: the progression is from gastritis, atrophy, intestinal metaplasia, dysplasia, to cancer. However, it remains unclear whether metaplasia is a direct precursor of gastric cancer or merely a marker of high cancer risk. Here, we review human studies on the relationship between metaplasia and cancer in the stomach, data from mouse models of metaplasia regarding the mechanism of metaplasia development, and the cellular responses induced by H. pylori infection.
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Affiliation(s)
- Hiroto Kinoshita
- Graduate School of Medicine, Department of Gastroenterology, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
| | - Yoku Hayakawa
- Graduate School of Medicine, Department of Gastroenterology, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
| | - Kazuhiko Koike
- Graduate School of Medicine, Department of Gastroenterology, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
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Tegtmeyer N, Neddermann M, Asche CI, Backert S. Subversion of host kinases: a key network in cellular signaling hijacked byHelicobacter pyloriCagA. Mol Microbiol 2017; 105:358-372. [DOI: 10.1111/mmi.13707] [Citation(s) in RCA: 65] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/11/2017] [Indexed: 12/16/2022]
Affiliation(s)
- Nicole Tegtmeyer
- Department of Biology, Division of Microbiology; Friedrich Alexander University Erlangen-Nuremberg; Staudtstr. 5 Erlangen D-91058 Germany
| | - Matthias Neddermann
- Department of Biology, Division of Microbiology; Friedrich Alexander University Erlangen-Nuremberg; Staudtstr. 5 Erlangen D-91058 Germany
| | - Carmen Isabell Asche
- Department of Biology, Division of Microbiology; Friedrich Alexander University Erlangen-Nuremberg; Staudtstr. 5 Erlangen D-91058 Germany
| | - Steffen Backert
- Department of Biology, Division of Microbiology; Friedrich Alexander University Erlangen-Nuremberg; Staudtstr. 5 Erlangen D-91058 Germany
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Li Q, Liu J, Gong Y, Yuan Y. Association of CagA EPIYA-D or EPIYA-C phosphorylation sites with peptic ulcer and gastric cancer risks: A meta-analysis. Medicine (Baltimore) 2017; 96:e6620. [PMID: 28445260 PMCID: PMC5413225 DOI: 10.1097/md.0000000000006620] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Increasingly, studies have focused on the relationship between Helicobacter pylori (H pylori) cytotoxin associated gene A protein (CagA) Glu-Pro-Ile-Tyr-Ala (EPIYA)-D motifs or multiple EPIYA-C phosphorylation sites and peptic ulcer disease (PUD) or gastric cancer (GC) risk. However, the conclusions have been inconsistent. The aim of this meta-analysis was to evaluate whether 1 CagA EPIYA-D motif or multiple EPIYA-C phosphorylation sites were associated with PUD or GC risk. MATERIALS AND METHODS A literature search was performed in PubMed, Web of Science, Wanfang Data, Excerpt Medica Database, and the Chinese National Knowledge Infrastructure database to identify eligible research. We analyzed the odds ratios (OR) and 95% confidence intervals (CI) to assess the strength of association. RESULTS Compared with 1 EPIYA-C motif in Asian populations, 1 EPIYA-D site was associated with an increased GC risk (OR=1.91, 95% CI=1.19-3.07, P = .008). However, 1 EPIYA-D motif was not significantly associated with PUD (OR = 0.90, 95% CI = 0.46-1.76, P = .764), gastric ulcer (GU) (OR = 0.85, 95% CI = 0.27-2.63, P = .771), or duodenal ulcer (DU) (OR = 0.89, 95% CI = 0.25-3.16, P = .859) risk. Compared with no more than 1 EPIYA-C motif, multiple motifs were associated with increased PUD (OR = 2.33, 95% CI = 1.29-4.20, P = .005) and DU (OR = 2.32, 95% CI = 1.08-5.00, P = .031) risk in Asia and GC risk in the United States and Europe (OR = 3.28, 95% CI = 2.32-4.64, P < .001). Multiple EPIYA-C sites were not associated with GU risk (OR = 4.54, 95% CI = 0.95-21.83, P = .059). There was no publication bias identified in these comparisons. CONCLUSIONS In Asia, 1 EPIYA-D motif was significantly associated with increased GC risk. Multiple EPIYA-C motifs were associated with increased PUD and DU risk, particularly in Asia. In the United States and Europe, multiple EPIYA-C motifs were associated with increased GC risk. Therefore, detection of polymorphic CagA EPIYA motifs may improve clinical prediction of disease risk.
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Imamura R, Matsumoto K. Hepatocyte growth factor in physiology and infectious diseases. Cytokine 2017; 98:97-106. [PMID: 28094206 DOI: 10.1016/j.cyto.2016.12.025] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Revised: 12/26/2016] [Accepted: 12/26/2016] [Indexed: 01/14/2023]
Abstract
Hepatocyte growth factor (HGF) is a pleiotropic cytokine composed of an α-chain and a β-chain, and these chains contain four kringle domains and a serine protease-like structure, respectively. The receptor for HGF was identified as the c-met proto-oncogene product of transmembrane receptor tyrosine kinase. HGF-induced signaling through the receptor Met provokes dynamic biological responses that support morphogenesis, regeneration, and the survival of various cells and tissues, which includes hepatocytes, renal tubular cells, and neurons. Characterization of tissue-specific Met knockout mice has further indicated that the HGF-Met system modulates immune cell functions and also plays an inhibitory role in the progression of chronic inflammation and fibrosis. However, the biological actions that are driven by the HGF-Met pathway all play a role in the acquisition of the malignant characteristics in tumor cells, such as invasion, metastasis, and drug resistance in the tumor microenvironment. Even though oncogenic Met signaling remains the major research focus, the HGF-Met axis has also been implicated in infectious diseases. Many pathogens try to utilize host HGF-Met system to establish comfortable environment for infection. Their strategies are not only simply change the expression level of HGF or Met, but also actively hijack HGF-Met system and deregulating Met signaling using their pathogenic factors. Consequently, the monitoring of HGF and Met expression, along with real-time detection of Met activation, can be a beneficial biomarker of these infectious diseases. Preclinical studies designed to address the therapeutic significance of HGF have been performed on injury/disease models, including acute tissue injury, chronic fibrosis, and cardiovascular and neurodegenerative diseases. Likewise, manipulating the HGF-Met system with complete control will lead to a tailor made treatment for those infectious diseases.
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Affiliation(s)
- Ryu Imamura
- Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
| | - Kunio Matsumoto
- Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
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Sue S, Shibata W, Kameta E, Sato T, Ishii Y, Kaneko H, Miwa H, Sasaki T, Tamura T, Kondo M, Maeda S. Intestine-specific homeobox (ISX) induces intestinal metaplasia and cell proliferation to contribute to gastric carcinogenesis. J Gastroenterol 2016; 51:949-60. [PMID: 26872890 DOI: 10.1007/s00535-016-1176-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2015] [Accepted: 01/26/2016] [Indexed: 02/04/2023]
Abstract
BACKGROUND Helicobacter pylori induces chronic inflammation and intestinal metaplasia (IM) through genetic and epigenetic changes and activation of intracellular signaling pathways that contribute to gastric carcinogenesis. However, the precise mechanism of IM in gastric carcinogenesis has not been fully elucidated. We previously found that intestine-specific homeobox (ISX) mRNA expression increased in organoids cultured from Helicobacter-infected mouse mucosa. In this study, we elucidate the role of ISX in the development of IM and gastric carcinogenesis. METHODS ISX expression was assessed in Helicobacter-infected mouse and human gastric mucosa. MKN45 gastric cancer cells were co-cultured with H. pylori to determine whether Helicobacter infection induced ISX expression. We established stable MKN45 transfected cells expressing ISX (Stable-ISX MKN45) and performed a spheroid colony formation assay and a xenograft model. We performed ISX immunohistochemistry in cancer and adjacent gastric tissues. RESULTS ISX expression was increased in mouse and human gastric mucosa infected with Helicobacter. The presence of IM and H. pylori infection in human stomach was correlated with ISX expression. H. pylori induced ISX mRNA and protein expression. CDX1/2, cyclinD1, and MUC2 were upregulated in Stable-ISX MKN45, whereas MUC5AC was downregulated. Stable-ISX MKN45 cells formed more spheroid colonies, and had high tumorigenic ability. ISX expression in gastric cancer and adjacent mucosa were correlated. CONCLUSIONS ISX expression induced by H. pylori infection may lead to IM and hyperproliferation of gastric mucosa through CDX1/2 and cyclinD1 expression, contributing to gastric carcinogenesis.
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Affiliation(s)
- Soichiro Sue
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan
| | - Wataru Shibata
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan.,Advanced Medical Research Center, Yokohama City University, Yokohama, Japan
| | - Eri Kameta
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan
| | - Takeshi Sato
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan
| | - Yasuaki Ishii
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan
| | - Hiroaki Kaneko
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan
| | - Haruo Miwa
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan
| | - Tomohiko Sasaki
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan
| | - Toshihide Tamura
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan
| | - Masaaki Kondo
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan
| | - Shin Maeda
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan.
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Randomized controlled trial comparing gastric cancer screening by gastrointestinal X-ray with serology for Helicobacter pylori and pepsinogens followed by gastrointestinal endoscopy. Gastric Cancer 2015; 18:605-11. [PMID: 25118857 DOI: 10.1007/s10120-014-0408-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2014] [Accepted: 07/13/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND Based on the results of several case-control and cohort studies gastrointestinal X-ray (GI X-ray) has been recommended for use in the nationwide screening program for gastric cancer.. Although this was the only effective screening program when almost all of the Japanese population were Helicobacter pylori (H. pylori) positive, there has been concern whether an alternative effective screening system should be established for the future H. pylori-negative generation. We therefore conducted the first randomized controlled trial (RCT) comparing GI X-ray and gastrointestinal endoscopy (GIE) scheduled according to results of serological testing (ST); this was done to determine the potential for an alternative screening method. METHODS Subjects who fulfilled the inclusion criteria were residents between the ages of 30 and 74 and who were able to receive gastric cancer screening in the Yurihonjo area. Participants were assigned to the GI X-ray group or the GIE-ST group by computer randomization. Subjects in each group were further subdivided into 4 categories according to their different risks for gastric cancer. The feasibility of stratified randomization was serologically assessed and detection rates of gastric cancer at entry by the different screening methods were also compared. RESULTS Of the 2,962 subjects invited, 1,206 individuals (41 percent) were included in the first stage of this stratified RCT, and 604 and 602 individuals were assigned to the GI X-ray group and the GIE-ST group, respectively. There were no statistically significant differences in sex, age, height, body weight, smoking, alcohol intake and family history of cancer between the 2 groups. During ST the GI X-ray group showed a distribution that was not statistically different from that of the GIE-ST group. Although 3 cases of gastric cancer were detected in the GIE-ST group, there was no statistically significant difference between the 2 groups. One complication found was barium aspiration during the examination in the X-ray group. CONCLUSION We confirmed that baseline demographic features of the 2 groups were well balanced. We are now organizing the first RCT to compare the existing screening method and the alternative method (Clinical trial registration number: UMIN000005962).
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Ferreira RM, Machado JC, Figueiredo C. Clinical relevance of Helicobacter pylori vacA and cagA genotypes in gastric carcinoma. Best Pract Res Clin Gastroenterol 2014; 28:1003-15. [PMID: 25439067 DOI: 10.1016/j.bpg.2014.09.004] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Revised: 08/21/2014] [Accepted: 09/15/2014] [Indexed: 02/08/2023]
Abstract
Helicobacter pylori infection is the major etiological factor of gastric carcinoma. This disease is the result of a long, multistep, and multifactorial process, which occurs only in a small proportion of patients infected with H. pylori. Gastric carcinoma development is influenced by host genetic susceptibility factors, environmental factors, and H. pylori virulence. H. pylori is genetically highly variable, and variability that affects H. pylori virulence factors may be useful to identify strains with different degrees of pathogenicity. This review will focus on VacA and CagA that have polymorphic regions that impact their functional properties. The characterization of H. pylori vacA and cagA-associated could be useful for identifying patients at highest risk of disease, who could be offered H. pylori eradication therapy and who could be included in programs of more intensive surveillance in an attempt to reduce gastric carcinoma incidence.
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Affiliation(s)
- Rui M Ferreira
- Ipatimup - Institute of Molecular Pathology and Immunology of the University of Porto, Portugal
| | - José C Machado
- Ipatimup - Institute of Molecular Pathology and Immunology of the University of Porto, Portugal; Department of Pathology and Oncology, Faculty of Medicine of the University of Porto, Porto, Portugal
| | - Ceu Figueiredo
- Ipatimup - Institute of Molecular Pathology and Immunology of the University of Porto, Portugal; Department of Pathology and Oncology, Faculty of Medicine of the University of Porto, Porto, Portugal.
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Wu J, Xu S, Zhu Y. Helicobacter pylori CagA: a critical destroyer of the gastric epithelial barrier. Dig Dis Sci 2013; 58:1830-7. [PMID: 23423500 DOI: 10.1007/s10620-013-2589-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2012] [Accepted: 01/24/2013] [Indexed: 12/15/2022]
Abstract
The destruction of the integrity of the gastric epithelial barrier underlies the pathology of many gastric diseases, including gastric tumors. The Helicobacter pylori virulence factor CagA is one of the main destroyers of the gastric epithelial barrier. There are differences among CagA proteins that originate from different isolates. CagA translocated into the gastric epithelial cells causes significant changes in cell signaling pathways in phosphorylation-dependent and phosphorylation-independent manners, leading to cell morphological changes and host cell epithelial barrier injury, which lay the foundation for the occurrence of related diseases. As a newly identified pathogenic mechanism of CagA, miRNA is involved in the remodeling of the gastric epithelial barrier. Both the eradication of H. pylori infection and interventions against CagA-induced gastric epithelial barrier lesions may contribute to the prevention of the development of gastric tumors.
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Affiliation(s)
- Jia Wu
- Department of Gastroenterology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
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13
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Abstract
Helicobacter pylori infection is associated with gastritis and gastric cancer. An H. pylori virulence factor, the cag pathogenicity island (PAI), is related to host cell cytokine induction and gastric inflammation. Since elucidation of the mechanisms of inflammation is important for therapy, the associations between cytokines and inflammatory diseases have been investigated vigorously. Levels of interleukin-32 (IL-32), a recently described inflammatory cytokine, are increased in various inflammatory diseases, such as rheumatoid arthritis and Crohn's disease, and in malignancies, including gastric cancer. In this report, we examined IL-32 expression in human gastric disease. We also investigated the function of IL-32 in activation of the inflammatory cytokines in gastritis. IL-32 expression paralleled human gastric tissue pathology, with low IL-32 expression in H. pylori-uninfected gastric mucosa and higher expression levels in gastritis and gastric cancer tissues. H. pylori infection increased IL-32 expression in human gastric epithelial cell lines. H. pylori-induced IL-32 expression was dependent on the bacterial cagPAI genes and on activation of nuclear factor κB (NF-κB). IL-32 expression induced by H. pylori was not detected in the supernatant of AGS cells but was found in the cytosol. Expression of the H. pylori-induced cytokines CXCL1, CXCL2, and IL-8 was decreased in IL-32-knockdown AGS cell lines compared to a control AGS cell line. We also found that NF-κB activation was decreased in H. pylori-infected IL-32-knockdown cells. These results suggest that IL-32 has important functions in the regulation of cytokine expression in H. pylori-infected gastric mucosa.
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Smolka AJ, Backert S. How Helicobacter pylori infection controls gastric acid secretion. J Gastroenterol 2012; 47:609-18. [PMID: 22565637 DOI: 10.1007/s00535-012-0592-1] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2012] [Accepted: 03/29/2012] [Indexed: 02/06/2023]
Abstract
Infection of the human stomach mucosa by Helicobacter pylori induces strong inflammatory responses and a transitory hypochlorhydria which can progress in ~2 % of patients to atrophic gastritis, dysplasia, or gastric adenocarcinoma. H. pylori infection of gastric biopsies or cultured gastric epithelial cells in vitro represses the activity of endogenous or transfected promoter of the alpha-subunit (HKα) of gastric H,K-adenosine triphosphatase (H,K-ATPase), the parietal cell enzyme mediating acid secretion. Some mechanistic details of H. pylori-mediated repression of HKα and ensuing hypochlorhydria have been recently elucidated. H. pylori strains expressing a type IV secretion system (T4SS) encoded by the cag pathogenicity island are known to upregulate the transcription factor nuclear factor (NF)-κB. The NF-κB-binding regions in the HKα promoter were identified and shown to repress its transcriptional activity. Interaction studies have indicated that although active phosphorylated NF-κB p65 is present in infected cells, an NF-κB p50/p65 heterodimeric complex fails to bind to the HKα promoter. Point mutations at -159 and -161 bp in the HKα promoter NF-κB binding sequence prevent the binding of NF-κB p50 and prevent H. pylori repression of point-mutated HKα promoter activity. The T4SS factors CagL, CagE, CagM, and possibly CagA and the lytic transglycosylase Slt, are mechanistically involved in NF-κB activation and repression of HKα transcription. CagL, a T4SS pilus component, binds to the integrin α(5)β(1) to mediate translocation of virulence factors into the host cell and initiate signaling. During acute H. pylori infection, CagL dissociates ADAM 17 (a disintegrin and a metalloprotease 17) from the integrin α(5)β(1) complex and stimulates ADAM17-dependent release of heparin-binding epidermal growth factor (HB-EGF), EGF receptor (EGFR) stimulation, ERK1/2 kinase activation, and NF-κB-mediated repression of HKα. These studies suggest that H. pylori inhibits HKα gene expression by an integrin α(5)β(1) → ADAM17 → HB-EGF → EGFR → ERK1/2 → NF-κB pathway mediating NF-κB p50 homodimer binding to the HKα promoter. Here we review the molecular basis and recent progress of this novel pathogen-dependent mechanism of H,K-ATPase inhibition, which contributes significantly to our current understanding of H. pylori pathophysiology.
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Affiliation(s)
- Adam J Smolka
- Department of Medicine, Medicine/Gastro CSB 921E, Medical University of South Carolina, Charleston, SC 29425, USA.
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Zhu Y, Jiang Q, Lou X, Ji X, Wen Z, Wu J, Tao H, Jiang T, He W, Wang C, Du Q, Zheng S, Mao J, Huang J. MicroRNAs up-regulated by CagA of Helicobacter pylori induce intestinal metaplasia of gastric epithelial cells. PLoS One 2012; 7:e35147. [PMID: 22536353 PMCID: PMC3335061 DOI: 10.1371/journal.pone.0035147] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2012] [Accepted: 03/08/2012] [Indexed: 02/07/2023] Open
Abstract
CagA of Helicobacter pylori is a bacterium-derived oncogenic protein closely associated with the development of gastric cancers. MicroRNAs (miRNAs) are a class of widespread non-coding RNAs, many of which are involved in cell growth, cell differentiation and tumorigenesis. The relationship between CagA protein and miRNAs is unclear. Using mammalian miRNA profile microarrays, we found that miRNA-584 and miRNA-1290 expression was up-regulated in CagA-transformed cells, miRNA-1290 was up-regulated in an Erk1/2-dependent manner, and miRNA-584 was activated by NF-κB. miRNA-584 sustained Erk1/2 activities through inhibition of PPP2a activities, and miRNA-1290 activated NF-κB by knockdown of NKRF. Foxa1 was revealed to be an important target of miRNA-584 and miRNA-1290. Knockdown of Foxa1 promoted the epithelial-mesenchymal transition significantly. Overexpression of miRNA-584 and miRNA-1290 induced intestinal metaplasia of gastric epithelial cells in knock-in mice. These results indicate that miRNA-584 and miRNA-1290 interfere with cell differentiation and remodel the tissues. Thus, the miRNA pathway is a new pathogenic mechanism of CagA.
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Affiliation(s)
- Yongliang Zhu
- Department of Gastroenterology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China.
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16
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Increased miR-222 in H. pylori-associated gastric cancer correlated with tumor progression by promoting cancer cell proliferation and targeting RECK. FEBS Lett 2012; 586:722-8. [PMID: 22321642 DOI: 10.1016/j.febslet.2012.01.025] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2011] [Revised: 12/20/2011] [Accepted: 01/16/2012] [Indexed: 12/21/2022]
Abstract
Little is known about the potential role of microRNAs (miRNAs) in the carcinogenesis of gastric cancer induced by Helicobacter pylori (H. pylori). Here, we showed that microRNA-222 (miR-222) was up-regulated in H. pylori-infected gastric mucosa and gastric cancer. Ectopic expression of miR-222 promoted cell proliferation and colony formation in vitro. Mechanistically, we identified RECK as a novel target of miR-222, and also confirmed their relationship by the inverse correlation of mRNA expression ex vivo. Furthermore, we found that RNA interference silencing of RECK can mimic the oncogenic effects of miR-222. Collectively, H. pylori may function as an initiator in the process of carcinogenesis by up-regulating miR-222, which further participates in the progression of cancer by promoting proliferation and inhibiting RECK.
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Cheng HC, Yang HB, Chang WL, Yeh YC, Tsai YC, Sheu BS. Weak up-regulation of serum response factor in gastric ulcers in patients with co-morbidities is associated with increased risk of recurrent bleeding. BMC Gastroenterol 2011; 11:24. [PMID: 21410985 PMCID: PMC3069945 DOI: 10.1186/1471-230x-11-24] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2010] [Accepted: 03/16/2011] [Indexed: 01/22/2023] Open
Abstract
Background Serum response factor (SRF) is crucial for gastric ulcer healing process. The study determined if gastric ulcer tissues up-regulate SRF and if such up-regulation correlated with co-morbidities and the risk of recurrent bleeding. Methods Ulcer and non-ulcer tissues were obtained from 142 patients with active gastric ulcers for SRF expression assessed by immunohistochemistry. Based on the degree of SRF expression between these two tissue types, SRF up-regulation was classified as strong, intermediate, and weak patterns. The patients were followed-up to determine if SRF up-regulation correlated to recurrent bleeding. Results Gastric ulcer tissues had higher SRF expression than non-ulcer tissues (p < 0.05). Patients with strong SRF up-regulation had lower rates of stigmata of recent hemorrhage (SRH) on the ulcer base than the others (p < 0.05). Multivariate logistic regression confirmed that co-morbidities and weak SRF up-regulation were two independent factors of recurrent gastric ulcer bleeding (p < 0.05). Combining both factors, there was an 8.29-fold (95% CI, 1.31~52.62; p = 0.03) higher risk of recurrent gastric ulcer bleeding. Conclusions SRF expression is higher in gastric ulcer tissues than in non-ulcer tissues. Weak SRF up-regulation, combined with the presence of co-morbidities, increase the risk of the recurrent gastric ulcer bleeding.
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Affiliation(s)
- Hsiu-Chi Cheng
- Institute of Clinical Medicine, Medical College, National Cheng Kung University, Tainan, Taiwan
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18
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Pelz C, Steininger S, Weiss C, Coscia F, Vogelmann R. A novel inhibitory domain of Helicobacter pylori protein CagA reduces CagA effects on host cell biology. J Biol Chem 2011; 286:8999-9008. [PMID: 21212271 DOI: 10.1074/jbc.m110.166504] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
The Helicobacter pylori protein CagA (cytotoxin-associated gene A) is associated with an increased risk for gastric cancer formation. After attachment to epithelial cells, the bacteria inject CagA via a type IV secretion apparatus into host cells, where it exerts its biological activity. Host cell responses to intracellular CagA have been linked exclusively to signaling motifs in the C terminus of the CagA protein. Little is known about the functional role of the remaining CagA protein. Using transgenic expression of CagA mutants in epithelial cells, we were able to identify a novel CagA inhibitory domain at the N terminus consisting of the first 200 amino acids. This domain localizes to cell-cell contacts and increases the rate and strength of cell-cell adhesion in epithelial cells. Thus, it compensates for the loss of cell-cell adhesion induced by the C terminus of the CagA protein. Consistent with its stabilizing role on cell-cell adhesion, the CagA N terminus domain reduces the CagA-induced β-catenin transcriptional activity in the nucleus. Furthermore, it inhibits apical surface constriction and cell elongations, host cell phenotypes induced by the C terminus in polarized epithelia. Therefore, our study suggests that CagA contains an intrinsic inhibitory domain that reduces host cell responses to CagA, which have been associated with the formation of cancer.
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Affiliation(s)
- Christiane Pelz
- Second Department of Internal Medicine, Klinikum rechts der Isar, Technical University Munich, 81675 Munich, Germany
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Allison CC, Ferrero RL. Role of virulence factors and host cell signaling in the recognition of Helicobacter pylori and the generation of immune responses. Future Microbiol 2010; 5:1233-55. [PMID: 20722601 DOI: 10.2217/fmb.10.84] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Helicobacter pylori colonizes a large proportion of the world's population, with infection invariably leading to chronic, lifelong gastritis. While the infection often persists undiagnosed and without causing severe pathology, there are a number of host, bacterial and environmental factors that can influence whether infection provokes a mild inflammatory response or results in significant morbidity. Intriguingly, the most virulent H. pylori strains appear to deliberately induce the epithelial signaling cascades responsible for activating the innate immune system. While the reason for this remains unclear, the resulting adaptive immune responses are largely ineffective in clearing the bacterium once infection has become established and, as a result, inflammation likely causes more damage to the host itself.
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Affiliation(s)
- Cody C Allison
- Centre for Innate Immunity & Infectious Diseases, Monash Institute of Medical Research, Clayton, Australia.
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20
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Jones KR, Whitmire JM, Merrell DS. A Tale of Two Toxins: Helicobacter Pylori CagA and VacA Modulate Host Pathways that Impact Disease. Front Microbiol 2010; 1:115. [PMID: 21687723 PMCID: PMC3109773 DOI: 10.3389/fmicb.2010.00115] [Citation(s) in RCA: 116] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2010] [Accepted: 09/27/2010] [Indexed: 12/16/2022] Open
Abstract
Helicobacter pylori is a pathogenic bacterium that colonizes more than 50% of the world's population, which leads to a tremendous medical burden. H. pylori infection is associated with such varied diseases as gastritis, peptic ulcers, and two forms of gastric cancer: gastric adenocarcinoma and mucosa-associated lymphoid tissue lymphoma. This association represents a novel paradigm for cancer development; H. pylori is currently the only bacterium to be recognized as a carcinogen. Therefore, a significant amount of research has been conducted to identify the bacterial factors and the deregulated host cell pathways that are responsible for the progression to more severe disease states. Two of the virulence factors that have been implicated in this process are cytotoxin-associated gene A (CagA) and vacuolating cytotoxin A (VacA), which are cytotoxins that are injected and secreted by H. pylori, respectively. Both of these virulence factors are polymorphic and affect a multitude of host cellular pathways. These combined facts could easily contribute to differences in disease severity across the population as various CagA and VacA alleles differentially target some pathways. Herein we highlight the diverse types of cellular pathways and processes targeted by these important toxins.
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Affiliation(s)
- Kathleen R Jones
- Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences Bethesda, MD, USA
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21
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Kwak MS, Kim N, Lee HS, Lee HE, Jung HC, Song IS. Predictive power of serum pepsinogen tests for the development of gastric cancer in comparison to the histologic risk index. Dig Dis Sci 2010; 55:2275-82. [PMID: 20306133 DOI: 10.1007/s10620-010-1181-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2009] [Accepted: 02/25/2010] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIM The selection of a high-risk group of gastric cancer is important. This study was performed to compare the efficacy of non-invasive gastric cancer screening through the measurement of pepsinogen (PG) I/II ratio and endoscopic screening using histologic criteria (Meining's risk index for gastric cancer) in Korean patients. METHODS Included in the study were 460 gastric cancer patients and 460 control cases who underwent upper endoscopy between June 2003 and July 2008 at Seoul National University Bundang Hospital. Serum PG I/II ratio and histologic characteristics were evaluated for each participant. Multivariate logistic regression was performed to compare the predictive power for gastric cancer of both the PG II/I ratio (the inverse form of PG I/II ratio) and the histologic gastric cancer risk index. RESULTS A higher PG II/I ratio was significantly associated with a higher risk for gastric cancer (odds ratio of highest quartile for cancer vs. lowest quartile, 3.51; 95% confidence interval, 2.29-5.36) in the multivariate logistic model. The validity (in terms of calibration and discrimination) of the PG-including multivariate logistic model was comparable to the histologic gastric cancer risk index model. The results were similar regardless of the staging of the cancer, Lauren's histologic classification, and the location of the cancer. CONCLUSIONS These results suggest that non-invasive measurement of serum PG I/II ratio is as effective as Meining's histologic gastric cancer risk index in predicting gastric cancer occurrence.
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Affiliation(s)
- Min Sun Kwak
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea
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Mimuro H. [Strategy of Helicobacter pylori to enhance colonization of the stomach]. Nihon Saikingaku Zasshi 2010; 64:311-7. [PMID: 19628929 DOI: 10.3412/jsb.64.311] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Hitomi Mimuro
- Division of Bacterial Infection, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
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Abstract
Several bacterial pathogens inject virulence proteins into host target cells that are substrates of eukaryotic tyrosine kinases. One of the key examples is the Helicobacter pylori CagA effector protein which is translocated by a type-IV secretion system. Injected CagA becomes tyrosine-phosphorylated on EPIYA sequence motifs by Src and Abl family kinases. CagA then binds to and activates/inactivates multiple signaling proteins in a phosphorylation-dependent and phosphorylation-independent manner. A recent proteomic screen systematically identified eukaryotic binding partners of the EPIYA phosphorylation sites of CagA and similar sites in other bacterial effectors by high-resolution mass spectrometry. Individual phosphorylation sites recruited a surprisingly high number of interaction partners suggesting that each phosphorylation site can interfere with many downstream pathways. We now count 20 reported cellular binding partners of CagA, which represents the highest quantitiy among all yet known virulence-associated effector proteins in the microbial world. This complexity generates a highly remarkable and puzzling scenario. In addition, the first crystal structure of CagA provided us with new information on the function of this important virulence determinant. Here we review the recent advances in characterizing the multiple binding signaling activities of CagA. Injected CagA can act as a 'master key' that evolved the ability to highjack multiple host cell signalling cascades, which include the induction of membrane dynamics, actin-cytoskeletal rearrangements and the disruption of cell-to-cell junctions as well as proliferative, pro-inflammatory and anti-apoptotic nuclear responses. The discovery that different pathogens use this common strategy to subvert host cell functions suggests that more examples will emerge soon.
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Suzuki M. [Helicobacter pylori infection and gastric epithelial responses]. Nihon Saikingaku Zasshi 2010; 65:289-96. [PMID: 20505268 DOI: 10.3412/jsb.65.289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Affiliation(s)
- Masato Suzuki
- Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan
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Abstract
Serum response factor (SRF) is a transcription factor that regulates many genes involved in cellular activities such as proliferation, migration, differentiation, angiogenesis, and apoptosis. Although it has only been known for about two decades, SRF has been studied extensively. To date, over a thousand SRF studies have been published, but it still remains a hot topic. Due to its critical role in mesoderm-derived tissues, most of the SRF studies focused on muscle structure/function, cardiovascular development/maintenance, and smooth muscle generation/repair. Recently, SRF has received more attention in the digestive field and several important discoveries have been made. This review will summarize what we have learned about SRF in the gastrointestinal tract and provide insights into possible future directions in this area.
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DNA sequence analysis of cagA 3′ motifs of Helicobacter pylori strains from patients with peptic ulcer diseases. J Med Microbiol 2010; 59:144-148. [DOI: 10.1099/jmm.0.014894-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
The Helicobacter pylori cagA gene is a major virulence factor that plays an important role in gastric pathologies. DNA sequence data for the cagA 3′ region of Western isolates differ markedly in their EPIYA motifs from those of East Asian isolates. An increase in the number of these motifs is known to be associated with gastric cancer. Whether such an association is also the case for peptic ulceration was investigated in this study. Gastric biopsies were collected from 96 patients with duodenal ulcer (DU), gastric ulcer (GU) and gastritis. The types of EPIYA motif detected by PCR among 28 DU strains were 13 ABC, eight ABCC, six ABCCC, and in one patient both ABC and ABCCCCC; among nine GU strains were two ABC, five ABCC and two ABCCC; and among 40 gastritis strains were 35 ABC and five ABCC. DNA sequencing was carried out to confirm the detection of the EPIYA motif types and to analyse their peptide sequences. A significant association was found between the number of the EPIYA-C motifs (≥2) and peptic ulceration (P=0.00001) compared with gastritis. In conclusion, this study shows that our patients harboured cagA-positive H. pylori strains with EPIYA motifs of the Western type and that the increase in the number of EPIYA-C motifs was significantly associated with DU and GU but not with gastritis, indicating predictive association with the severity of the disease.
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Kim KK, Kim HB. Protein interaction network related to Helicobacter pylori infection response. World J Gastroenterol 2009. [PMID: 19777610 DOI: 10.3748//wjg.15.4518] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
AIM To understand the complex reaction of gastric inflammation induced by Helicobacter pylori (H pylori) in a systematic manner using a protein interaction network. METHODS The expression of genes significantly changed on microarray during H pylori infection was scanned from the web literary database and translated into proteins. A network of protein interactions was constructed by searching the primary interactions of selected proteins. The constructed network was mathematically analyzed and its biological function was examined. In addition, the nodes on the network were checked to determine if they had any further functional importance or relation to other proteins by extending them. RESULTS The scale-free network showing the relationship between inflammation and carcinogenesis was constructed. Mathematical analysis showed hub and bottleneck proteins, and these proteins were mostly related to immune response. The network contained pathways and proteins related to H pylori infection, such as the JAK-STAT pathway triggered by interleukins. Activation of nuclear factor (NF)-kappaB, TLR4, and other proteins known to function as core proteins of immune response were also found. These immune-related proteins interacted on the network with pathways and proteins related to the cell cycle, cell maintenance and proliferation, and transcription regulators such as BRCA1, FOS, REL, and zinc finger proteins. The extension of nodes showed interactions of the immune proteins with cancer-related proteins. One extended network, the core network, a summarized form of the extended network, and cell pathway model were constructed. CONCLUSION Immune-related proteins activated by H pylori infection interact with proto-oncogene proteins. The hub and bottleneck proteins are potential drug targets for gastric inflammation and cancer.
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Affiliation(s)
- Kyu Kwang Kim
- Department of Biotechnology, The Research Institute for Basic Sciences, Hoseo University, Asan 336-795, South Korea.
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Kim KK, Kim HB. Protein interaction network related to Helicobacter pylori infection response. World J Gastroenterol 2009; 15:4518-28. [PMID: 19777610 PMCID: PMC2751996 DOI: 10.3748/wjg.15.4518] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2009] [Revised: 08/12/2009] [Accepted: 08/19/2009] [Indexed: 02/06/2023] Open
Abstract
AIM To understand the complex reaction of gastric inflammation induced by Helicobacter pylori (H pylori) in a systematic manner using a protein interaction network. METHODS The expression of genes significantly changed on microarray during H pylori infection was scanned from the web literary database and translated into proteins. A network of protein interactions was constructed by searching the primary interactions of selected proteins. The constructed network was mathematically analyzed and its biological function was examined. In addition, the nodes on the network were checked to determine if they had any further functional importance or relation to other proteins by extending them. RESULTS The scale-free network showing the relationship between inflammation and carcinogenesis was constructed. Mathematical analysis showed hub and bottleneck proteins, and these proteins were mostly related to immune response. The network contained pathways and proteins related to H pylori infection, such as the JAK-STAT pathway triggered by interleukins. Activation of nuclear factor (NF)-kappaB, TLR4, and other proteins known to function as core proteins of immune response were also found. These immune-related proteins interacted on the network with pathways and proteins related to the cell cycle, cell maintenance and proliferation, and transcription regulators such as BRCA1, FOS, REL, and zinc finger proteins. The extension of nodes showed interactions of the immune proteins with cancer-related proteins. One extended network, the core network, a summarized form of the extended network, and cell pathway model were constructed. CONCLUSION Immune-related proteins activated by H pylori infection interact with proto-oncogene proteins. The hub and bottleneck proteins are potential drug targets for gastric inflammation and cancer.
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Abstract
Gastric carcinoma is the second leading cause of cancer-related deaths in the world, accounting for more than 700,000 deaths each year. Recent studies have revealed that infection with cagA-positive Helicobacter pylori plays an essential role in the development of gastric carcinoma. The cagA-encoded CagA protein is delivered into gastric epithelial cells via the bacterial type IV secretion system, where it undergoes tyrosine phosphorylation by Src and Abl kinases. Tyrosine-phosphorylated CagA then acquires the ability to interact with and deregulate SHP-2 phosphatase, a bona-fide oncoprotein, deregulation of which is involved in a variety of human malignancies. CagA also binds to and inhibits PAR1b/MARK2 polarity-regulating kinase to disrupt tight junctions and epithelial apical-basolateral polarity. These CagA activities may collectively contribute to the transformation of gastric epithelial cells. Indeed, transgenic expression of CagA in mice results in the development of gastrointestinal and hematological malignancies, indicating that CagA is the first bacterial oncoprotein that acts in mammalian cells. The oncogenic potential of CagA may be further potentiated in the presence of chronic inflammation, which aberrantly induces activation-induced cytidine deaminase (AID), a member of the DNA/RNA-editing enzyme family. Ectopically expressed AID may contribute to H. pylori-initiated gastric carcinogenesis by increasing the risk of likelihood of epithelial cells acquiring mutations in cancer-related genes.
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Suzuki M, Mimuro H, Kiga K, Fukumatsu M, Ishijima N, Morikawa H, Nagai S, Koyasu S, Gilman RH, Kersulyte D, Berg DE, Sasakawa C. Helicobacter pylori CagA phosphorylation-independent function in epithelial proliferation and inflammation. Cell Host Microbe 2009; 5:23-34. [PMID: 19154985 DOI: 10.1016/j.chom.2008.11.010] [Citation(s) in RCA: 263] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2007] [Revised: 09/15/2008] [Accepted: 11/20/2008] [Indexed: 02/07/2023]
Abstract
CagA, a major virulence factor of Helicobacter pylori (Hp), is delivered into gastric epithelial cells and exists in phosphorylated and nonphosphorylated forms. The biological activity of the phosphorylated form is well established; however, function(s) of the nonphosphorylated form remain elusive. Here, we report that a conserved motif in the C-terminal region of CagA, which is distinct from the EPIYA motifs used for phosphorylation and which we designate CRPIA (conserved repeat responsible for phosphorylation-independent activity), plays pivotal roles in Hp pathogenesis. The CRPIA motif in nonphosphorylated CagA was involved in interacting with activated Met, the hepatocyte growth factor receptor, leading to the sustained activation of phosphatidylinositol 3-kinase/Akt signaling in response to Hp infection. This in turn led to the activation of beta-catenin and NF-kappaB signaling, which promote proliferation and inflammation, respectively. Thus, nonphosphorylated CagA activity contributes to the epithelial proliferative and proinflammatory responses associated with development of chronic gastritis and gastric cancer.
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Affiliation(s)
- Masato Suzuki
- Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
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Basso D, Zambon CF, Letley DP, Stranges A, Marchet A, Rhead JL, Schiavon S, Guariso G, Ceroti M, Nitti D, Rugge M, Plebani M, Atherton JC. Clinical relevance of Helicobacter pylori cagA and vacA gene polymorphisms. Gastroenterology 2008; 135:91-9. [PMID: 18474244 DOI: 10.1053/j.gastro.2008.03.041] [Citation(s) in RCA: 294] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2007] [Revised: 03/03/2008] [Accepted: 03/20/2008] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS The Helicobacter pylori gene cagA and s1 or m1 forms of vacA are more common in disease-associated strains. Recently, forms of cagA encoding multiple type C EPIYA segments (which increase phosphorylation-dependent CagA activity) and a new type i1 "intermediate region" polymorphism in vacA (which confers toxicity) have been described. We assessed the association of new and established cagA and vacA polymorphisms with disease. METHODS We studied 203 H pylori-infected subjects (53 gastric cancer [GC], 52 peptic ulcer [PU], and 98 gastritis). vacA signal, mid and intermediate region polymorphisms, cagA presence, and EPIYA-C segment number were analyzed by polymerase chain reaction. RESULTS cagA-positive strains were significantly associated with GC and PU (P < .001 and P < .05). GC risk was further associated with the number of cagA EPIYA-C segments (odds ratio [OR] = 7.37, 95% confidence interval [CI] = 1.98-27.48 for 1 EPIYA-C segment; OR = 32.5, 95% CI = 8.41-125.58 for 2 or more EPIYA-C segments). Increasing number of EPIYA-C segments also increased the risk of intestinal metaplasia. Type s1 and i1 vacA alleles were also associated with GC and type i1 vacA with PU (OR = 2.58, 95% CI = 1.19-5.61), including a significant association with duodenal ulcer. In multivariate analysis, the associations of cagA EPIYA-C segment number with GC and intestinal metaplasia as well as vacA i1 type association with PU remained. CONCLUSIONS We confirmed the associations of cagA and vacA polymorphisms with disease but now define their most important features. For cancer risk, among Western strains, the most important factor is the number of cagA EPIYA-C segment. For PU risk, it is the intermediate region type of vacA.
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Affiliation(s)
- Daniela Basso
- Department of Laboratory Medicine, University of Padova, Padova, Italy.
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Saha A, Hammond CE, Trojanowska M, Smolka AJ. Helicobacter pylori-induced H,K-ATPase alpha-subunit gene repression is mediated by NF-kappaB p50 homodimer promoter binding. Am J Physiol Gastrointest Liver Physiol 2008; 294:G795-807. [PMID: 18202112 DOI: 10.1152/ajpgi.00431.2007] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Infection of human gastric body mucosa by the gram-negative, microaerophilic bacterium Helicobacter pylori induces an inflammatory response and a transitory hypochlorhydria that progresses in approximately 2% of patients to atrophic gastritis, dysplasia, and gastric adenocarcinoma. We have previously shown that H. pylori infection of cultured gastric epithelial cells (AGS) represses the activity of the transfected alpha-subunit (HKalpha) promoter of H,K-ATPase, the parietal cell enzyme mediating acid secretion. However, the mechanistic details of H. pylori-mediated repression of HKalpha and ensuing hypochlorhydria are unknown. H. pylori is known to upregulate the transcription factor NF-kappaB through the ERK1/2 MAPK pathway. We identified NF-kappaB-binding regions in the HKalpha promoter and found that H. pylori inoculation of AGS cells increased NF-kappaB p50 binding to the transfected HKalpha promoter and repressed its transcriptional activity. Immunoblot and DNA-protein interaction studies showed that although active phosphorylated NF-kappaB p65 is present in H. pylori-infected AGS cells, an NF-kappaB p50/p65 heterodimeric complex fails to bind to the HKalpha promoter. Point mutations at -159 and -161 bp in the HKalpha promoter NF-kappaB binding sequence prevented binding of NF-kappaB p50 and prevented H. pylori repression of point-mutated HKalpha promoter activity in transfected AGS cells. Small interfering RNA-mediated knockdown of NF-kappaB p50 in H. pylori-infected AGS cells also abrogated H. pylori-induced HKalpha repression, whereas NF-kappaB p65 knockdown did not. We conclude that H. pylori inhibits HKalpha gene expression by ERK1/2-mediated NF-kappaB p50 homodimer binding to the HKalpha promoter. This study identifies a novel pathogen-dependent mechanism of H,K-ATPase inhibition and contributes to understanding of H. pylori pathophysiology.
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Affiliation(s)
- Arindam Saha
- Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
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Mimuro H, Berg DE, Sasakawa C. Control of epithelial cell structure and developmental fate: Lessons fromHelicobacter pylori. Bioessays 2008; 30:515-20. [DOI: 10.1002/bies.20768] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Mimuro H, Suzuki T, Nagai S, Rieder G, Suzuki M, Nagai T, Fujita Y, Nagamatsu K, Ishijima N, Koyasu S, Haas R, Sasakawa C. Helicobacter pylori dampens gut epithelial self-renewal by inhibiting apoptosis, a bacterial strategy to enhance colonization of the stomach. Cell Host Microbe 2007; 2:250-63. [PMID: 18005743 DOI: 10.1016/j.chom.2007.09.005] [Citation(s) in RCA: 169] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2007] [Revised: 08/11/2007] [Accepted: 09/14/2007] [Indexed: 02/06/2023]
Abstract
Colonization of the gastric pits in the stomach by Helicobacter pylori (Hp) is a major risk factor for gastritis, gastric ulcers, and cancer. Normally, rapid self-renewal of gut epithelia, which occurs by a balance of progenitor proliferation and pit cell apoptosis, serves as a host defense mechanism to limit bacterial colonization. To investigate how Hp overcomes this host defense, we use the Mongolian gerbil model of Hp infection. Apoptotic loss of pit cells induced by a proapoptotic agent is suppressed by Hp. The ability of Hp to suppress apoptosis contributed to pit hyperplasia and persistent bacterial colonization of the stomach. Infection with WT Hp but not with a mutant in the virulence effector cagA increased levels of the prosurvival factor phospho-ERK and antiapoptotic protein MCL1 in the gastric pits. Thus, CagA activates host cell survival and antiapoptotic pathways to overcome self-renewal of the gastric epithelium and help sustain Hp infection.
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Affiliation(s)
- Hitomi Mimuro
- Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
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Atherton JC. The pathogenesis of Helicobacter pylori-induced gastro-duodenal diseases. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2007; 1:63-96. [PMID: 18039108 DOI: 10.1146/annurev.pathol.1.110304.100125] [Citation(s) in RCA: 409] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Helicobacter pylori is the main cause of peptic ulceration, distal gastric adenocarcinoma, and gastric lymphoma. Only 15% of those colonized develop disease, and pathogenesis depends upon strain virulence, host genetic susceptibility, and environmental cofactors. Virulence factors include the cag pathogenicity island, which induces proinflammatory, pro-proliferative epithelial cell signaling; the cytotoxin VacA, which causes epithelial damage; and an adhesin, BabA. Host genetic polymorphisms that lead to high-level pro-inflammatory cytokine release in response to infection increase cancer risk. Pathogenesis is dependent upon inflammation, a Th-1 acquired immune response and hormonal changes including hypergastrinaemia. Antral-predominant inflammation leads to increased acid production from the uninflamed corpus and predisposes to duodenal ulceration; corpus-predominant gastritis leads to hypochlorhydria and predisposes to gastric ulceration and adenocarcinoma. Falling prevalence of H. pylori in developed countries has led to a falling incidence of associated diseases. However, whether there are disadvantages of an H. pylori-free stomach, for example increased risk of esosphageal adenocarcinoma, remains unclear.
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Affiliation(s)
- John C Atherton
- Wolfson Digestive Diseases Centre and Institute of Infections, Immunity, and Inflammation, University of Nottingham, Nottingham NG7 2UH, United Kingdom.
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Abstract
Isolation of the gastric spiral bacterium Helicobacter pylori totally reversed the false dogma that the stomach was sterile. In addition to its causal role in peptic ulceration, the newly identified bacterium has now been implicated in other gastric and even extragastric diseases, including chronic atrophic gastritis, gastric MALT lymphoma, gastric cancer, functional dyspepsia, idiopathic thrombocytopenic purpura (ITP), iron deficiency anemia, chronic urticaria, ischemic heart disease, and others. The majority of the reports are anecdotal, epidemiologic, or eradication studies, but there are also relevant in vitro studies. ITP represents one disease showing a strong link with H pylori infection. There are also accumulating data on the role of H pylori infection in iron deficiency anemia and ischemic heart disease. In summary, the association between H pylori infection and other extragut diseases is still controversial but worthy of further investigation.
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Affiliation(s)
- Hidekazu Suzuki
- Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
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37
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Abstract
Gastric carcinoma is the second most common cause of cancer-related deaths in the world, accounting for more than 400,000 deaths each year. Infection with cagA-positive Helicobacter pylori plays a pivotal role in the development of gastric adenocarcinoma. The cagA gene product CagA is directly delivered into gastric epithelial cells via the type IV secretion system. Following membrane localization and subsequent tyrosine phosphorylation by Src family kinases, CagA interacts with a variety of host cell proteins that are involved in the regulation of cell growth and motility in both phosphorylation-dependent and -independent manners. Of special interest is the interaction of CagA with the SH2 domain-containing tyrosine phosphatase SHP-2, gain-of-function mutations of which have recently been found in human malignancies. CagA binds to and activates SHP-2 in a tyrosine phosphorylation-dependent manner, thereby provoking abnormal activation of Erk MAP kinase while inducing elevated cell motility. Perturbation of SHP-2 and other signaling molecules by H pylori CagA may predispose cells to accumulate multiple genetic and epigenetic changes that promote multistep gastric carcinogenesis. Intriguingly, the structural polymorphism of CagA accounts for the differences in pathophysiological activity of individual CagA proteins, raising the possibility of subclassification of H pylori strains into benign and malignant strains.
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Affiliation(s)
- Masanori Hatakeyama
- Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
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Shibata W, Hirata Y, Maeda S, Ogura K, Ohmae T, Yanai A, Mitsuno Y, Yamaji Y, Okamoto M, Yoshida H, Kawabe T, Omata M. CagA protein secreted by the intact type IV secretion system leads to gastric epithelial inflammation in the Mongolian gerbil model. J Pathol 2006; 210:306-14. [PMID: 16933206 DOI: 10.1002/path.2040] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Helicobacter pylori causes various gastro-duodenal diseases, including gastric cancer. The CagA protein, an H. pylori virulence factor, induces morphological changes in host cells and may be associated with the development of peptic ulcer and gastric carcinoma. The present study has analysed the role of CagA protein in the pathogenesis of H. pylori infection in the Mongolian gerbil model. Mongolian gerbils were challenged with wild-type H. pylori strain TN2, which has a functional cag pathogenicity island or isogenic mutants with disrupted cagA (DeltacagA) or cagE (DeltacagE) genes. They were sacrificed at 7, 13, and 25 weeks after inoculation. Pathological changes of the gastric mucosa were determined and apoptosis was assessed by the TUNEL assay. Immunohistochemistry for PCNA, phospho-IkappaBalpha, and phospho-Erk was also performed. All of the bacterial strains colonized the gerbil stomach at similar densities; however, the DeltacagA mutant induced milder gastritis than did the wild type. The extent of apoptosis and lymphoid follicle formation in the epithelium appeared to depend on intact cagA. The DeltacagA mutant induced less phosphorylation of IkappaBalpha and Erk, and less expression of interferon-gamma and interleukin-1beta mRNA in the epithelium than did the wild type. It is concluded that CagA protein may be essential for the induction of severe gastritis in the Mongolian gerbil model.
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Affiliation(s)
- W Shibata
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
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Hatakeyama M. Helicobacter pylori CagA -- a bacterial intruder conspiring gastric carcinogenesis. Int J Cancer 2006; 119:1217-23. [PMID: 16557568 DOI: 10.1002/ijc.21831] [Citation(s) in RCA: 80] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Infection with cagA-positive Helicobacter pylori (H. pylori) is associated with the development of gastric adenocarcinoma. The cagA gene product CagA is delivered from the bacterium into the cytoplasm of the bacterium-attached gastric epithelial cell via the type-IV secretion system. Upon membrane localization and subsequent tyrosine phosphorylation by Src family kinases, translocated CagA functions as a scaffolding adaptor that interacts with a number of host proteins involved in cell signaling in both tyrosine phosphorylation-dependent and -independent manners. Of special interest is the interaction of CagA with the SHP-2 tyrosine phosphatase, of which gain-of-function mutations have recently been found in human malignancies. Through the complex formation, SHP-2 is catalytically activated and induces morphological transformation that is associated with increased cell motility. In addition to the perturbation of intracellular signaling, CagA disrupts the apical junctional complex that regulates the cell-cell contact and maintains the integrity of the epithelial structure. These CagA activities may collectively cause cellular dysfunctions that promote accumulation of multiple genetic changes involved in malignant transformation. Further elucidation of host cell signaling targeted by CagA should provide a new paradigm for 'bacterial carcinogenesis' and also give insights into general understanding of inflammation-mediated cancers. Clinically, detailed studies on the relationship between structural diversity and degree of pathogenic activity of CagA should make it possible to identify a high-risk group for gastric carcinoma among H. pylori-infected populations through cagA genotyping.
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Affiliation(s)
- Masanori Hatakeyama
- Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
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Hirata Y, Ohmae T, Shibata W, Maeda S, Ogura K, Yoshida H, Kawabe T, Omata M. MyD88 and TNF receptor-associated factor 6 are critical signal transducers in Helicobacter pylori-infected human epithelial cells. THE JOURNAL OF IMMUNOLOGY 2006; 176:3796-803. [PMID: 16517750 DOI: 10.4049/jimmunol.176.6.3796] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Helicobacter pylori induces NF-kappaB activation, leading to mucosal inflammation via cag pathogenicity island. Although recent studies have implicated several candidate proteins of both H. pylori and host, the molecular mechanism by which H. pylori activates NF-kappaB remains unclear. The aim of this study was to analyze the mechanism of cag pathogenicity island-mediated NF-kappaB activation in epithelial cells. The responses of human cell lines and mouse embryonic fibroblasts to infection with wild-type H. pylori or cagE mutant were investigated. The effect of small interfering RNAs (siRNAs) for several NF-kappaB signaling intermediate molecules was evaluated in H. pylori-induced IkappaBalpha phosphorylation and IL-8 production. Protein interactions of exogenously expressed TNFR-associated factor 6 (TRAF6) and MyD88 or receptor-interacting protein 2 and nucleotide-binding oligomerization domain 1 or those of endogenous IkappaB kinase, TGF-beta-activated kinase 1 (TAK1), and TRAF6 were assessed by immunoprecipitation. Cag pathogenicity island-dependent NF-kappaB activation was observed in human cell lines, but not in mouse fibroblasts. In human epithelial cells, H. pylori-induced IkappaBalpha phosphorylation and IL-8 production were severely inhibited by siRNAs directed against TAK1, TRAF6, and MyD88. In contrast, siRNAs for TRAF2, IL-1R-associated kinases 1 and 4, and cell surface receptor proteins did not affect these responses. H. pylori infection greatly enhanced MyD88 and TRAF6 complex formation in a cag-dependent manner, but did not enhance Nod1 and receptor-interacting protein 2 complex formation. H. pylori also induced TAK1 and TRAF6 complexes. These results suggest that the cag pathogenicity island of H. pylori is a cell type-specific NF-kappaB activator. TAK1, TRAF6, and MyD88 are important signal transducers in H. pylori-infected human epithelial cells.
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Affiliation(s)
- Yoshihiro Hirata
- Department of Gastroenterology, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
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Matysiak-Budnik T, Mégraud F. Helicobacter pylori infection and gastric cancer. Eur J Cancer 2006; 42:708-16. [PMID: 16556496 DOI: 10.1016/j.ejca.2006.01.020] [Citation(s) in RCA: 80] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2006] [Accepted: 01/13/2006] [Indexed: 02/06/2023]
Abstract
The pathogenesis of gastric cancer (GC) includes a sequence of events that begins with Helicobacter pylori-induced chronic superficial gastritis, progressing towards atrophic gastritis, intestinal metaplasia, dysplasia and eventually GC. The association between H. pylori and GC is supported by experimental data showing a capacity of H. pylori to induce GC in animals, and the results of interventional studies showing that H. pylori eradication can lower the risk of GC and prevent development of pre-cancerous lesions in humans and in experimental animals. The "driving force" of gastric carcinogenesis is a chronic gastric inflammation, whose intensity and localisation depending on bacterial, host and environmental factors, determines the risk of GC. The mechanisms by which chronic inflammation lead to epithelial and pre-cancerous lesions include induction of oxidative stress, perturbation of the epithelial cells proliferation/apoptosis ratio, and cytokine secretion. Several molecular alterations associated with gastric carcinogenesis have also been described.
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Backert S, Gressmann H, Kwok T, Zimny-Arndt U, König W, Jungblut PR, Meyer TF. Gene expression and protein profiling of AGS gastric epithelial cells upon infection with Helicobacter pylori. Proteomics 2006; 5:3902-18. [PMID: 16145711 DOI: 10.1002/pmic.200401240] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Helicobacter pylori, one of the most common bacterial pathogens, colonizes the human stomach and causes a variety of gastric diseases. This pathogen elicits a range of phenotypic responses in infected cultured AGS gastric epithelial cells, including expression of proinflammatory genes and changes in the actin cytoskeleton. Some of these responses are mediated by the type IV secretion system (T4SS) encoded by the cag pathogenicity island. We have used two global approaches, namely 2-DE combined with PMF and cDNA expression array analyses, to study in both a comprehensive and quantitative manner the protein profile and the temporal patterns of mRNA accumulation in AGS cells upon infection with H. pylori and isogenic T4SS mutants. We identified 140 transcripts and detected 190 protein species that were differentially regulated upon infection. Infection with wild-type H. pylori induced expression of a variety of host genes and changes in protein pattern involved in transcriptional responses, cell shape regulation and signal transduction. Among them, some were differentially regulated in a cag PAI-dependent manner, as shown by both the proteomic and cDNA expression array approaches. While 2-DE and PMF allowed us to examine the protein profiles in the infected host, array analysis enabled us to demonstrate dynamic temporal changes in host gene expression profile. In conclusion, our combined application of the two global approaches provides further molecular details on how the host cell responds to infection by H. pylori and its isogenic T4SS mutants on both transcriptional and protein levels. The findings pinpoint host proteins such as serine/threonine and tyrosine kinases, transcription factors, cell cycle related components and actin cytoskeletal signaling molecules as potential targets of individual H. pylori virulence determinants. This study serves as a basis for future work on transcription and proteome analyses of the H. pylori infection model.
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Affiliation(s)
- Steffen Backert
- Department of Medical Microbiology, Otto von Guericke University, Magdeburg, Germany.
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Suzuki M, Mimuro H, Suzuki T, Park M, Yamamoto T, Sasakawa C. Interaction of CagA with Crk plays an important role in Helicobacter pylori-induced loss of gastric epithelial cell adhesion. ACTA ACUST UNITED AC 2006; 202:1235-47. [PMID: 16275761 PMCID: PMC2213224 DOI: 10.1084/jem.20051027] [Citation(s) in RCA: 185] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
CagA protein is a major virulence factor of Helicobacter pylori, which is delivered into gastric epithelial cells and elicits growth factor-like responses. Once within the cells, CagA is tyrosine phosphorylated by Src family kinases and targets host proteins required to induce the cell responses. We show that the phosphorylated CagA binds Crk adaptor proteins (Crk-II, Crk-I, and Crk-L) and that the interaction is important for the CagA-mediated host responses during H. pylori infection. H. pylori-induced scattering of gastric epithelial cells in culture was blocked by overexpression of dominant-negative Crk and by RNA interference-mediated knockdown of endogenous Crk. H. pylori infection of the gastric epithelium induced disruption of E-cadherin/catenin-containing adherens junctions, which was also dependent on CagA/Crk signaling. Furthermore, inhibition of the SoS1/H-Ras/Raf1, C3G/Rap1/B-Raf, or Dock180/Rac1/Wiskott-Aldrich syndrome protein family verprolin homologous protein pathway, all of which are involved downstream of Crk adaptors, greatly diminished the CagA-associated host responses. Thus, CagA targeting of Crk plays a central role in inducing the pleiotropic cell responses to H. pylori infection that cause several gastric diseases, including gastric cancer.
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Affiliation(s)
- Masato Suzuki
- Department of Microbiology and Immunology, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Minato-ku, Japan
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Ernst PB, Peura DA, Crowe SE. The translation of Helicobacter pylori basic research to patient care. Gastroenterology 2006; 130:188-206; quiz 212-3. [PMID: 16401482 DOI: 10.1053/j.gastro.2005.06.032] [Citation(s) in RCA: 105] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2005] [Accepted: 06/09/2005] [Indexed: 12/14/2022]
Abstract
In 1984, Barry Marshall and Robin Warren proposed a role for bacterial infections in the pathogenesis of gastroduodenal disease, which triggered an avalanche of research intended to prove or disprove their theory. The result has been a series of advances that have enhanced our understanding of these diseases and completely modernized the clinical approach to their management. In just over 20 years, many aspects of the immunopathogenesis of these diseases have been dissected at the molecular level, with key pathogenic mechanisms being validated by the identification of genes that are associated with the development of gastric cancer. There has been particular emphasis on understanding the molecular structures associated with Helicobacter pylori and their role in modifying the host responses. Gastric immune and inflammatory responses have emerged as key elements in the pathogenesis of gastritis and epithelial cell damage. This review summarizes important findings emanating from basic research primarily related to the immunopathogenesis of H pylori that have advanced the practice of medicine or our understanding of gastroduodenal disease.
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Affiliation(s)
- Peter B Ernst
- Digestive Health Center of Excellence, Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, Virginia 22908-0708, USA.
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Backert S, Selbach M. Tyrosine-phosphorylated bacterial effector proteins: the enemies within. Trends Microbiol 2005; 13:476-84. [PMID: 16099656 DOI: 10.1016/j.tim.2005.08.002] [Citation(s) in RCA: 74] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2005] [Revised: 07/06/2005] [Accepted: 08/05/2005] [Indexed: 12/14/2022]
Abstract
The tyrosine phosphorylation of proteins has a central role during signal transduction in eukaryotes. Recent progress shows that tyrosine phosphorylation is also a common feature of several effector proteins translocated by bacterial type III and type IV secretion systems. The involvement of these secretion systems in disease development is exemplified by a variety of pathogenic processes: pedestal formation (Tir of EPEC and Citrobacter), cell scattering (CagA of Helicobacter), invasion (Tarp of Chlamydia) and possibly proinflammatory responses and cell proliferation (BepD-F of Bartonella). The discovery that different bacterial pathogens use this common strategy to subvert host-cell function suggests that more examples will soon emerge.
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Affiliation(s)
- Steffen Backert
- Otto-von-Guericke-Universität Magdeburg, Institut für Medizinische Mikrobiologie, Leipziger Str. 44, D-39120 Magdeburg, Germany.
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Abstract
Infection with CagA-positive Helicobacter pylori is associated with the development of gastric adenocarcinoma. The CagA gene product CagA is injected directly from the bacterium into the bacterium-attached gastric epithelial cells via the type-IV secretion system. Upon membrane localization and subsequent tyrosine phosphorylation by Src family kinases, CagA functions as a scaffolding adaptor and interacts with a number of host proteins that regulate cell growth, cell motility and cell polarity in both CagA phosphorylation-dependent and phosphorylation-independent manners. Of special interest is the interaction of CagA with the SHP-2 tyrosine phosphatase, gain-of-function mutations that of which have recently been found in a variety of human malignancies. The CagA-SHP-2 interaction is entirely dependent on CagA tyrosine phosphorylation and, through the complex formation, SHP-2 is catalytically activated and induces morphological transformation with elevated cell motility. Intriguingly, structural diversity of the tyrosine phosphorylation sites of CagA accounts for the differential activity of individual CagA to bind and activate SHP-2. Deregulation of SHP-2 and other intracellular signaling molecules by H. pylori CagA may predispose cells to accumulate multiple genetic and epigenetic changes involved in gastric carcinogenesis. Furthermore, the differential potential of individual CagA to disturb cellular functions indicates that H. pylori strains carrying biologically more active CagA are more virulent than those with less active CagA and are more closely associated with gastric carcinoma.
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Affiliation(s)
- Masanori Hatakeyama
- Division of Molecular Oncology, Institute for Genetic Medicine and Division of Chemistry, Graduate School of Science, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060-0815, Japan.
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Shibata W, Hirata Y, Yoshida H, Otsuka M, Hoshida Y, Ogura K, Maeda S, Ohmae T, Yanai A, Mitsuno Y, Seki N, Kawabe T, Omata M. NF-kappaB and ERK-signaling pathways contribute to the gene expression induced by cag PAI-positive-Helicobacter pylori infection. World J Gastroenterol 2005; 11:6134-6143. [PMID: 16273640 PMCID: PMC4436630 DOI: 10.3748/wjg.v11.i39.6134] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2005] [Revised: 04/23/2005] [Accepted: 04/26/2005] [Indexed: 02/06/2023] Open
Abstract
AIM To elucidate the sequential gene expression profile in AGS cells co-cultured with wild-type Helicobacter pylori (H pylori) as a model of H pylori-infected gastric epithelium, and to further examine the contribution of cag-pathogenicity islands (cagPAI)-coding type IV secretion system and the two pathways, nuclear factor kappa B (NF-kappaB) and extracellular signal-regulated kinases (ERK) on wild-type H pylori-induced gene expression. METHODS Gene expression profiles induced by H pylori were evaluated in AGS gastric epithelial cells using cDNA microarray, which were present in the 4 600 independent clones picked up from the human gastric tissue. We also analyzed the contribution of NF-kappaB and ERK signaling on H pylori-induced gene expression by using inhibitors of specific signal pathways. The isogenic mutant with disrupted cagE (Delta cagE) was used to elucidate the role of cagPAI-encoding type IV secretion system in the gene expression profile. RESULTS According to the expression profile, the genes were classified into four clusters. Among them, the clusters characterized by continuous upregulation were most conspicuous, and it contained many signal transducer activity-associated genes. The role of cagPAI on cultured cells was also investigated using isogenic mutant cagE, which carries non-functional cagPAI. Then the upregulation of more than 80% of the induced genes (476/566) was found to depend on cagPAI. Signal transducer pathway through NF-kappaB or ERK are the major pathways which are known to be activated by cagPAI-positive H pylori. The role of these pathways in the whole signal activation by cagPAI-positive H pylori was analyzed. The specific inhibitors against NF-kappaB or ERK pathway blocked the activation of gene expression in 65% (367/566) or 76% (429/566) of the genes whose activation appealed to depend on cagPAI. CONCLUSION These results suggest that more than half of the genes induced by cagPAI-positive H pylori depend on NF-kappaB and ERK signaling activation, and these pathways may play a role in the gene expression induced by host-bacterial interaction which may associate with H pylori-related gastro-duodenal diseases.
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Affiliation(s)
- Wataru Shibata
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
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Peek RM. Pathogenesis of Helicobacter pylori infection. ACTA ACUST UNITED AC 2005; 27:197-215. [PMID: 15928915 DOI: 10.1007/s00281-005-0204-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2004] [Accepted: 03/15/2005] [Indexed: 01/08/2023]
Abstract
Helicobacter pylori induces chronic gastritis, the strongest known risk factor for peptic ulcer disease and distal gastric cancer, yet only a fraction of colonized individuals ever develop clinical disease. H. pylori isolates possess substantial genotypic diversity, which engenders differential host inflammatory responses that influence pathologic outcome. However, clinical sequelae are not completely dependent upon bacterial virulence factors, and disease is also influenced by host genetic diversity, particularly within immune response genes. The focus of this article will be to provide an understanding of mechanisms that underlie H. pylori persistence and pathogenesis as a framework for understanding disease processes that develop from chronic inflammation. Identification of mechanisms that regulate ongoing H. pylori-host interactions will not only improve targeted diagnostic and therapeutic modalities, but may also provide insights into other diseases that arise within the context of pathogen-initiated inflammatory states.
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Affiliation(s)
- Richard M Peek
- Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
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Ohnita K, Isomoto H, Honda S, Wada A, Wen CY, Nishi Y, Mizuta Y, Hirayama T, Kohno S. Helicobacter pylori strain-specific modulation of gastric inflammation in Mongolian gerbils. World J Gastroenterol 2005; 11:1549-53. [PMID: 15770736 PMCID: PMC4305702 DOI: 10.3748/wjg.v11.i10.1549] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: The cag pathogenicity island (PAI) is one of potential virulence determinants of Helicobacter pylori. The Mongolian gerbil is a suitable experimental animal for the screening of virulence factors of H pylori.
METHODS: Five-week-old Mongolian gerbils were inoculated with a standard H pylori strain (ATCC 43504) possessing the cag PAI or a clinical isolate lacking the genes’ cluster (OHPC-0002). The animals were killed at 2, 4, 8, 24 and 48 wk after inoculation (n = 5 each), and macroscopic and histopathological findings in the stomachs were compared.
RESULTS: In gerbils infected with ATCC 43504, a more severe degree of infiltration of polynuclear and mononuclear cells and lymphoid follicles was observed from 4 wk after inoculation compared to gerbils infected with OHPC-0002 especially in the antrum and transitional zone from the fundic to pyloric gland area. In addition, glandular atrophy, intestinal metaplasia, gastric ulcer and hyperplastic polyps were noted in gerbils infected with ATCC 43504, whereas only mild gastric erosions occurred in those infected with OHPC-0002.
CONCLUSION: Our results indicate that the cag PAI could be directly involved in gastric immune and inflammatory responses in the Mongolian gerbils, leading to a more advanced gastric disease.
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Affiliation(s)
- Ken Ohnita
- Second Department of Internal Medicine, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki, Japan
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Nozaki K, Tanaka H, Ikehara Y, Cao X, Nakanishi H, Azuma T, Yamazaki S, Yamaoka Y, Shimizu N, Mafune KI, Kaminishi M, Tatematsu M. Helicobacter pylori-dependent NF-kappa B activation in newly established Mongolian gerbil gastric cancer cell lines. Cancer Sci 2005; 96:170-5. [PMID: 15771620 PMCID: PMC11159330 DOI: 10.1111/j.1349-7006.2005.00030.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Mongolian gerbils are an ideal animal model to explore the role of H. pylori on cancer development. However, there have been no established adenocarcinoma cell lines from this model animal. In the present study, we have established cancer cell lines from a primary gastric cancer tissue of a Mongolian gerbil. The derived cells could be stably attached with H. pylori, revealed under a scanning electron microscope, and easily transplanted to the nude mice. Rapid phosphorylation of IkappaB, Erk1/2, and AKT of these cells was observed by Interleukin-1 beta stimulation, and luciferase reporter gene assay on transcriptional activation of Nuclear Factor kappa B after challenging with either H. pylori NCTC11637 or its isogenic cagE-knockout mutant, H. pylori revealed the cagE-dependent NF-kappaB transcriptional activation. The newly established cancer cell lines from the in vivo gastric carcinogenesis model animal, the Mongolian gerbil, can be used to develop effective therapeutic strategies against gastric cancer, especially in exploring the effect of H. pylori, and thus might greatly contribute to gastric cancer prevention and treatment in humans.
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Affiliation(s)
- Koji Nozaki
- Division of Oncological Pathology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi 464-8681, Japan
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