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Lialios P, Alimperti S. Role of E-cadherin in epithelial barrier dysfunction: implications for bacterial infection, inflammation, and disease pathogenesis. Front Cell Infect Microbiol 2025; 15:1506636. [PMID: 40007608 PMCID: PMC11850337 DOI: 10.3389/fcimb.2025.1506636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Accepted: 01/15/2025] [Indexed: 02/27/2025] Open
Abstract
Epithelial barriers serve as critical defense lines against microbial infiltration and maintain tissue homeostasis. E-cadherin, an essential component of adherens junctions, has emerged as a pivotal molecule that secures epithelial homeostasis. Lately, its pleiotropic role beyond barrier function, including its involvement in immune responses, has become more evident. Herein, we delve into the intricate relationship between (dys)regulation of epithelial homeostasis and the versatile functionality of E-cadherin, describing complex mechanisms that underlie barrier integrity and disruption in disease pathogenesis such as bacterial infection and inflammation, among others. Clinical implications of E-cadherin perturbations in host pathophysiology are emphasized; downregulation, proteolytic phenomena, abnormal localization/signaling and aberrant immune reactions are linked with a broad spectrum of pathology beyond infectious diseases. Finally, potential therapeutic interventions that may harness E-cadherin to mitigate barrier-associated tissue damage are explored. Overall, this review highlights the crucial role of E-cadherin in systemic health, offering insights that could pave the way for strategies to reinforce/restore barrier integrity and treat related diseases.
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Affiliation(s)
- Peter Lialios
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC, United States
- Center for Biological and Biomedical Engineering, Georgetown University, Washington, DC, United States
| | - Stella Alimperti
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC, United States
- Center for Biological and Biomedical Engineering, Georgetown University, Washington, DC, United States
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2
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Vo HVT, Nguyen YT, Kim N, Lee HJ. Vitamin A, D, E, and K as Matrix Metalloproteinase-2/9 Regulators That Affect Expression and Enzymatic Activity. Int J Mol Sci 2023; 24:17038. [PMID: 38069361 PMCID: PMC10707015 DOI: 10.3390/ijms242317038] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 11/25/2023] [Accepted: 11/29/2023] [Indexed: 12/18/2023] Open
Abstract
Fat-soluble vitamins (vitamin A, D, E, and K) assume a pivotal role in maintaining human homeostasis by virtue of their enzymatic functions. The daily inclusion of these vitamins is imperative to the upkeep of various physiological processes including vision, bone health, immunity, and protection against oxidative stress. Current research highlights fat-soluble vitamins as potential therapeutics for human diseases, especially cancer. Fat-soluble vitamins exert their therapeutic effects through multiple pathways, including regulation of matrix metalloproteinases' (MMPs) expression and enzymatic activity. As MMPs have been reported to be involved in the pathology of various diseases, such as cancers, cardiovascular diseases, and neurological disorders, regulating the expression and/or activity of MMPs could be considered as a potent therapeutic strategy. Here, we summarize the properties of fat-soluble vitamins and their potential as promising candidates capable of effectively modulating MMPs through multiple pathways to treat human diseases.
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Affiliation(s)
- Ha Vy Thi Vo
- Department of Chemistry Education, Kongju National University, Gongju 32588, Republic of Korea;
| | - Yen Thi Nguyen
- Department of Chemistry, Kongju National University, Gongju 32588, Republic of Korea;
| | - Namdoo Kim
- Department of Chemistry, Kongju National University, Gongju 32588, Republic of Korea;
| | - Hyuck Jin Lee
- Department of Chemistry Education, Kongju National University, Gongju 32588, Republic of Korea;
- Kongju National University Institute of Science Education, Kongju National University, Gongju 32588, Republic of Korea
- Kongju National University’s Physical Fitness for Health Research Lab (KNUPFHR), Kongju National University, Gongju 32588, Republic of Korea
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3
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González MF, Burgos-Ravanal R, Shao B, Heinecke J, Valenzuela-Valderrama M, Corvalán AH, Quest AFG. Extracellular vesicles from gastric epithelial GES-1 cells infected with Helicobacter pylori promote changes in recipient cells associated with malignancy. Front Oncol 2022; 12:962920. [PMID: 36313672 PMCID: PMC9596800 DOI: 10.3389/fonc.2022.962920] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 09/19/2022] [Indexed: 10/29/2023] Open
Abstract
Chronic Helicobacter pylori (H. pylori) infection is considered the main risk factor for the development of gastric cancer. Pathophysiological changes in the gastric mucosa initiated by this bacterium can persist even after pharmacological eradication and are likely attributable also to changes induced in non-infected cells as a consequence of intercellular communication via extracellular vesicles (EVs). To better understand what such changes might entail, we isolated EVs from immortalized normal gastric GES-1 cells infected (EVHp+) or not with H. pylori (EVHp-) by ultracentrifugation and characterized them. Infection of GES-1 cells with H. pylori significantly increased the release of EVs and slightly decreased the EV mean size. Incubation with EVHp+ for 24 h decreased the viability of GES-1 cells, but increased the levels of IL-23 in GES-1 cells, as well as the migration of GES-1 and gastric cancer AGS cells. Furthermore, incubation of GES-1 and AGS cells with EVHp+, but not with EVHp-, promoted cell invasion and trans-endothelial migration in vitro. Moreover, stimulation of endothelial EA.hy926 cells for 16 h with EVHp+ promoted the formation of linked networks. Finally, analysis by mass spectrometry identified proteins uniquely present and others enriched in EVHp+ compared to EVHp-, several of which are known targets of hypoxia induced factor-1α (HIF-1α) that may promote the acquisition of traits important for the genesis/progression of gastric pre-neoplastic changes associated with H. pylori infection. In conclusion, the harmful effects of H. pylori infection associated with the development of gastric malignancies may spread via EVs to non-infected areas in the early and later stages of gastric carcinogenesis.
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Affiliation(s)
- María Fernanda González
- Laboratorio de Comunicaciones Celulares, Centro de Estudios en Ejercicio, Metabolismo y Cáncer (CEMC), Programa de Biología Celular y Molecular, Facultad de Medicina, Universidad de Chile, Santiago, Chile
- Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Centro Avanzado para Estudios en Enfermedades Crónicas (ACCDIS), Santiago, Chile
| | - Renato Burgos-Ravanal
- Laboratorio de Comunicaciones Celulares, Centro de Estudios en Ejercicio, Metabolismo y Cáncer (CEMC), Programa de Biología Celular y Molecular, Facultad de Medicina, Universidad de Chile, Santiago, Chile
- Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Centro Avanzado para Estudios en Enfermedades Crónicas (ACCDIS), Santiago, Chile
| | - Baohai Shao
- Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA, United States
| | - Jay Heinecke
- Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA, United States
| | - Manuel Valenzuela-Valderrama
- Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Centro Avanzado para Estudios en Enfermedades Crónicas (ACCDIS), Santiago, Chile
- Laboratorio de Microbiología Celular, Instituto de Investigación y Postgrado, Universidad Central de Chile, Santiago, Chile
| | - Alejandro H. Corvalán
- Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Centro Avanzado para Estudios en Enfermedades Crónicas (ACCDIS), Santiago, Chile
- Departamento de Hematología-Oncología, Facultad de Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Andrew F. G. Quest
- Laboratorio de Comunicaciones Celulares, Centro de Estudios en Ejercicio, Metabolismo y Cáncer (CEMC), Programa de Biología Celular y Molecular, Facultad de Medicina, Universidad de Chile, Santiago, Chile
- Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Centro Avanzado para Estudios en Enfermedades Crónicas (ACCDIS), Santiago, Chile
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4
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Astaxanthin Inhibits Matrix Metalloproteinase Expression by Suppressing PI3K/AKT/mTOR Activation in Helicobacter pylori-Infected Gastric Epithelial Cells. Nutrients 2022; 14:nu14163427. [PMID: 36014933 PMCID: PMC9412703 DOI: 10.3390/nu14163427] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 08/16/2022] [Accepted: 08/18/2022] [Indexed: 12/13/2022] Open
Abstract
Helicobacter pylori (H. pylori) increases production of reactive oxygen species (ROS) and activates signaling pathways associated with gastric cell invasion, which are mediated by matrix metalloproteinases (MMPs). We previously demonstrated that H. pylori activated mitogen-activated protein kinase (MAPK) and increased expression of MMP-10 in gastric epithelial cells. MMPs degrade the extracellular matrix, enhancing tumor invasion and cancer progression. The signaling pathway of phosphatidylinositol 3-kinase (PI3K)/serine/threonine protein kinase B (AKT)/mammalian target of rapamycin (mTOR) is associated with MMP expression. ROS activates PIK3/AKT/mTOR signaling in cancer. Astaxanthin, a xanthophyll carotenoid, shows antioxidant activity by reducing ROS levels in gastric epithelial cells infected with H. pylori. This study aimed to determine whether astaxanthin inhibits MMP expression, cell invasion, and migration by reducing the PI3K/AKT/mTOR signaling in H. pylori-infected gastric epithelial AGS cells. H. pylori induced PIK3/AKT/mTOR and NF-κB activation, decreased IκBα, and induced MMP (MMP-7 and -10) expression, the invasive phenotype, and migration in AGS cells. Astaxanthin suppressed these H. pylori-induced alterations in AGS cells. Specific inhibitors of PI3K, AKT, and mTOR reversed the H. pylori-stimulated NF-κB activation and decreased IκBα levels in the cells. In conclusion, astaxanthin suppressed MMP expression, cell invasion, and migration via inhibition of PI3K/AKT/mTOR/NF-κB signaling in H. pylori-stimulated gastric epithelial AGS cells.
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Larochelle J, Yang C, Liu L, Candelario-Jalil E. An Unexplored Role for MMP-7 (Matrix Metalloproteinase-7) in Promoting Gut Permeability After Ischemic Stroke. Stroke 2022; 53:3238-3242. [PMID: 35904018 DOI: 10.1161/strokeaha.122.040144] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Poststroke infections are common complications of stroke and are highly associated with poor outcomes for patients. Stroke induces profound immunodepression coupled with alterations to autonomic signaling, which together render the body more susceptible to infection from without (nosocomial/community-acquired infection) and from within (commensal bacterial infection). Critical to the hypothesis of commensal infection is the phenomenon of poststroke gut permeability and gut dysbiosis. Few studies have provided adequate explanations for the mechanisms underlying the molecular alterations that produce a more permeable gut and perturbed gut microbiota after stroke. A dysregulation in the production of matrix MMP-7 (metalloproteinase-7) may play a critical role in the progression of gut permeability after stroke. By cleaving junctional and extracellular matrix proteins, MMP-7 is capable of compromising gut barrier integrity. Because of MMP-7's unique abundance in the small intestine and its capacity to be induced in states of bacterial invasion and inflammation, along with its unique degradative capability, MMP-7 may be crucially important to the progression of gut permeability after ischemic stroke.
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Affiliation(s)
- Jonathan Larochelle
- Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville
| | - Changjun Yang
- Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville
| | - Lei Liu
- Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville
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Bernegger S, Jarzab M, Wessler S, Posselt G. Proteolytic Landscapes in Gastric Pathology and Cancerogenesis. Int J Mol Sci 2022; 23:2419. [PMID: 35269560 PMCID: PMC8910283 DOI: 10.3390/ijms23052419] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 02/17/2022] [Accepted: 02/18/2022] [Indexed: 02/01/2023] Open
Abstract
Gastric cancer is a leading cause of cancer-related death, and a large proportion of cases are inseparably linked to infections with the bacterial pathogen and type I carcinogen Helicobacter pylori. The development of gastric cancer follows a cascade of transformative tissue events in an inflammatory environment. Proteases of host origin as well as H. pylori-derived proteases contribute to disease progression at every stage, from chronic gastritis to gastric cancer. In the present article, we discuss the importance of (metallo-)proteases in colonization, epithelial inflammation, and barrier disruption in tissue transformation, deregulation of cell proliferation and cell death, as well as tumor metastasis and neoangiogenesis. Proteases of the matrix metalloproteinase (MMP) and a disintegrin and metalloproteinase domain-containing protein (ADAM) families, caspases, calpain, and the H. pylori proteases HtrA, Hp1012, and Hp0169 cleave substrates including extracellular matrix molecules, chemokines, and cytokines, as well as their cognate receptors, and thus shape the pathogenic microenvironment. This review aims to summarize the current understanding of how proteases contribute to disease progression in the gastric compartment.
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Affiliation(s)
- Sabine Bernegger
- Division of Microbiology, Department of Biosciences and Medical Biology, Paris Lodron University of Salzburg, Hellbrunner Strasse 34, 5020 Salzburg, Austria; (S.B.); (M.J.); (S.W.)
| | - Miroslaw Jarzab
- Division of Microbiology, Department of Biosciences and Medical Biology, Paris Lodron University of Salzburg, Hellbrunner Strasse 34, 5020 Salzburg, Austria; (S.B.); (M.J.); (S.W.)
| | - Silja Wessler
- Division of Microbiology, Department of Biosciences and Medical Biology, Paris Lodron University of Salzburg, Hellbrunner Strasse 34, 5020 Salzburg, Austria; (S.B.); (M.J.); (S.W.)
- Cancer Cluster Salzburg and Allergy Cancer BioNano Research Centre, University of Salzburg, Hellbrunner Strasse 34, 5020 Salzburg, Austria
| | - Gernot Posselt
- Division of Microbiology, Department of Biosciences and Medical Biology, Paris Lodron University of Salzburg, Hellbrunner Strasse 34, 5020 Salzburg, Austria; (S.B.); (M.J.); (S.W.)
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Sokolova O, Naumann M. Matrix Metalloproteinases in Helicobacter pylori-Associated Gastritis and Gastric Cancer. Int J Mol Sci 2022; 23:1883. [PMID: 35163805 PMCID: PMC8836485 DOI: 10.3390/ijms23031883] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 02/02/2022] [Accepted: 02/04/2022] [Indexed: 02/05/2023] Open
Abstract
Gastric cancer is one of the leading causes of the cancer-related mortality worldwide. The etiology of this disease is complex and involves genetic predisposition and environmental factors, including Helicobacter pylori. Infection of the stomach with H. pylori leads to gastritis and gastric atrophy, which can progress stepwise to gastric cancer. Matrix metalloproteinases (MMPs) actively participate in the pathology development. The further progression of gastric cancer seems to be less dependent on bacteria but of intra-tumor cell dynamics. Bioinformatics data confirmed an important role of the extracellular matrix constituents and specific MMPs in stomach carcinoma invasion and metastasis, and revised their potential as predictors of the disease outcome. In this review, we describe, in detail, the impact of MMPs in H. pylori-associated gastritis and gastric cancer.
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Affiliation(s)
- Olga Sokolova
- Institute of Experimental Internal Medicine, Medical Faculty, Otto von Guericke University, Leipziger Str. 44, 39120 Magdeburg, Germany
| | - Michael Naumann
- Institute of Experimental Internal Medicine, Medical Faculty, Otto von Guericke University, Leipziger Str. 44, 39120 Magdeburg, Germany
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Rawson A, Saxena V, Gao H, Hooks J, Xuei X, McGuire P, Hato T, Hains DS, Anderson RM, Schwaderer AL. A Pilot Single Cell Analysis of the Zebrafish Embryo Cellular Responses to Uropathogenic Escherichia coli Infection. Pathog Immun 2022; 7:1-18. [PMID: 35178490 PMCID: PMC8843076 DOI: 10.20411/pai.v7i1.479] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 12/06/2021] [Indexed: 11/23/2022] Open
Abstract
Background: Uropathogenic Escherichia coli (UPEC) infections are common and when they disseminate can be of high morbidity.
Methods: We studied the effects of UPEC infection using single cell RNA sequencing (scRNAseq) in zebrafish. Bulk RNA sequencing has historically been used to evaluate gene expression patterns, but scRNAseq allows gene expression to be evaluated at the single cell level and is optimal for evaluating heterogeneity within cell types and rare cell types. Zebrafish cohorts were injected with either saline or UPEC,and scRNAseq and canonical pathway analyses were performed.
Results: Canonical pathway analysis of scRNAseq data provided key information regarding innate immune pathways in the cells determined to be thymus cells, ionocytes, macrophages/monocytes, and pronephros cells. Pathways activated in thymus cells included interleukin 6 (IL-6) signaling and production of reactive oxygen species. Fc receptor-mediated phagocytosis was a leading canonical pathway in the pronephros and macrophages. Genes that were downregulated in UPEC vs saline exposed embryos involved the cellular response to the Gram-negative endotoxin lipopolysaccharide (LPS) and included Forkhead Box O1a (Foxo1a), Tribbles Pseudokinase 3 (Trib3), Arginase 2 (Arg2) and Polo Like Kinase 3 (Plk3).
Conclusions: Because 4-day post fertilization zebrafish embryos only have innate immune systems, the scRNAseq provides insights into pathways and genes that cell types utilize in the bacterial response. Based on our analysis, we have identified genes and pathways that might serve as genetic targets for treatment and further investigation in UPEC infections at the single cell level.
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Affiliation(s)
- Ashley Rawson
- Indiana University School of Medicine, Department of Pediatrics, Division of Nephrology
| | - Vijay Saxena
- Indiana University School of Medicine, Department of Pediatrics, Division of Nephrology
| | - Hongyu Gao
- Indiana University School of Medicine, Department of Medical & Molecular Genetics
| | - Jenaya Hooks
- Indiana University School of Medicine, Department of Pediatrics, Division of Nephrology
| | - Xiaoling Xuei
- Indiana University School of Medicine, Department of Medical & Molecular Genetics
| | - Patrick McGuire
- Indiana University School of Medicine, Department of Medical & Molecular Genetics
| | - Takashi Hato
- Indiana University School of Medicine, Department of Medicine, Division of Nephrology
| | - David S. Hains
- Indiana University School of Medicine, Department of Pediatrics, Division of Nephrology
| | - Ryan M. Anderson
- University of Chicago, Section of Endocrinology, Diabetes and Metabolism
- CORRESPONDING AUTHOR Andrew Schwaderer, Indiana University School of Medicine, Riley Hospital for Children, 699 Riley Hospital Dr., RR230, Indianapolis, IN 46202; Phone: 317-274-2527;
| | - Andrew L. Schwaderer
- Indiana University School of Medicine, Department of Pediatrics, Division of Nephrology
- CORRESPONDING AUTHOR Ryan M Anderson, University of Chicago, Medicine-Endocrinology, Chicago, IL 60637;
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Mirbagheri SZ, Bakhtiari R, Fakhre Yaseri H, Rahimi Foroushani A, Eshraghi SS, Alebouyeh M. Transcriptional alteration of genes linked to gastritis concerning Helicobacter pylori infection status and its virulence factors. Mol Biol Rep 2021; 48:6481-6489. [PMID: 34427890 DOI: 10.1007/s11033-021-06654-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Accepted: 08/16/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND Helicobacter pylori infection and heterogeneity in its pathogenesis could describe diversity in the expression of inflammatory genes in the gastric tissue. We aimed to investigate transcriptional alteration of genes linked to gastritis concerning the H. pylori infection status and its virulence factors. METHODS AND RESULTS Biopsy samples of 12 infected and 12 non-infected patients with H. pylori that showed moderate chronic gastritis were selected for transcriptional analysis. Genotyping of H. pylori strains was done using PCR and relative expression of inflammatory genes was compared between the infected and non-infected patients using relative quantitative real-time PCR. Positive correlations between transcriptional changes of IL8 with TNF-α and Noxo1 in the infected and TNF-α with Noxo1, MMP7, and Atp4A in the non-infected patients were detected. Six distinct genotypes of H. pylori were detected that showed no correlation with gender, ethnicity, age, endoscopic findings, and transcriptional levels of host genes. Irrespective of the characterized genotypes, our results showed overexpression of TNF-α, MMP7, Noxo1, and ATP4A in the infected and IL-8, Noxo1, and ATP4A in the non-infected patients. CONCLUSIONS A complexity in transcription of genes respective to the characterized H. pylori genotypes in the infected patients was detected in our study. The observed difference in co-regulation of genes linked to gastritis in the infected and non-infected patients proposed involvement of different regulatory pathways in the inflammation of the gastric tissue in the studied groups.
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Affiliation(s)
- Seyedeh Zohre Mirbagheri
- Department of Pathobiology, School of Public Health and Institute Health Research, Tehran University of Medical Sciences, Tehran, Iran
| | - Ronak Bakhtiari
- Department of Pathobiology, School of Public Health and Institute Health Research, Tehran University of Medical Sciences, Tehran, Iran.
| | - Hashem Fakhre Yaseri
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran.,Gastroenterology, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Abbas Rahimi Foroushani
- Department of Epidemiology and Biostatistics, School of Public Health and Institute Health Research, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyyed Saeed Eshraghi
- Department of Pathobiology, School of Public Health and Institute Health Research, Tehran University of Medical Sciences, Tehran, Iran
| | - Masoud Alebouyeh
- Pediatric Infections Research Centre, Research Institute for Children's Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Abdi E, Latifi-Navid S, Abedi Sarvestani F, Esmailnejad MH. Emerging therapeutic targets for gastric cancer from a host- Helicobacter pylori interaction perspective. Expert Opin Ther Targets 2021; 25:685-699. [PMID: 34410200 DOI: 10.1080/14728222.2021.1971195] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Gastric cancer (GC) has the higher genetic, cytologic, and architectural heterogeneity compared to other gastrointestinal cancers. By inducing gastric inflammation, Helicobacter pylori (HP) may lead to GC through combining bacterial factors with host factors. In this regard, identification of the major therapeutic targets against the host-HP interactions plays a critical role in GC prevention, diagnosis, and treatment. AREAS COVERED This study offers new insights into the promising therapeutic targets against the angiogenesis, invasion, or metastasis of GC from a host-HP interaction perspective. To this end, MEDLINE, EMBASE, LILACS, AIM, and IndMed databases were searched for relevant articles since 1992. EXPERT OPINION Wnt signaling and COX pathway have a well-documented history in the genesis of GC by HP and might be considered as the most promising targets for early GC treatment. Destroying HP may decrease the risk of GC, but it cannot fully hinder the GC development induced by HP infection. Therefore, targeting HP-activated pathways, especially COX-2/Wnt/beta-catenin/VEGF, TLR2/TLR9/COX-2, COX2-PGE2, and NF-κB/COX-2, as well as EPHA2, MMPs, and miR-543/SIRT1 axis, can be an effective measure in the early treatment of GC. However, different clinical trials and large, multi-center cohorts are required to validate these potentially effective targets for GC therapy.
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Affiliation(s)
- Esmat Abdi
- Department of Biology, Faculty of Sciences, University of Mohaghegh Ardabili, Ardabil, Iran
| | - Saeid Latifi-Navid
- Department of Biology, Faculty of Sciences, University of Mohaghegh Ardabili, Ardabil, Iran
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β-Carotene Inhibits Expression of Matrix Metalloproteinase-10 and Invasion in Helicobacter pylori-Infected Gastric Epithelial Cells. Molecules 2021; 26:molecules26061567. [PMID: 33809289 PMCID: PMC8002206 DOI: 10.3390/molecules26061567] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 03/02/2021] [Accepted: 03/10/2021] [Indexed: 02/08/2023] Open
Abstract
Matrix metalloproteinases (MMPs), key molecules of cancer invasion and metastasis, degrade the extracellular matrix and cell–cell adhesion molecules. MMP-10 plays a crucial role in Helicobacter pylori-induced cell-invasion. The mitogen-activated protein kinase (MAPK) signaling pathway, which activates activator protein-1 (AP-1), is known to mediate MMP expression. Infection with H. pylori, a Gram-negative bacterium, is associated with gastric cancer development. A toxic factor induced by H. pylori infection is reactive oxygen species (ROS), which activate MAPK signaling in gastric epithelial cells. Peroxisome proliferator-activated receptor γ (PPAR-γ) mediates the expression of antioxidant enzymes including catalase. β-Carotene, a red-orange pigment, exerts antioxidant and anti-inflammatory properties. We aimed to investigate whether β-carotene inhibits H. pylori-induced MMP expression and cell invasion in gastric epithelial AGS (gastric adenocarcinoma) cells. We found that H. pylori induced MMP-10 expression and increased cell invasion via the activation of MAPKs and AP-1 in gastric epithelial cells. Specific inhibitors of MAPKs suppressed H. pylori-induced MMP-10 expression, suggesting that H. pylori induces MMP-10 expression through MAPKs. β-Carotene inhibited the H. pylori-induced activation of MAPKs and AP-1, expression of MMP-10, and cell invasion. Additionally, it promoted the expression of PPAR-γ and catalase, which reduced ROS levels in H. pylori-infected cells. In conclusion, β-carotene exerts an inhibitory effect on MAPK-mediated MMP-10 expression and cell invasion by increasing PPAR-γ-mediated catalase expression and reducing ROS levels in H. pylori-infected gastric epithelial cells.
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12
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Liao HY, Da CM, Liao B, Zhang HH. Roles of matrix metalloproteinase-7 (MMP-7) in cancer. Clin Biochem 2021; 92:9-18. [PMID: 33713636 DOI: 10.1016/j.clinbiochem.2021.03.003] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 02/13/2021] [Accepted: 03/03/2021] [Indexed: 12/19/2022]
Abstract
Matrix metalloproteinase-7 (MMP-7) is a small proteolytic enzyme that secretes zinc and calcium endopeptidases. It can degrade a variety of extracellular matrix substrates and other substrates and plays important regulatory roles in many human pathophysiological processes. Since its discovery, MMP-7 has been recognized as a regulatory protein in wound healing, bone growth, and remodeling. Later, MMP-7 was reported to regulate the occurrence and development of cancers and mediate the proliferation, differentiation, metastasis, and invasion of several types of cancer cells via various mechanisms. Thus, matrix metalloproteinase-7 may be a promising tumor biomarker and therapeutic target. The expression of MMP-7 correlates with the clinical characteristics of cancer patients, and its expression profile is a new diagnostic and prognostic biomarker for a variety of human diseases. Hence, manipulating the expression or function of MMP-7 may be a potential treatment strategy for different diseases including cancers. This review summarizes the role played by MMP-7 in carcinogenesis of several human cancers, underlying mechanisms, and its clinical significance of the occurrence and development of cancers.
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Affiliation(s)
- Hai-Yang Liao
- The Second Clinical Medical College of Lanzhou University, 82 Cuiying Men, Lanzhou 730030, PR China; Orthopaedics Key Laboratory of Gansu Province, Lanzhou 730000, PR China.
| | - Chao-Ming Da
- The Second Clinical Medical College of Lanzhou University, 82 Cuiying Men, Lanzhou 730030, PR China; Orthopaedics Key Laboratory of Gansu Province, Lanzhou 730000, PR China.
| | - Bei Liao
- Orthopaedics Key Laboratory of Gansu Province, Lanzhou 730000, PR China; The First Clinical Medical College of Lanzhou University, 1 Donggang Road, Lanzhou 730000, PR China
| | - Hai-Hong Zhang
- The Second Clinical Medical College of Lanzhou University, 82 Cuiying Men, Lanzhou 730030, PR China; Orthopaedics Key Laboratory of Gansu Province, Lanzhou 730000, PR China.
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13
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Zhang Y, Qin L, Ma X, Wang Y, Wu Y, Jiang J. Coexpression of Matrix Metalloproteinase-7 and Tissue Inhibitor of Metalloproteinase-1 as a Prognostic Biomarker in Gastric Cancer. DISEASE MARKERS 2020; 2020:8831466. [PMID: 33005257 PMCID: PMC7509560 DOI: 10.1155/2020/8831466] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 07/24/2020] [Accepted: 08/01/2020] [Indexed: 01/09/2023]
Abstract
BACKGROUND Degradation of the extracellular matrix (ECM), an essential step in tumour invasion and metastasis, is mainly dependent on the activities of both matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). This study aimed to explore whether expression of MMP-7 and TIMP-1 alone and in combination can be used as a prognostic marker for gastric cancer (GC). METHOD A total of 285 patients who had undergone tumourectomy for GC were included. Gastric tumour tissues were stained immunohistochemically to evaluate expression of MMP-7 and TIMP-1. RESULTS Expression of MMP-7 was associated with tumour N stage and neural invasion. Multivariate Cox regression analysis suggested that expression of MMP-7 or TIMP-1 alone cannot serve as an indicator of patient prognosis; however, coexpression of MMP-7 and TIMP-1 was found to be an independent predictive factor of overall survival in patients with GC (HR = 1.74, 95% CI: 1.08-2.80). The results of stratified analysis also showed that the predictive value of MMP-7 and TIMP-1 coexpression was stronger in patients with N3 stage disease and not receiving chemotherapy. CONCLUSIONS In conclusion, coexpression of MMP-7 and its inhibitor TIMP-1 in gastric tumour tissues is a potential prognostic marker for GC. Greater knowledge of protein expression will lead to new paradigms and possible improvements in therapeutics.
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Affiliation(s)
- Yangyu Zhang
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Lili Qin
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Xiaobo Ma
- Department of Pathology, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Yueqi Wang
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Yanhua Wu
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Jing Jiang
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin Province, China
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14
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Kim SH, Kim H. Transcriptome Analysis of the Inhibitory Effect of Astaxanthin on Helicobacter pylori-Induced Gastric Carcinoma Cell Motility. Mar Drugs 2020; 18:md18070365. [PMID: 32679742 PMCID: PMC7404279 DOI: 10.3390/md18070365] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Revised: 07/14/2020] [Accepted: 07/14/2020] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori (H. pylori) infection promotes the metastasis of gastric carcinoma cells by modulating signal transduction pathways that regulate cell proliferation, motility, and invasion. Astaxanthin (ASTX), a xanthophyll carotenoid, is known to inhibit cancer cell migration and invasion, however the mechanism of action of ASTX in H. pylori-infected gastric epithelial cells is not well understood. To gain insight into this process, we carried out a comparative RNA sequencing (RNA-Seq) analysis of human gastric cancer AGS (adenocarcinoma gastric) cells as a function of H. pylori infection and ASTX administration. The results were used to identify genes that are differently expressed in response to H. pylori and ASTX. Gene ontology (GO) analysis identified differentially expressed genes (DEGs) to be associated with cell cytoskeleton remodeling, motility, and/or migration. Among the 20 genes identified, those encoding c-MET, PI3KC2, PLCγ1, Cdc42, and ROCK1 were selected for verification by real-time PCR analysis. The verified genes were mapped, using signaling networks contained in the KEGG database, to create a signaling pathway through which ASTX might mitigate the effects of H. pylori-infection. We propose that H. pylori-induced upregulation of the upstream regulator c-MET, and hence, its downstream targets Cdc42 and ROCK1, is suppressed by ASTX. ASTX is also suggested to counteract H. pylori-induced activation of PI3K and PLCγ. In conclusion, ASTX can suppress H. pylori-induced gastric cancer progression by inhibiting cytoskeleton reorganization and reducing cell motility through downregulation of c-MET, EGFR, PI3KC2, PLCγ1, Cdc42, and ROCK1.
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15
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Lloyd KA, Parsons BN, Burkitt MD, Moore AR, Papoutsopoulou S, Boyce M, Duckworth CA, Exarchou K, Howes N, Rainbow L, Fang Y, Oxvig C, Dodd S, Varro A, Hall N, Pritchard DM. Netazepide Inhibits Expression of Pappalysin 2 in Type 1 Gastric Neuroendocrine Tumors. Cell Mol Gastroenterol Hepatol 2020; 10:113-132. [PMID: 32004755 PMCID: PMC7215182 DOI: 10.1016/j.jcmgh.2020.01.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 01/23/2020] [Accepted: 01/23/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS In patients with autoimmune atrophic gastritis and achlorhydria, hypergastrinemia is associated with the development of type 1 gastric neuroendocrine tumors (gNETs). Twelve months of treatment with netazepide (YF476), an antagonist of the cholecystokinin B receptor (CCKBR or CCK2R), eradicated some type 1 gNETs in patients. We investigated the mechanisms by which netazepide induced gNET regression using gene expression profiling. METHODS We obtained serum samples and gastric corpus biopsy specimens from 8 patients with hypergastrinemia and type 1 gNETs enrolled in a phase 2 trial of netazepide. Control samples were obtained from 10 patients without gastric cancer. We used amplified and biotinylated sense-strand DNA targets from total RNA and Affymetrix (Thermofisher Scientific, UK) Human Gene 2.0 ST microarrays to identify differentially expressed genes in stomach tissues from patients with type 1 gNETs before, during, and after netazepide treatment. Findings were validated in a human AGSGR gastric adenocarcinoma cell line that stably expresses human CCK2R, primary mouse gastroids, transgenic hypergastrinemic INS-GAS mice, and patient samples. RESULTS Levels of pappalysin 2 (PAPPA2) messenger RNA were reduced significantly in gNET tissues from patients receiving netazepide therapy compared with tissues collected before therapy. PAPPA2 is a metalloproteinase that increases the bioavailability of insulin-like growth factor (IGF) by cleaving IGF binding proteins (IGFBPs). PAPPA2 expression was increased in the gastric corpus of patients with type 1 gNETs, and immunohistochemistry showed localization in the same vicinity as CCK2R-expressing enterochromaffin-like cells. Up-regulation of PAPPA2 also was found in the stomachs of INS-GAS mice. Gastrin increased PAPPA2 expression with time and in a dose-dependent manner in gastric AGSGR cells and mouse gastroids by activating CCK2R. Knockdown of PAPPA2 in AGSGR cells with small interfering RNAs significantly decreased their migratory response and tissue remodeling in response to gastrin. Gastrin altered the expression and cleavage of IGFBP3 and IGFBP5. CONCLUSIONS In an analysis of human gNETS and mice, we found that gastrin up-regulates the expression of gastric PAPPA2. Increased PAPPA2 alters IGF bioavailability, cell migration, and tissue remodeling, which are involved in type 1 gNET development. These effects are inhibited by netazepide.
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Affiliation(s)
- Katie A Lloyd
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
| | - Bryony N Parsons
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
| | - Michael D Burkitt
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
| | - Andrew R Moore
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; Liverpool University Hospitals, National Health Service Foundation Trust, Liverpool, United Kingdom
| | - Stamatia Papoutsopoulou
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
| | - Malcolm Boyce
- Trio Medicines, Ltd, Hammersmith Medicines Research, London, United Kingdom
| | - Carrie A Duckworth
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
| | - Klaire Exarchou
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; Liverpool University Hospitals, National Health Service Foundation Trust, Liverpool, United Kingdom
| | - Nathan Howes
- Liverpool University Hospitals, National Health Service Foundation Trust, Liverpool, United Kingdom
| | - Lucille Rainbow
- Centre for Genomic Research, Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom
| | - Yongxiang Fang
- Centre for Genomic Research, Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom
| | - Claus Oxvig
- Department of Molecular Biology and Genetics, Aarhus University, Aarhus C, Denmark
| | - Steven Dodd
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
| | - Andrea Varro
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
| | - Neil Hall
- Centre for Genomic Research, Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom; The Earlham Institute, Norwich, Norfolk, United Kingdom; School of Biological Sciences, University of East Anglia, Norwich, Norfolk, United Kingdom
| | - D Mark Pritchard
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; Liverpool University Hospitals, National Health Service Foundation Trust, Liverpool, United Kingdom.
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Tafrihi M, Golbabaei M, Shokrzadeh M. Association of the −181 G→A polymorphism in the MMP-7 gene promoter and gastric cancer: A case-control study. Meta Gene 2019. [DOI: 10.1016/j.mgene.2019.100594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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Yao X, Smolka AJ. Gastric Parietal Cell Physiology and Helicobacter pylori-Induced Disease. Gastroenterology 2019; 156:2158-2173. [PMID: 30831083 PMCID: PMC6715393 DOI: 10.1053/j.gastro.2019.02.036] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Revised: 02/12/2019] [Accepted: 02/14/2019] [Indexed: 12/13/2022]
Abstract
Acidification of the gastric lumen poses a barrier to transit of potentially pathogenic bacteria and enables activation of pepsin to complement nutrient proteolysis initiated by salivary proteases. Histamine-induced activation of the PKA signaling pathway in gastric corpus parietal cells causes insertion of proton pumps into their apical plasma membranes. Parietal cell secretion and homeostasis are regulated by signaling pathways that control cytoskeletal changes required for apical membrane remodeling and organelle and proton pump activities. Helicobacter pylori colonization of human gastric mucosa affects gastric epithelial cell plasticity and homeostasis, promoting epithelial progression to neoplasia. By intervening in proton pump expression, H pylori regulates the abundance and diversity of microbiota that populate the intestinal lumen. We review stimulation-secretion coupling and renewal mechanisms in parietal cells and the mechanisms by which H pylori toxins and effectors alter cell secretory pathways (constitutive and regulated) and organelles to establish and maintain their inter- and intracellular niches. Studies of bacterial toxins and their effector proteins have provided insights into parietal cell physiology and the mechanisms by which pathogens gain control of cell activities, increasing our understanding of gastrointestinal physiology, microbial infectious disease, and immunology.
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Affiliation(s)
- Xuebiao Yao
- MOE Key Laboratory of Cellular Dynamics, CAS Center for Excellence in Molecular Cell Science, University of Science and Technology of China, Hefei, China; Keck Center for Cellular Dynamics and Organoids Plasticity, Morehouse School of Medicine, Atlanta, Georgia.
| | - Adam J. Smolka
- Gastroenterology and Hepatology Division, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
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Tsugawa H, Mori H, Matsuzaki J, Sato A, Saito Y, Imoto M, Suematsu M, Suzuki H. CAPZA1 determines the risk of gastric carcinogenesis by inhibiting Helicobacter pylori CagA-degraded autophagy. Autophagy 2019; 15:242-258. [PMID: 30176157 PMCID: PMC6333452 DOI: 10.1080/15548627.2018.1515530] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Revised: 06/18/2018] [Accepted: 08/21/2018] [Indexed: 01/04/2023] Open
Abstract
Helicobacter pylori-derived CagA, a type IV secretion system effector, plays a role as an oncogenic driver in gastric epithelial cells. However, upon delivery into gastric epithelial cells, CagA is usually degraded by macroautophagy/autophagy. Hence, the induction of autophagy in H. pylori-infected epithelial cells is an important host-protective ability against gastric carcinogenesis. However, the mechanisms by which autophagosome-lysosome fusion is regulated, are unknown. Here, we report that enhancement of LAMP1 (lysosomal associated membrane protein 1) expression is necessary for autolysosome formation. LAMP1 expression is induced by nuclear translocated LRP1 (LDL receptor related protein 1) intracellular domain (LRP1-ICD) binding to the proximal LAMP1 promoter region. Nuclear translocation of LRP1-ICD is enhanced by H. pylori infection. In contrast, CAPZA1 (capping actin protein of muscle Z-line alpha subunit 1) inhibits LAMP1 expression via binding to LRP1-ICD in the nuclei. The binding of CAPZA1 to LRP1-ICD prevents LRP1-ICD binding to the LAMP1 proximal promoter. Thus, in CAPZA1-overexpressing gastric epithelial cells infected with H. pylori, autolysosome formation is inhibited and CagA escapes autophagic degradation. These findings identify CAPZA1 as a novel negative regulator of autolysosome formation and suggest that deregulation of CAPZA1 expression leads to increased risk of gastric carcinogenesis. Abbreviations: CagA: cytotoxin-associated gene A; CAPZA1: capping actin protein of muscle Z-line alpha subunit 1; ChIP: chromatin immunoprecipitation; GTF2I: general transcription factor IIi; HDAC: histone deacetylase; LAMP1: lysosomal associated membrane protein 1; LRP1: LDL receptor related protein 1; LRP1-ICD: CagA intracellular domain; qPCR: quantitative polymerase chain reaction; VacA: vacuolating cytotoxin.
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Affiliation(s)
- Hitoshi Tsugawa
- Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan
| | - Hideki Mori
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Juntaro Matsuzaki
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan
| | - Akira Sato
- Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan
| | - Yoshimasa Saito
- Division of Pharmacotherapeutics, Keio University Faculty of Pharmacy, Tokyo, Japan
| | - Masaya Imoto
- Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Kohoku-ku, Yokohama, Japan
| | - Makoto Suematsu
- Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan
| | - Hidekazu Suzuki
- Fellowship Training Center and Medical Education Center, Keio University School of Medicine, Tokyo, Japan
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Molina-Castro S, Ramírez-Mayorga V, Alpízar-Alpízar W. Priming the seed: Helicobacter pylori alters epithelial cell invasiveness in early gastric carcinogenesis. World J Gastrointest Oncol 2018; 10:231-243. [PMID: 30254719 PMCID: PMC6147766 DOI: 10.4251/wjgo.v10.i9.231] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 06/13/2018] [Accepted: 06/27/2018] [Indexed: 02/05/2023] Open
Abstract
Helicobacter pylori (H. pylori) infection is a well-established risk factor for the development of gastric cancer (GC), one of the most common and deadliest neoplasms worldwide. H. pylori infection induces chronic inflammation in the gastric mucosa that, in the absence of treatment, may progress through a series of steps to GC. GC is only one of several clinical outcomes associated with this bacterial infection, which may be at least partially attributed to the high genetic variability of H. pylori. The biological mechanisms underlying how and under what circumstances H. pylori alters normal physiological processes remain enigmatic. A key aspect of carcinogenesis is the acquisition of traits that equip preneoplastic cells with the ability to invade. Accumulating evidence implicates H. pylori in the manipulation of cellular and molecular programs that are crucial for conferring cells with invasive capabilities. We present here an overview of the main findings about the involvement of H. pylori in the acquisition of cell invasive behavior, specifically focusing on the epithelial-to-mesenchymal transition, changes in cell polarity, and deregulation of molecules that control extracellular matrix remodeling.
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Affiliation(s)
- Silvia Molina-Castro
- Cancer Epidemiology Research Program, Health Research Institute, University of Costa Rica, San José 2060, Costa Rica
- Clinical Department, School of Medicine, University of Costa Rica, San José 2060, Costa Rica
| | - Vanessa Ramírez-Mayorga
- Cancer Epidemiology Research Program, Health Research Institute, University of Costa Rica, San José 2060, Costa Rica
- Public Nutrition Section, School of Nutrition, University of Costa Rica, San José 2060, Costa Rica
| | - Warner Alpízar-Alpízar
- Center for Research in Microscopic Structures, University of Costa Rica, San José 2060, Costa Rica
- Department of Biochemistry, School of Medicine, University of Costa Rica, San José 2060, Costa Rica
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Shapla UM, Raihan J, Islam A, Alam F, Solayman N, Gan SH, Hossen S, Khalil I. Propolis: The future therapy against Helicobacter pylori-mediated gastrointestinal diseases. J Appl Biomed 2018. [DOI: 10.1016/j.jab.2017.10.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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21
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Garalla HM, Lertkowit N, Tiszlavicz L, Reisz Z, Holmberg C, Beynon R, Simpson D, Varga A, Kumar JD, Dodd S, Pritchard DM, Moore AR, Rosztóczy AI, Wittman T, Simpson A, Dockray GJ, Varro A. Matrix metalloproteinase (MMP)-7 in Barrett's esophagus and esophageal adenocarcinoma: expression, metabolism, and functional significance. Physiol Rep 2018; 6:e13683. [PMID: 29845775 PMCID: PMC5974721 DOI: 10.14814/phy2.13683] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Revised: 03/08/2018] [Accepted: 03/09/2018] [Indexed: 12/18/2022] Open
Abstract
Matrix metalloproteinase (MMP)-7, unlike many MMPs, is typically expressed in epithelial cells. It has been linked to epithelial responses to infection, injury, and tissue remodeling including the progression of a number of cancers. We have now examined how MMP-7 expression changes in the progression to esophageal adenocarcinoma (EAC), and have studied mechanisms regulating its expression and its functional significance. Immunohistochemistry revealed that MMP-7 was weakly expressed in normal squamous epithelium adjacent to EAC but was abundant in epithelial cells in both preneoplastic lesions of Barrett's esophagus and EAC particularly at the invasive front. In the stroma, putative myofibroblasts expressing MMP-7 were abundant at the invasive front but were scarce or absent in adjacent tissue. Western blot and ELISA revealed high constitutive secretion of proMMP-7 in an EAC cell line (OE33) that was inhibited by the phosphatidylinositol (PI) 3-kinase inhibitor LY294002 but not by inhibitors of protein kinase C, or MAP kinase activation. There was detectable proMMP-7 in cultured esophageal myofibroblasts but it was undetectable in media. Possible metabolism of MMP-7 by myofibroblasts studied by proteomic analysis indicated degradation via extensive endopeptidase, followed by amino- and carboxpeptidase, cleavages. Myofibroblasts exhibited increased migration and invasion in response to conditioned media from OE33 cells that was reduced by MMP-7 knockdown and immunoneutralization. Thus, MMP-7 expression increases at the invasive front in EAC which may be partly attributable to activation of PI 3-kinase. Secreted MMP-7 may modify the tumor microenvironment by stimulating stromal cell migration and invasion.
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Affiliation(s)
- Hanan M. Garalla
- Institute of Translational MedicineUniversity of LiverpoolLiverpoolUnited kingdom
| | - Nantaporn Lertkowit
- Institute of Translational MedicineUniversity of LiverpoolLiverpoolUnited kingdom
| | | | - Zita Reisz
- Department of PathologyUniversity of SzegedSzegedHungary
| | - Chris Holmberg
- Institute of Translational MedicineUniversity of LiverpoolLiverpoolUnited kingdom
| | - Rob Beynon
- Institute of Integrative BiologyUniversity of LiverpoolLiverpoolUnited kingdom
| | - Deborah Simpson
- Institute of Integrative BiologyUniversity of LiverpoolLiverpoolUnited kingdom
| | - Akos Varga
- Institute of Translational MedicineUniversity of LiverpoolLiverpoolUnited kingdom
| | - Jothi Dinesh Kumar
- Institute of Translational MedicineUniversity of LiverpoolLiverpoolUnited kingdom
| | - Steven Dodd
- Institute of Translational MedicineUniversity of LiverpoolLiverpoolUnited kingdom
| | - David Mark Pritchard
- Institute of Translational MedicineUniversity of LiverpoolLiverpoolUnited kingdom
| | - Andrew R. Moore
- Institute of Translational MedicineUniversity of LiverpoolLiverpoolUnited kingdom
| | | | - Tibor Wittman
- First Department of Internal MedicineUniversity of SzegedSzegedHungary
| | - Alec Simpson
- Institute of Translational MedicineUniversity of LiverpoolLiverpoolUnited kingdom
| | - Graham J. Dockray
- Institute of Translational MedicineUniversity of LiverpoolLiverpoolUnited kingdom
| | - Andrea Varro
- Institute of Translational MedicineUniversity of LiverpoolLiverpoolUnited kingdom
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Yang Z, Cao X, Xu W, Xie C, Chen J, Zhu Y, Lu N. Phosphorylation of phosphatase and tensin homolog induced by Helicobacter pylori promotes cell invasion by activation of focal adhesion kinase. Oncol Lett 2017; 15:1051-1057. [PMID: 29399165 PMCID: PMC5772772 DOI: 10.3892/ol.2017.7430] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Accepted: 10/18/2017] [Indexed: 02/06/2023] Open
Abstract
Phosphorylation of the phosphatase and tensin homolog (PTEN) tumor suppressor at Ser380/Thr382/Thr383 residues is a novel mechanism underlying PTEN inactivation in gastric carcinogenesis, which may be triggered by Helicobacter pylori infection. To investigate this further, the effect of H. pylori infection on PTEN phosphorylation and the subsequent activation of focal adhesion kinase (FAK), were evaluated in gastric tissue samples from Mongolian gerbils and in the human gastric epithelial mucosa cell line GES-1 using immunohistochemistry, western blotting and Transwell assays. The in vivo and in vitro results of the present study demonstrated that H. pylori infection induced the phosphorylation and inactivation of PTEN at Ser380/Thr382/383, and the subsequent phosphorylation and activation of FAK at Tyr397. Gastric epithelial cell invasion was also increased. Furthermore, stable expression of a dominant-negative PTEN mutant inhibited the enhanced FAK activation and cell invasion induced by H. pylori infection. These results suggest that the mechanism underlying H. pylori-induced carcinogenesis may involve promoting cell invasion through the phosphorylation of PTEN and the activation of FAK.
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Affiliation(s)
- Zhen Yang
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Ximei Cao
- Department of Gastroenterology, First Peoples' Hospital of Jiujiang, Jiujiang, Jiangxi 332000, P.R. China
| | - Wenting Xu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Chuan Xie
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Jiang Chen
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Yin Zhu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Nonghua Lu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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Mechanisms of angiogenesis in microbe-regulated inflammatory and neoplastic conditions. Angiogenesis 2017; 21:1-14. [PMID: 29110215 DOI: 10.1007/s10456-017-9583-4] [Citation(s) in RCA: 103] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2017] [Accepted: 10/24/2017] [Indexed: 12/19/2022]
Abstract
Commensal microbiota inhabit all the mucosal surfaces of the human body. It plays significant roles during homeostatic conditions, and perturbations in numbers and/or products are associated with several pathological disorders. Angiogenesis, the process of new vessel formation, promotes embryonic development and critically modulates several biological processes during adulthood. Indeed, deregulated angiogenesis can induce or augment several pathological conditions. Accumulating evidence has implicated the angiogenic process in various microbiota-associated human diseases. Herein, we critically review diseases that are regulated by microbiota and are affected by angiogenesis, aiming to provide a broad understanding of how angiogenesis is involved and how microbiota regulate angiogenesis in microbiota-associated human conditions.
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Varga A, Kumar JD, Simpson AWM, Dodd S, Hegyi P, Dockray GJ, Varro A. Cell cycle dependent expression of the CCK2 receptor by gastrointestinal myofibroblasts: putative role in determining cell migration. Physiol Rep 2017; 5:5/19/e13394. [PMID: 29038353 PMCID: PMC5641928 DOI: 10.14814/phy2.13394] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Accepted: 07/27/2017] [Indexed: 01/11/2023] Open
Abstract
The well‐known action of the gastric hormone gastrin in stimulating gastric acid secretion is mediated by activation of cholecystokinin‐2 receptors (CCK2R). The latter are expressed by a variety of cell types suggesting that gastrin is implicated in multiple functions. During wound healing in the stomach CCK2R may be expressed by myofibroblasts. We have now characterized CCK2R expression in cultured myofibroblasts. Immunocytochemistry showed that a relatively small proportion (1–6%) of myofibroblasts expressed the receptor regardless of the region of the gut from which they were derived, or whether from cancer or control tissue. Activation of CCK2R by human heptadecapeptide gastrin (hG17) increased intracellular calcium concentrations in a small subset of myofibroblasts indicating the presence of a functional receptor. Unexpectedly, we found over 80% of cells expressing CCK2R were also labeled with 5‐ethynyl‐2′‐deoxyuridine (EdU) which is incorporated into DNA during S‐phase of the cell cycle. hG17 did not stimulate EdU incorporation but increased migration of both EdU‐labeled and unlabelled myofibroblasts; the migratory response was inhibited by a CCK2R antagonist and by an inhibitor of IGF receptor tyrosine kinase; hG17 also increased IGF‐2 transcript abundance. The data suggest myofibroblasts express CCK2R in a restricted period of the cell cycle during S‐phase, and that gastrin accelerates migration of these cells; it also stimulates migration of adjacent cells probably through paracrine release of IGF. Together with previous findings, the results raise the prospect that gastrin controls the position of dividing myofibroblasts which may be relevant in wound healing and cancer progression in the gastrointestinal tract.
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Affiliation(s)
- Akos Varga
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
| | - Jothi Dinesh Kumar
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
| | - Alec W M Simpson
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
| | - Steven Dodd
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
| | - Peter Hegyi
- First Department of Medicine, University of Szeged, Szeged, Hungary.,Institute of Translational Medicine, University of Pecs, Pecs, Hungary
| | - Graham J Dockray
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
| | - Andrea Varro
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
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Leushacke M, Tan SH, Wong A, Swathi Y, Hajamohideen A, Tan LT, Goh J, Wong E, Denil SLIJ, Murakami K, Barker N. Lgr5-expressing chief cells drive epithelial regeneration and cancer in the oxyntic stomach. Nat Cell Biol 2017; 19:774-786. [PMID: 28581476 DOI: 10.1038/ncb3541] [Citation(s) in RCA: 183] [Impact Index Per Article: 22.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Accepted: 04/28/2017] [Indexed: 02/08/2023]
Abstract
The daily renewal of the corpus epithelium is fuelled by adult stem cells residing within tubular glands, but the identity of these stem cells remains controversial. Lgr5 marks homeostatic stem cells and 'reserve' stem cells in multiple tissues. Here, we report Lgr5 expression in a subpopulation of chief cells in mouse and human corpus glands. Using a non-variegated Lgr5-2A-CreERT2 mouse model, we show by lineage tracing that Lgr5-expressing chief cells do not behave as corpus stem cells during homeostasis, but are recruited to function as stem cells to effect epithelial renewal following injury by activating Wnt signalling. Ablation of Lgr5+ cells severely impairs epithelial homeostasis in the corpus, indicating an essential role for these Lgr5+ cells in maintaining the homeostatic stem cell pool. We additionally define Lgr5+ chief cells as a major cell-of-origin of gastric cancer. These findings reveal clinically relevant insights into homeostasis, repair and cancer in the corpus.
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Affiliation(s)
| | - Si Hui Tan
- A*STAR Institute of Medical Biology, 138648, Singapore
| | - Angeline Wong
- A*STAR Institute of Medical Biology, 138648, Singapore
| | - Yada Swathi
- A*STAR Institute of Medical Biology, 138648, Singapore
| | | | | | - Jasmine Goh
- A*STAR Institute of Medical Biology, 138648, Singapore
| | - Esther Wong
- A*STAR Institute of Medical Biology, 138648, Singapore
| | | | - Kazuhiro Murakami
- Cancer Research Institute, Kanazawa University, Kakuma-machi Kanazawa 920-1192, Japan
| | - Nick Barker
- A*STAR Institute of Medical Biology, 138648, Singapore.,Cancer Research Institute, Kanazawa University, Kakuma-machi Kanazawa 920-1192, Japan.,Centre for Regenerative Medicine, The University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
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26
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Proteolysis in Helicobacter pylori-Induced Gastric Cancer. Toxins (Basel) 2017; 9:toxins9040134. [PMID: 28398251 PMCID: PMC5408208 DOI: 10.3390/toxins9040134] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Revised: 04/03/2017] [Accepted: 04/06/2017] [Indexed: 12/15/2022] Open
Abstract
Persistent infections with the human pathogen and class-I carcinogen Helicobacter pylori (H. pylori) are closely associated with the development of acute and chronic gastritis, ulceration, gastric adenocarcinoma and lymphoma of the mucosa-associated lymphoid tissue (MALT) system. Disruption and depolarization of the epithelium is a hallmark of H. pylori-associated disorders and requires extensive modulation of epithelial cell surface structures. Hence, the complex network of controlled proteolysis which facilitates tissue homeostasis in healthy individuals is deregulated and crucially contributes to the induction and progression of gastric cancer through processing of extracellular matrix (ECM) proteins, cell surface receptors, membrane-bound cytokines, and lateral adhesion molecules. Here, we summarize the recent reports on mechanisms how H. pylori utilizes a variety of extracellular proteases, involving the proteases Hp0169 and high temperature requirement A (HtrA) of bacterial origin, and host matrix-metalloproteinases (MMPs), a disintegrin and metalloproteinases (ADAMs) and tissue inhibitors of metalloproteinases (TIMPs). H. pylori-regulated proteases represent predictive biomarkers and attractive targets for therapeutic interventions in gastric cancer.
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27
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Banerjee S, Ghosh S, Sinha K, Sil PC. Unfolding the Mechanism of Proteases in Pathophysiology of Gastrointestinal Diseases. PATHOPHYSIOLOGICAL ASPECTS OF PROTEASES 2017:583-603. [DOI: 10.1007/978-981-10-6141-7_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Siregar G, Halim S, Sitepu R. Serum IL-10, MMP-7, MMP-9 Levels in Helicobacter pylori Infection and Correlation with Degree of Gastritis. Open Access Maced J Med Sci 2016; 4:359-363. [PMID: 27703556 PMCID: PMC5042616 DOI: 10.3889/oamjms.2016.099] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Revised: 08/22/2016] [Accepted: 08/24/2016] [Indexed: 12/12/2022] Open
Abstract
AIM Helicobacter pylori causes gastric mucosal inflammation and immune reaction. However, the increase of IL-10, MMP-7, and MMP-7 levels in the serum is still controversial. The objective of this study was to investigate the serum levels of IL-10, MMP-7 & MMP-9 in gastritis patients with H. pylori infection. MATERIALS AND METHODS A cross-sectional study was done on seventy gastritis patients that consecutive admitted to endoscopy units. The diagnosis of gastritis was made based on histopathology and diagnosis of H. pylori infection was based on rapid urease test. Serum samples were obtained to determine to circulate IL-10, MMP-7, and MMP-9 level. Univariate and bivariate analysis were done by SPSS version 22. RESULTS Forthy percentages of the patients were infected with H. pylori. The IL-10 level was significantly higher in H. pylori-infected patients compared to non-infected patients. However, there were no differences between serum levels of MMP-7 and MMP-9 in infected and non-infected H. pylori patients. CONCLUSIONS The immune response to H. pylori promotes systemic inflammation, which was reflected by the increased levels of serum IL-10. However, there were no significant differences in MMP-7 and MMP-9 serum levels between positive and negative infected H. pylori patients.
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Affiliation(s)
- Gontar Siregar
- University of Sumatera Utara, Gastroentero-Hepatology, Komp. Tasbi YY No 203, Medan, Sumatera Utara 20122, Indonesia
| | - Sahat Halim
- University of Sumatera Utara, Internal Medicine, Medan, Sumatera Utara, Indonesia
| | - Ricky Sitepu
- University of Sumatera Utara, Internal Medicine, Medan, Sumatera Utara, Indonesia
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29
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Ma HY, Liu XZ, Liang CM. Inflammatory microenvironment contributes to epithelial-mesenchymal transition in gastric cancer. World J Gastroenterol 2016; 22:6619-6628. [PMID: 27547005 PMCID: PMC4970470 DOI: 10.3748/wjg.v22.i29.6619] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Revised: 06/12/2016] [Accepted: 07/06/2016] [Indexed: 02/07/2023] Open
Abstract
Gastric cancer (GC) is the fifth most common malignancy in the world. The major cause of GC is chronic infection with Helicobacter pylori (H. pylori). Infection with H. pylori leads to an active inflammatory microenvironment that is maintained by immune cells such as T cells, macrophages, natural killer cells, among other cells. Immune cell dysfunction allows the initiation and accumulation of mutations in GC cells, inducing aberrant proliferation and protection from apoptosis. Meanwhile, immune cells can secrete certain signals, including cytokines, and chemokines, to alter intracellular signaling pathways in GC cells. Thus, GC cells obtain the ability to metastasize to lymph nodes by undergoing the epithelial-mesenchymal transition (EMT), whereby epithelial cells lose their epithelial attributes and acquire a mesenchymal cell phenotype. Metastasis is a leading cause of death for GC patients, and the involved mechanisms are still under investigation. In this review, we summarize the current research on how the inflammatory environment affects GC initiation and metastasis via EMT.
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30
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Shimizu T, Choi E, Petersen CP, Noto JM, Romero-Gallo J, Piazuelo MB, Washington MK, Peek RM, Goldenring JR. Characterization of progressive metaplasia in the gastric corpus mucosa of Mongolian gerbils infected with Helicobacter pylori. J Pathol 2016; 239:399-410. [PMID: 27125972 PMCID: PMC4958595 DOI: 10.1002/path.4735] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Revised: 04/02/2016] [Accepted: 04/09/2016] [Indexed: 12/11/2022]
Abstract
Spasmolytic polypeptide-expressing metaplasia (SPEM) and intestinal metaplasia are considered neoplastic precursors of gastric adenocarcinoma in humans. Loss of parietal cells causes the development of SPEM in the gastric corpus and then chronic inflammation drives SPEM toward a more proliferative lineage. Mongolian gerbils infected with Helicobacter pylori develop chronic gastritis and metaplasia, mimicking aspects of human gastritis with H. pylori infection. We therefore examined metaplastic lineages in the gastric corpus mucosa of gerbils infected by H. pylori strain 7.13, which produces rapid onset of severe inflammation. Six weeks following H. pylori infection, Griffonia simplicifolia lectin II (GSII)-positive SPEM developed in the base of oxyntic glands in association with parietal cell loss and inflammation. In association with severe inflammation, SPEM glands evolved into aberrant phenotypes, including branched lesions, dilated lesions, and penetrating invasive glands. Mucin 4 (MUC4) was up-regulated in SPEM and progressive SPEM. Clusterin was expressed in the tips of branched and dilated lesions and throughout regions of invasive glands. Intriguingly, clusterin-positive regions in these lesions expressed Ki67 and matrix metalloproteinase 7 (MMP-7). These same regions were also positive for expression of phospho-IkBα, suggestive of activated NFkB signalling. These findings suggest that clusterin-positive regions in progressive phenotypes of SPEM have invasive characteristics. Thus, H. pylori infection in gerbils induces SPEM, which then can progress to further aberrant and invasive metaplastic phenotypes. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Takahiro Shimizu
- Nashville VA Medical Center, Nashville, Tennessee
- Departments of Surgery and Cell and Developmental Biology and the Epithelial Biology Center Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Eunyoung Choi
- Nashville VA Medical Center, Nashville, Tennessee
- Departments of Surgery and Cell and Developmental Biology and the Epithelial Biology Center Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Christine P. Petersen
- Nashville VA Medical Center, Nashville, Tennessee
- Departments of Surgery and Cell and Developmental Biology and the Epithelial Biology Center Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Jennifer M. Noto
- Division of Gastroenterology, Departments of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Judith Romero-Gallo
- Division of Gastroenterology, Departments of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Maria B. Piazuelo
- Division of Gastroenterology, Departments of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - M. Kay Washington
- Department of Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Richard M. Peek
- Division of Gastroenterology, Departments of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee
- Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - James R. Goldenring
- Nashville VA Medical Center, Nashville, Tennessee
- Departments of Surgery and Cell and Developmental Biology and the Epithelial Biology Center Vanderbilt University School of Medicine, Nashville, Tennessee
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31
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Amieva M, Peek RM. Pathobiology of Helicobacter pylori-Induced Gastric Cancer. Gastroenterology 2016; 150:64-78. [PMID: 26385073 PMCID: PMC4691563 DOI: 10.1053/j.gastro.2015.09.004] [Citation(s) in RCA: 625] [Impact Index Per Article: 69.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Revised: 09/01/2015] [Accepted: 09/03/2015] [Indexed: 02/07/2023]
Abstract
Colonization of the human stomach by Helicobacter pylori and its role in causing gastric cancer is one of the richest examples of a complex relationship among human cells, microbes, and their environment. It is also a puzzle of enormous medical importance given the incidence and lethality of gastric cancer worldwide. We review recent findings that have changed how we view these relationships and affected the direction of gastric cancer research. For example, recent data have indicated that subtle mismatches between host and microbe genetic traits greatly affect the risk of gastric cancer. The ability of H pylori and its oncoprotein CagA to reprogram epithelial cells and activate properties of stemness show the sophisticated relationship between H pylori and progenitor cells in the gastric mucosa. The observation that cell-associated H pylori can colonize the gastric glands and directly affect precursor and stem cells supports these observations. The ability to mimic these interactions in human gastric organoid cultures as well as animal models will allow investigators to more fully unravel the extent of H pylori control on the renewing gastric epithelium. Finally, our realization that external environmental factors, such as dietary components and essential micronutrients, as well as the gastrointestinal microbiota, can change the balance between H pylori's activity as a commensal or a pathogen has provided direction to studies aimed at defining the full carcinogenic potential of this organism.
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Affiliation(s)
- Manuel Amieva
- Department of Microbiology and Immunology, Stanford University, Palo Alto, California; Department of Pediatrics, Stanford University, Palo Alto, California
| | - Richard M Peek
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University, Nashville, Tennessee; Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.
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32
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Bornschein J, Seidel T, Langner C, Link A, Wex T, Selgrad M, Jechorek D, Meyer F, Bird-Lieberman E, Vieth M, Malfertheiner P. MMP2 and MMP7 at the invasive front of gastric cancer are not associated with mTOR expression. Diagn Pathol 2015; 10:212. [PMID: 26652716 PMCID: PMC4676863 DOI: 10.1186/s13000-015-0449-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2015] [Accepted: 12/05/2015] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Regulation of MMP expression by activation of mTOR signalling has been demonstrated for several tumor types, but has thus far not been confirmed in gastric cancer. FINDINGS The study compromised 128 patients who underwent gastric resection for cancer (66.4 % male; 86 intestinal, 42 diffuse type). Immunohistochemical staining of MMPs was performed to analyse the topographical pattern of MMP expression at the tumor center and the invasive front, respectively. MMP2 showed higher expression at the invasive front compared to the tumor center, whereas MMP7 staining scores were higher in the tumor center, and there was no difference for MMP9. The expression of p-mTOR was higher in the tumor center than at the invasive front, with a similar trend for mTOR. For intestinal type gastric cancer there was a weak correlation of MMP9 with expression of mTOR in the tumor center. Otherwise, there was no correlation of the MMPs with mTOR. By treatment of MKN45 gastric cancer cells with rapamycin, a reduction of p-mTOR in the Western blot was achieved; however, expression of MMPs remained unaffected. CONCLUSIONS Expression of MMP2 and MMP7 in gastric cancer is not associated with mTOR, MMP9 expression might be related to mTOR signalling in a subset of tumors.
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Affiliation(s)
- Jan Bornschein
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Leipziger Str. 44, Magdeburg, 39120, Germany.
| | - Tina Seidel
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Leipziger Str. 44, Magdeburg, 39120, Germany
| | - Cosima Langner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Leipziger Str. 44, Magdeburg, 39120, Germany
| | - Alexander Link
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Leipziger Str. 44, Magdeburg, 39120, Germany
| | - Thomas Wex
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Leipziger Str. 44, Magdeburg, 39120, Germany
- Department of Molecular Genetics, Medical Laboratory for Clinical Chemistry, Microbiology and Infectious Diseases, Am Neustädter Feld 47, Magdeburg, 39124, Germany
| | - Michael Selgrad
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Leipziger Str. 44, Magdeburg, 39120, Germany
| | - Doerthe Jechorek
- Institute for Pathology, Otto-von-Guericke University, Leipziger Str. 44, Magdeburg, 39120, Germany
| | - Frank Meyer
- Department for General, Visceral and Vascular Surgery, Otto-von-Guericke University, Leipziger Str. 44, Magdeburg, 39120, Germany
| | - Elizabeth Bird-Lieberman
- Translational Gastroenterology Unit, Experimental Medicine Division, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Michael Vieth
- Institute for Pathology, Otto-von-Guericke University, Leipziger Str. 44, Magdeburg, 39120, Germany
| | - Peter Malfertheiner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Leipziger Str. 44, Magdeburg, 39120, Germany
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33
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Sougleri IS, Papadakos KS, Zadik MP, Mavri-Vavagianni M, Mentis AF, Sgouras DN. Helicobacter pylori CagA protein induces factors involved in the epithelial to mesenchymal transition (EMT) in infected gastric epithelial cells in an EPIYA- phosphorylation-dependent manner. FEBS J 2015; 283:206-20. [PMID: 26907789 DOI: 10.1111/febs.13592] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Revised: 11/04/2015] [Accepted: 11/06/2015] [Indexed: 12/16/2022]
Abstract
As a result of Helicobacter pylori adhesion to gastric epithelial cells, the bacterial effector cytotoxin-associated gene A (CagA) is translocated intracellularly, and after hierarchical tyrosine phosphorylation on multiple EPIYA motifs, de-regulates cellular polarity and contributes to induction of an elongation and scattering phenotype that resembles the epithelial to mesenchymal transition (EMT). Stromelysin-1/matrix metalloproteinase-3 (MMP-3) has been reported to induce a sequence of molecular alterations leading to stable EMT transition and carcinogenesis in epithelial cells. To identify the putative role of CagA protein in MMP-3 induction, we exploited an experimental H. pylori infection system in gastric epithelial cell lines. We utilized isogenic mutants expressing CagA protein with variable numbers of EPIYA and phosphorylation-deficient EPIFA motifs, as well as cagA knockout and translocation-deficient cagE knockout strains. Increased levels of MMP-3 transcriptional activation were demonstrated by quantitative real time-PCR for strains with more than two terminal EPIYA phosphorylation motifs in CagA. MMP-3 expression in total cell lysates and the corresponding culture supernatants was associated with CagA expression and translocation and was dependent on CagA phosphorylation. A CagA EPIYA phosphorylation-dependent increase in gelatinase and caseinolytic activity was also detected in culture supernatants by zymography. A significant increase in the transcriptional activity of the mesenchymal markers Vimentin, Snail and ZEB1 and the stem cell marker CD44 was observed in the case of CagA containing phosphorylation-functional EPIYA motifs. Our data suggest that CagA protein induces EMT through EPIYA phosphorylation-dependent up-regulation of MMP-3. Moreover, no significant increase in EMT and stem cell markers was observed following infection with H. pylori strains that cannot effectively translocate CagA protein.
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Affiliation(s)
- Ioanna S Sougleri
- Laboratory of Medical Microbiology, Hellenic Pasteur Institute, Athens, Greece
| | | | - Mairi P Zadik
- Laboratory of Medical Microbiology, Hellenic Pasteur Institute, Athens, Greece
| | - Mary Mavri-Vavagianni
- Laboratory of Biochemistry, Department of Chemistry, National and Kapodistrian University of Athens, Greece
| | - Andreas F Mentis
- Laboratory of Medical Microbiology, Hellenic Pasteur Institute, Athens, Greece
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Mesenchymal Stem Cells Exhibit Regulated Exocytosis in Response to Chemerin and IGF. PLoS One 2015; 10:e0141331. [PMID: 26513261 PMCID: PMC4626093 DOI: 10.1371/journal.pone.0141331] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Accepted: 10/07/2015] [Indexed: 12/17/2022] Open
Abstract
Mesenchymal stem cells (MSCs) play important roles in tissue repair and cancer progression. Our recent work suggests that some mesenchymal cells, notably myofibroblasts exhibit regulated exocytosis resembling that seen in neuroendocrine cells. We now report that MSCs also exhibit regulated exocytosis. Both a G-protein coupled receptor agonist, chemerin, and a receptor tyrosine kinase stimulant, IGF-II, evoked rapid increases in secretion of a marker protein, TGFβig-h3. The calcium ionophore, ionomycin, also rapidly increased secretion of TGFβig-h3 while inhibitors of translation (cycloheximide) or secretory protein transport (brefeldin A) had no effect, indicating secretion from preformed secretory vesicles. Inhibitors of the chemerin and IGF receptors specifically reduced the secretory response. Confocal microscopy of MSCs loaded with Fluo-4 revealed chemerin and IGF-II triggered intracellular Ca2+ oscillations requiring extracellular calcium. Immunocytochemistry showed co-localisation of TGFβig-h3 and MMP-2 to secretory vesicles, and transmission electron-microscopy showed dense-core secretory vesicles in proximity to the Golgi apparatus. Proteomic studies on the MSC secretome identified 64 proteins including TGFβig-h3 and MMP-2 that exhibited increased secretion in response to IGF-II treatment for 30min and western blot of selected proteins confirmed these data. Gene ontology analysis of proteins exhibiting regulated secretion indicated functions primarily associated with cell adhesion and in bioassays chemerin increased adhesion of MSCs and adhesion, proliferation and migration of myofibroblasts. Thus, MSCs exhibit regulated exocytosis that is compatible with an early role in tissue remodelling.
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35
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Manna SK, Golla S, Golla JP, Tanaka N, Cai Y, Takahashi S, Krausz KW, Matsubara T, Korboukh I, Gonzalez FJ. St. John's Wort Attenuates Colorectal Carcinogenesis in Mice through Suppression of Inflammatory Signaling. Cancer Prev Res (Phila) 2015; 8:786-795. [PMID: 26069204 PMCID: PMC4584416 DOI: 10.1158/1940-6207.capr-14-0113] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2014] [Accepted: 05/28/2015] [Indexed: 12/13/2022]
Abstract
Despite widespread use as well as epidemiologic indications, there have been no investigations into the effect of St. John's wort (SJW) extract on colorectal carcinogenesis in vivo. This study reports a systematic evaluation of the impact of dietary supplementation of SJW extract on azoxymethane-induced colorectal carcinogenesis in mice. Mice were fed with either AIN-93G (control) diet or SJW extract-supplemented diet (SJW diet) prior to azoxymethane treatment. SJW diet was found to significantly improve the overall survival of azoxymethane-treated mice. Pretreatment with the SJW diet significantly reduced body weight loss as well as decrease of serum albumin and cholesterol levels associated with azoxymethane-induced colorectal tumorigenesis. SJW diet-fed mice showed a significant decrease in tumor multiplicity along with a decrease in incidence of large tumors and a trend toward decreased total tumor volume in a dose-dependent manner. A short-term study, which examined the effect of SJW prior to rectal bleeding, also showed decrease in colorectal polyps in SJW diet-fed mice. Nuclear factor kappa B (NF-κB) and extracellular signal-regulated kinase (ERK1/2) pathways were attenuated by SJW administration. SJW extract resulted in early and continuous attenuation of these pathways in the colon epithelium of SJW diet-fed mice under both short-term and long-term treatment regimens. In conclusion, this study demonstrated the chemopreventive potential of SJW extract against colorectal cancer through attenuation of proinflammatory processes.
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Affiliation(s)
- Soumen K Manna
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Srujana Golla
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Jaya Prakash Golla
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Naoki Tanaka
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Yan Cai
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Shogo Takahashi
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Kristopher W Krausz
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Tsutomu Matsubara
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | | | - Frank J Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
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36
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De Falco M, Lucariello A, Iaquinto S, Esposito V, Guerra G, De Luca A. Molecular Mechanisms of Helicobacter pylori Pathogenesis. J Cell Physiol 2015; 230:1702-7. [PMID: 25639461 DOI: 10.1002/jcp.24933] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2014] [Accepted: 01/16/2015] [Indexed: 12/12/2022]
Abstract
Helicobacter pylori infects 50% of mankind. The vast majority of H. pylori infection occurs in the developing countries where up to 80% of the middle-aged adults may be infected. Bacterial infection causes an inflammatory response that proceeds through a series of intermediated stages of precancerous lesions (gastritis, atrophy, intestinal metaplasia, and dysplasia). Among infected individuals, approximately 10% develops severe gastric lesions such as peptic ulcer disease, 1-3% progresses to gastric cancer (GC) with a low 5-year survival rate, and 0.1% develops mucosa-associated lymphoid tissue (MALT). GC is one of the most common cancer and the third leading cause of cancer-related deaths worldwide. In this review, we have summarized the most recent papers about molecular mechanisms of H. pylori pathogenesis. The main important steps of H. pylori infection such as adhesion, entry in epithelial gastric cells, activation of intracellular pathways until epigenetic modifications have been described.
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Affiliation(s)
- Maria De Falco
- Department of Biology, University Federico II of Naples, Naples, Italy; National Institute of Biostructures and Biosystems (INBB), Rome, Italy
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Kumar JD, Steele I, Moore AR, Murugesan SV, Rakonczay Z, Venglovecz V, Pritchard DM, Dimaline R, Tiszlavicz L, Varro A, Dockray GJ. Gastrin stimulates MMP-1 expression in gastric epithelial cells: putative role in gastric epithelial cell migration. Am J Physiol Gastrointest Liver Physiol 2015; 309:G78-86. [PMID: 25977510 PMCID: PMC4504956 DOI: 10.1152/ajpgi.00084.2015] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2015] [Accepted: 05/06/2015] [Indexed: 01/31/2023]
Abstract
The pyloric antral hormone gastrin plays a role in remodeling of the gastric epithelium, but the specific targets of gastrin that mediate these effects are poorly understood. Glandular epithelial cells of the gastric corpus express matrix metalloproteinase (MMP)-1, which is a potential determinant of tissue remodeling; some of these cells express the CCK-2 receptor at which gastrin acts. We have now examined the hypothesis that gastrin stimulates expression of MMP-1 in the stomach. We determined MMP-1 transcript abundance in gastric mucosal biopsies from Helicobacter pylori negative human subjects with normal gastric mucosal histology, who had a range of serum gastrin concentrations due in part to treatment with proton pump inhibitors (PPI). The effects of gastrin were studied on gastric epithelial AGS-GR cells using Western blot and migration assays. In human subjects with increased serum gastrin due to PPI usage, MMP-1 transcript abundance was increased 2-fold; there was also increased MMP-7 transcript abundance but not MMP-3. In Western blots, gastrin increased proMMP-1 abundance, as well that of a minor band corresponding to active MMP-1, in the media of AGS-GR cells, and the response was mediated by protein kinase C and p42/44 MAP kinase. There was also increased MMP-1 enzyme activity. Gastrin-stimulated AGS-GR cell migration in both scratch wound and Boyden chamber assays was inhibited by MMP-1 immunoneutralization. We conclude that MMP-1 expression is a target of gastrin implicated in mucosal remodeling.
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Affiliation(s)
- J. Dinesh Kumar
- 1Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; and
| | - Islay Steele
- 1Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; and
| | - Andrew R. Moore
- 1Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; and
| | - Senthil V. Murugesan
- 1Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; and
| | - Zoltan Rakonczay
- 1Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; and
| | - Viktoria Venglovecz
- 1Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; and
| | - D. Mark Pritchard
- 1Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; and
| | - Rodney Dimaline
- 1Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; and
| | | | - Andrea Varro
- 1Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; and
| | - Graham J. Dockray
- 1Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; and
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Wroblewski LE, Piazuelo MB, Chaturvedi R, Schumacher M, Aihara E, Feng R, Noto JM, Delgado A, Israel DA, Zavros Y, Montrose MH, Shroyer N, Correa P, Wilson KT, Peek RM. Helicobacter pylori targets cancer-associated apical-junctional constituents in gastroids and gastric epithelial cells. Gut 2015; 64:720-30. [PMID: 25123931 PMCID: PMC4329117 DOI: 10.1136/gutjnl-2014-307650] [Citation(s) in RCA: 111] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2014] [Accepted: 07/30/2014] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Helicobacter pylori strains that express the oncoprotein CagA augment risk for gastric cancer. However, the precise mechanisms through which cag(+) strains heighten cancer risk have not been fully delineated and model systems that recapitulate the gastric niche are critical for understanding pathogenesis. Gastroids are three-dimensional organ-like structures that provide unique opportunities to study host-H. pylori interactions in a preclinical model. We used gastroids to inform and direct in vitro studies to define mechanisms through which H. pylori modulates expression of the cancer-associated tight junction protein claudin-7. DESIGN Gastroids were infected by luminal microinjection, and MKN28 gastric epithelial cells were cocultured with H. pylori wild-type cag(+) strains or isogenic mutants. β-catenin, claudin-7 and snail localisation was determined by immunocytochemistry. Proliferation was assessed using 5-ethynyl-2'-deoxyuridine, and levels of claudin-7 and snail were determined by western blot and flow cytometry. RESULTS Gastroids developed into a self-organising differentiation axis and H. pylori induced mislocalisation of claudin-7 and increased proliferation in a CagA- and β-catenin-dependent manner. In MKN28 cells, H pylori-induced suppression of claudin-7 was regulated by β-catenin and snail. Similarly, snail expression was increased and claudin-7 levels were decreased among H. pylori-infected individuals. CONCLUSIONS H. pylori increase proliferation in a strain-specific manner in a novel gastroid system. H. pylori also alter expression and localisation of claudin-7 in gastroids and human epithelial cells, which is mediated by β-catenin and snail activation. These data provide new insights into molecular interactions with carcinogenic potential that occur between H. pylori and epithelial cells within the gastric niche.
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Affiliation(s)
- Lydia E Wroblewski
- Division of Gastroenterology, Departments of Medicine and Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - M Blanca Piazuelo
- Division of Gastroenterology, Departments of Medicine and Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Rupesh Chaturvedi
- Division of Gastroenterology, Departments of Medicine and Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Michael Schumacher
- Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio, USA
| | - Eitaro Aihara
- Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio, USA
| | - Rui Feng
- Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio, USA
| | - Jennifer M Noto
- Division of Gastroenterology, Departments of Medicine and Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Alberto Delgado
- Division of Gastroenterology, Departments of Medicine and Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Dawn A Israel
- Division of Gastroenterology, Departments of Medicine and Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Yana Zavros
- Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio, USA
| | - Marshall H Montrose
- Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio, USA
| | - Noah Shroyer
- Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital, Cincinnati, Ohio, USA
| | - Pelayo Correa
- Division of Gastroenterology, Departments of Medicine and Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Keith T Wilson
- Division of Gastroenterology, Departments of Medicine and Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Richard M Peek
- Division of Gastroenterology, Departments of Medicine and Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
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Matrix remodeling by MMPs during wound repair. Matrix Biol 2015; 44-46:113-21. [PMID: 25770908 DOI: 10.1016/j.matbio.2015.03.002] [Citation(s) in RCA: 277] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2015] [Revised: 03/05/2015] [Accepted: 03/06/2015] [Indexed: 12/16/2022]
Abstract
Repair following injury involves a range of processes - such as re-epithelialization, scar formation, angiogenesis, inflammation, and more - that function, often together, to restore tissue architecture. MMPs carry out diverse roles in all of these activities. In this article, we discuss how specific MMPs act on ECM during two critical repair processes: re-epithelialization and resolution of scar tissue. For wound closure, we discuss how two MMPs - MMP1 in human epidermis and MMP7 in mucosal epithelia - facilitate re-epithelialization by cleaving different ECM or ECM-associated proteins to affect similar integrin:matrix adhesion. In scars and fibrotic tissues, we discuss that a variety of MMPs carry out a diverse range of activities that can either promote or limit ECM deposition. However, few of these MMP-driven activities have been demonstrated to be due a direct action on ECM.
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40
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Ahmed Haji Omar A, Haglund C, Virolainen S, Häyry V, Atula T, Kontio R, Salo T, Sorsa T, Hagström J. MMP-7, MMP-8, and MMP-9 in oral and cutaneous squamous cell carcinomas. Oral Surg Oral Med Oral Pathol Oral Radiol 2015; 119:459-67. [PMID: 25697929 DOI: 10.1016/j.oooo.2014.12.019] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Revised: 12/10/2014] [Accepted: 12/19/2014] [Indexed: 01/06/2023]
Abstract
OBJECTIVES Oral squamous cell carcinoma (OSCC) and cutaneous squamous cell carcinoma (CSCC) are epithelial neoplasms, of which OSCC has a worse prognosis. Matrix metalloproteinases (MMPs) are involved in the initiation, invasion, metastasis, and defense of cancer. This study aimed to compare differences in MMP expression in these cancers. STUDY DESIGN Sixty-one patients with early-stage (T1-T2 N0 M0) cancers, of which 36 were OSCC and 25 CSCC, were enrolled into this study. Immunohistochemical staining was performed with MMP-7, MMP-8, and MMP-9 antibodies. RESULTS MMP-7 expression was stronger in OSCC than in CSCC, mainly in the invasive front. MMP-8 was absent and MMP-9 was mildly expressed in OSCC and CSCC cells. However, MMP-8 and MMP-9 were positive in peritumoral inflammatory cells in both cancers. In addition, MMP-7, MMP-8, and MMP-9 were not associated with the overall survival of patients with OSCC and CSCC patients. CONCLUSIONS The increased expression of MMP-7 in the invasive front may partly explain the aggressiveness of OSCC.
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Affiliation(s)
| | - Caj Haglund
- Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland; Research Programs Unit, Translational Cancer Biology, University of Helsinki, Helsinki, Finland
| | - Susanna Virolainen
- Department of Pathology, Haartman Institute, University of Helsinki, Helsinki, Finland
| | - Valtteri Häyry
- Department of Otorhinolaryngology - Head and Neck Surgery, Helsinki University Central Hospital, Helsinki, Finland
| | - Timo Atula
- Department of Otorhinolaryngology - Head and Neck Surgery, Helsinki University Central Hospital, Helsinki, Finland
| | - Risto Kontio
- Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, Helsinki, Finland
| | - Tuula Salo
- Institute of Dentistry, University of Helsinki, Helsinki, Finland; Medical Research Center Oulu, University of Oulu, Oulu, Finland
| | - Timo Sorsa
- Institute of Dentistry, University of Helsinki, Helsinki, Finland; Division of Periodontology, Department of Dental Medicine, Karolinska Institute, Huddinge, Sweden
| | - Jaana Hagström
- Department of Pathology, Haartman Institute, University of Helsinki, Helsinki, Finland; Department of Oral Pathology, Institute of Dentistry, University of Helsinki, Helsinki, Finland
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Kumar JD, Holmberg C, Kandola S, Steele I, Hegyi P, Tiszlavicz L, Jenkins R, Beynon RJ, Peeney D, Giger OT, Alqahtani A, Wang TC, Charvat TT, Penfold M, Dockray GJ, Varro A. Increased expression of chemerin in squamous esophageal cancer myofibroblasts and role in recruitment of mesenchymal stromal cells. PLoS One 2014; 9:e104877. [PMID: 25127029 PMCID: PMC4134237 DOI: 10.1371/journal.pone.0104877] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2014] [Accepted: 07/15/2014] [Indexed: 12/20/2022] Open
Abstract
Stromal cells such as myofibroblasts influence tumor progression. The mechanisms are unclear but may involve effects on both tumor cells and recruitment of bone marrow-derived mesenchymal stromal cells (MSCs) which then colonize tumors. Using iTRAQ and LC-MS/MS we identified the adipokine, chemerin, as overexpressed in esophageal squamous cancer associated myofibroblasts (CAMs) compared with adjacent tissue myofibroblasts (ATMs). The chemerin receptor, ChemR23, is expressed by MSCs. Conditioned media (CM) from CAMs significantly increased MSC cell migration compared to ATM-CM; the action of CAM-CM was significantly reduced by chemerin-neutralising antibody, pretreatment of CAMs with chemerin siRNA, pretreatment of MSCs with ChemR23 siRNA, and by a ChemR23 receptor antagonist, CCX832. Stimulation of MSCs by chemerin increased phosphorylation of p42/44, p38 and JNK-II kinases and inhibitors of these kinases and PKC reversed chemerin-stimulated MSC migration. Chemerin stimulation of MSCs also induced expression and secretion of macrophage inhibitory factor (MIF) that tended to restrict migratory responses to low concentrations of chemerin but not higher concentrations. In a xenograft model consisting of OE21 esophageal cancer cells and CAMs, homing of MSCs administered i.v. was inhibited by CCX832. Thus, chemerin secreted from esophageal cancer myofibroblasts is a potential chemoattractant for MSCs and its inhibition may delay tumor progression.
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Affiliation(s)
- J. Dinesh Kumar
- Department of Cell and Molecular Physiology, University of Liverpool, Liverpool, United Kingdom
| | - Chris Holmberg
- Department of Cell and Molecular Physiology, University of Liverpool, Liverpool, United Kingdom
| | - Sandhir Kandola
- Department of Cell and Molecular Physiology, University of Liverpool, Liverpool, United Kingdom
| | - Islay Steele
- Department of Cell and Molecular Physiology, University of Liverpool, Liverpool, United Kingdom
| | - Peter Hegyi
- Department of Medicine and Surgery, University of Szeged, Szeged, Hungary
| | | | - Rosalind Jenkins
- Department of Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
| | - Robert J. Beynon
- Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom
| | - David Peeney
- Department of Cell and Molecular Physiology, University of Liverpool, Liverpool, United Kingdom
| | - Olivier T. Giger
- Department of Cell and Molecular Physiology, University of Liverpool, Liverpool, United Kingdom
| | - Ahlam Alqahtani
- Department of Cell and Molecular Physiology, University of Liverpool, Liverpool, United Kingdom
| | - Timothy C. Wang
- Department of Medicine, Columbia University Medical Center, New York, United States of America
| | | | - Mark Penfold
- ChemoCentryx, California, United States of America
| | - Graham J. Dockray
- Department of Cell and Molecular Physiology, University of Liverpool, Liverpool, United Kingdom
| | - Andrea Varro
- Department of Cell and Molecular Physiology, University of Liverpool, Liverpool, United Kingdom
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Chung HW, Lim JB. Role of the tumor microenvironment in the pathogenesis of gastric carcinoma. World J Gastroenterol 2014; 20:1667-1680. [PMID: 24587646 PMCID: PMC3930967 DOI: 10.3748/wjg.v20.i7.1667] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 11/22/2013] [Accepted: 12/06/2013] [Indexed: 02/06/2023] Open
Abstract
Gastric carcinoma (GC) is the 4th most prevalent cancer and has the 2nd highest cancer-related mortality rate worldwide. Despite the incidence of GC has decreased over the past few decades, it is still a serious health problem. Chronic inflammatory status of the stomach, caused by the infection of Helicobacter pylori (H. pylori) and through the production of inflammatory mediators within the parenchyma is suspected to play an important role in the initiation and progression of GC. In this review, the correlation between chronic inflammation and H. pylori infection as an important factor for the development of GC will be discussed. Major components, including tumor-associated macrophages, lymphocytes, cancer-associated fibroblasts, angiogenic factors, cytokines, and chemokines of GC microenvironment and their mechanism of action on signaling pathways will also be discussed. Increasing our understanding of how the components of the tumor microenviroment interact with GC cells and the signaling pathways involved could help identify new therapeutic and chemopreventive targets.
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Mesothelin binding to CA125/MUC16 promotes pancreatic cancer cell motility and invasion via MMP-7 activation. Sci Rep 2013; 3:1870. [PMID: 23694968 PMCID: PMC3660778 DOI: 10.1038/srep01870] [Citation(s) in RCA: 169] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2013] [Accepted: 04/30/2013] [Indexed: 12/24/2022] Open
Abstract
Mesothelin (MSLN) and cancer antigen125/mucin 16 (CA125/MUC16) are potential biomarkers for pancreatic cancer (PC) that are co-overexpressed at the invading edges of PC tissues, and their expression correlates with poor survival rates. However, the role of MSLN-MUC16 molecular interaction in PC cell motility and invasion has yet to be elucidated. Using sophisticated bioengineering and molecular biology tools, we report that the binding of MSLN to MUC16 markedly enhances PC cell motility and invasion via the selective induction of matrix metalloproteinase (MMP)-7. MSLN-mediated MMP-7 upregulation in MUC16-expressing PC cells occurs via a p38 MAPK-dependent pathway. Depletion of MMP-7 or inhibition of p38 activity abolishes MSLN-mediated PC motility and invasion. These findings provide a novel perspective on the enhanced invasive potential associated with MSLN and MUC16 co-overexpression, and the mechanism underlying MMP-7 activation in PC invasion and metastasis.
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Helicobacter pylori and gastritis: the role of extracellular matrix metalloproteases, their inhibitors, and the disintegrins and metalloproteases--a systematic literature review. Dig Dis Sci 2013; 58:2777-83. [PMID: 23817928 DOI: 10.1007/s10620-013-2767-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2013] [Accepted: 06/14/2013] [Indexed: 12/18/2022]
Abstract
Helicobacter pylori (H. pylori) is the etiologic agent of gastritis; it has been estimated that 50 % of the world's population could be infected by this bacteria. Gastritis may progress to chronic atrophic gastritis, a condition associated with the development of gastric cancer (GC). Several matrix metalloproteases (MMP) and tissue inhibitors of MMPs (TIMP) as well as disintegrins and metalloproteases (ADAM) have been reported as being involved in gastritis. Among other processes, these protein families participate in remodeling the extracellular matrix, cell signaling, immune response, angiogenesis, inflammation and epithelial mesenchymal transition. This systematic review analyzes the scientific evidence surrounding the relationship between members of the MMP, TIMP and ADAM families and infection by H. pylori in gastritis, considering both in vitro and in vivo studies. Given the potential clinical value of certain members of the MMP, TIMP and ADAM families as molecular markers in gastritis and the association of gastritis with GC, the need for further study is highlighted.
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45
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Wang LY, Liu YP, Chen LG, Chen YL, Tan L, Liu JJ, Jazag A, Ren JL, Guleng B. Pyruvate kinase M2 plays a dual role on regulation of the EGF/EGFR signaling via E-cadherin-dependent manner in gastric cancer cells. PLoS One 2013; 8:e67542. [PMID: 23840737 PMCID: PMC3695906 DOI: 10.1371/journal.pone.0067542] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2013] [Accepted: 05/20/2013] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND AND AIMS EGFR activation and PKM2 expression are instrumental in tumorigenesis. EGFR activation regulates PKM2 functions in a subcellular compartment-dependent manner and promotes gene transcription and tumor growth. In addition, PKM2 is upregulated in EGFR-induced pathways in glioma malignancies. However, we found that PKM2 could also regulate the activity of the EGF/EGFR signaling pathway in gastric cancer cells. We aimed to define the biological mechanisms for PKM2 in regulating the cell motility and invasion. METHODS We employed stable transfection with short hairpin RNA to stably silence the expression of PKM2 in the BGC823, SGC7901 and AGS gastric cancer cell lines. The effects of PKM2 in vitro were determined by assessing cell migration and invasion. Immunohistochemical analysis was used to explore the relationship among PKM2 and other proteins. RESULTS Our results indicate that the knockdown of PKM2 decreased the activity of E-cadherin and enhanced the EGF/EGFR signaling pathway in the gastric cell lines BGC823 and SGC7901 that were positive for E-cadherin expression. However, in the undifferentiated gastric carcinoma cell line AGS, which lacks E-cadherin expression, PKM2 promoted cell migration and invasion. Immunohistochemical analyses showed that the levels of E-cadherin expression, ERK1/2 phosphorylation, and cytoplasmic PKM2 expression were correlated with each other. CONCLUSION PKM2 may play different roles in differently differentiated gastric cancer cell types, and this finding would be consistent with the previous clinical research. The results of our study reveal an important link between PKM2 and E-cadherin during EGFR-stimulated gastric cancer cell motility and invasion.
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Affiliation(s)
- Le-Yi Wang
- Department of Gastroenterology, Zhongshan Hospital affiliated to Xiamen University, Xiamen, Fujian Province, China
| | - Yun-Peng Liu
- Department of Gastroenterology, Zhongshan Hospital affiliated to Xiamen University, Xiamen, Fujian Province, China
| | - Li-Gang Chen
- Department of Gastroenterology, Zhongshan Hospital affiliated to Xiamen University, Xiamen, Fujian Province, China
| | - Yan-Ling Chen
- Department of Gastroenterology, Zhongshan Hospital affiliated to Xiamen University, Xiamen, Fujian Province, China
| | - Li Tan
- Department of Gastroenterology, Zhongshan Hospital affiliated to Xiamen University, Xiamen, Fujian Province, China
| | - Jing-Jing Liu
- Department of Gastroenterology, Zhongshan Hospital affiliated to Xiamen University, Xiamen, Fujian Province, China
| | - Amarsanaa Jazag
- National Institute of Medical Research, 3rd General Hospital, Ulaanbaatar, Mongolia
| | - Jian-Lin Ren
- Department of Gastroenterology, Zhongshan Hospital affiliated to Xiamen University, Xiamen, Fujian Province, China
| | - Bayasi Guleng
- Department of Gastroenterology, Zhongshan Hospital affiliated to Xiamen University, Xiamen, Fujian Province, China
- Medical College of Xiamen University, Xiamen, Fujian Province, China
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Shin S, Oh S, An S, Janknecht R. ETS variant 1 regulates matrix metalloproteinase-7 transcription in LNCaP prostate cancer cells. Oncol Rep 2012; 29:306-14. [PMID: 23076342 DOI: 10.3892/or.2012.2079] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2012] [Accepted: 08/30/2012] [Indexed: 01/10/2023] Open
Abstract
Prostate cancer is characterized by the recurrent translocation of ETS transcription factors, including ETS variant 1 (ETV1) [also known as ETS-related 81 (ER81)]. Transgenic ETV1 mice develop prostatic intraepithelial neoplasia, yet the mechanisms by which ETV1 exerts its deleterious function remain largely unexplored. In this study, we demonstrated that ETV1 is capable of binding to the matrix metalloproteinase-7 (MMP-7) gene promoter both in vitro and in vivo. ETV1 stimulated the activity of the MMP-7 promoter, which was suppressed upon mutation of two ETV1 binding sites located within 200 base pairs upstream of the MMP-7 transcription start site. ETV1 overexpression in human LNCaP prostate cancer cells induced endogenous MMP-7 gene transcription, whereas ETV1 downregulation had the opposite effect. While MMP-7 overexpression did not influence LNCaP cell proliferation, it increased cell migration, which may be important during later stages of tumorigenesis. Finally, MMP-7 mRNA was significantly overexpressed in human prostate tumors compared to normal tissue. Together, these results showed that MMP-7 is a bona fide ETV1 target gene, implicating that MMP-7 upregulation is partially responsible for the oncogenic effects of ETV1 in the prostate.
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Affiliation(s)
- Sook Shin
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
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47
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Holmberg C, Quante M, Steele I, Kumar JD, Balabanova S, Duval C, Czepan M, Rakonczay Z, Tiszlavicz L, Nemeth I, Lazar G, Simonka Z, Jenkins R, Hegyi P, Wang TC, Dockray GJ, Varro A. Release of TGFβig-h3 by gastric myofibroblasts slows tumor growth and is decreased with cancer progression. Carcinogenesis 2012; 33:1553-1562. [PMID: 22610072 PMCID: PMC3499060 DOI: 10.1093/carcin/bgs180] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2012] [Revised: 04/26/2012] [Accepted: 05/10/2012] [Indexed: 01/21/2023] Open
Abstract
Tumor progression has been linked to changes in the stromal environment. Myofibroblasts are stromal cells that are often increased in tumors but their contribution to cancer progression is not well understood. Here, we show that the secretomes of myofibroblasts derived from gastric cancers [cancer-associated myofibroblasts (CAMs)] differ in a functionally significant manner from those derived from adjacent tissue [adjacent tissue myofibroblasts (ATMs)]. CAMs showed increased rates of migration and proliferation compared with ATMs or normal tissue myofibroblasts (NTMs). Moreover, conditioned medium (CM) from CAMs significantly stimulated migration, invasion and proliferation of gastric cancer cells compared with CM from ATMs or NTMs. Proteomic analysis of myofibroblast secretomes revealed decreased abundance of the extracellular matrix (ECM) adaptor protein like transforming growth factor-β-induced gene-h3 (TGFβig-h3) in CAMs, which was correlated with lymph node involvement and shorter survival. TGFβig-h3 inhibited IGF-II-stimulated migration and proliferation of both cancer cells and myofibroblasts, and suppressed IGF-II activation of p42/44 MAPkinase; TGFβig-h3 knockdown increased IGF-II- and CM-stimulated migration. Furthermore, administration of TGFβig-h3 inhibited myofibroblast-stimulated growth of gastric cancer xenografts. We conclude that stromal cells exert inhibitory as well as stimulatory effects on tumor cells; TGFβig-h3 is a stromal inhibitory factor that is decreased with progression of gastric cancers.
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Affiliation(s)
- Chris Holmberg
- Department of Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool,
Liverpool, UK
| | - Michael Quante
- II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München,
München, Germany
| | - Islay Steele
- Department of Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool,
Liverpool, UK
| | - Jothi Dinesh Kumar
- Department of Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool,
Liverpool, UK
| | - Silviya Balabanova
- Department of Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool,
Liverpool, UK
| | - Cedric Duval
- Department of Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool,
Liverpool, UK
| | | | | | | | | | - Gyorgy Lazar
- First Department of Surgery, University of Szeged,
Szeged, Hungary
| | - Zsolt Simonka
- First Department of Surgery, University of Szeged,
Szeged, Hungary
| | - Rosalind Jenkins
- Department of Molecular & Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool,
Liverpool, UK
| | | | - Timothy C. Wang
- Department of Medicine, Columbia University,
New York, NY, USAand
| | - Graham J. Dockray
- Department of Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool,
Liverpool, UK
| | - Andrea Varro
- Department of Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool,
Liverpool, UK
- Department of Molecular & Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool,
Liverpool, UK
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Baren JP, Stewart GD, Stokes A, Gray K, Pennington CJ, O'Neill R, Deans DAC, Paterson-Brown S, Riddick ACP, Edwards DR, Fearon KCH, Ross JA, Skipworth RJE. mRNA profiling of the cancer degradome in oesophago-gastric adenocarcinoma. Br J Cancer 2012; 107:143-9. [PMID: 22677901 PMCID: PMC3389427 DOI: 10.1038/bjc.2012.239] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Background: Degradation of the extracellular matrix is fundamental to tumour development, invasion and metastasis. Several protease families have been implicated in the development of a broad range of tumour types, including oesophago–gastric (OG) adenocarcinoma. The aim of this study was to analyse the expression levels of all core members of the cancer degradome in OG adenocarcinoma and to investigate the relationship between expression levels and tumour/patient variables associated with poor prognosis. Methods: Comprehensive expression profiling of the protease families (matrix metalloproteinases (MMPs), members of the ADAM metalloproteinase-disintegrin family (ADAMs)), their inhibitors (tissue inhibitors of metalloproteinase), and molecules involved in the c-Met signalling pathway, was performed using quantitative real-time reverse transcription polymerase chain reaction in a cohort of matched malignant and benign peri-tumoural OG tissue (n=25 patients). Data were analysed with respect to clinico-pathological variables (tumour stage and grade, age, sex and pre-operative plasma C-reactive protein level). Results: Gene expression of MMP1, 3, 7, 9, 10, 11, 12, 16 and 24 was upregulated by factors >4-fold in OG adenocarcinoma samples compared with matched benign tissue (P<0.01). Expression of ADAM8 and ADAM15 correlated significantly with tumour stage (P=0.048 and P=0.044), and ADAM12 expression correlated with tumour grade (P=0.011). Conclusion: This study represents the first comprehensive quantitative analysis of the expression of proteases and their inhibitors in human OG adenocarcinoma. These findings implicate elevated ADAM8, 12 and 15 mRNA expression as potential prognostic molecular markers.
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Affiliation(s)
- J P Baren
- Tissue Injury and Repair Group, Clinical and Surgical Sciences, University of Edinburgh-MRC Centre for Regenerative Medicine, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh, UK
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Cheng HC, Yang HB, Chang WL, Chen WY, Yeh YC, Sheu BS. Expressions of MMPs and TIMP-1 in gastric ulcers may differentiate H. pylori-infected from NSAID-related ulcers. ScientificWorldJournal 2012; 2012:539316. [PMID: 22645431 PMCID: PMC3353510 DOI: 10.1100/2012/539316] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2011] [Accepted: 01/03/2012] [Indexed: 01/12/2023] Open
Abstract
Background. Two major causes of gastric ulcers are Helicobacter pylori (H. pylori) infection and nonsteroidal anti-inflammatory drug (NSAID) use. Aims. This study aimed to determine if there were different expressions of matrix metalloproteinases (MMPs) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) between H. pylori-infected and NSAID-related ulcers. Methods. The 126 gastric ulcer patients (H. pylori infected n = 46; NSAID related n = 30; combined with two factors n = 50) provided ulcer and nonulcer tissues for assessment of MMP-3, -7, and -9 and TIMP-1 expression by immunohistochemical staining. Results. Gastric ulcer tissues had significantly higher MMP-3, -7, and -9 and TIMP-1 expressions than nonulcer tissues (P < 0.05). H. pylori-infected gastric ulcers had even higher MMP-7, MMP-9, and TIMP-1 expressions in epithelial cells than NSAID-related gastric ulcers (P < 0.05). In patients with the two combined factors, gastric ulcers expressed similar proportions of antral ulcers and MMP-7 and MMP-9 intensities to NSAID-related gastric ulcers, but lower MMP-9 and TIMP-1 than H. pylori-infected gastric ulcers (P < 0.05). Conclusions. H. pylori-infected gastric ulcers express higher MMP-7, MMP-9, and TIMP-1 than NSAID-related ulcers. In patients with the two combined factors, ulcer location and MMP-7 and MMP-9 intensities are similar to NSAID use.
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Affiliation(s)
- Hsiu-Chi Cheng
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, 138 Sheng Li Road, Tainan 70403, Taiwan
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Wessler S, Gimona M, Rieder G. Regulation of the actin cytoskeleton in Helicobacter pylori-induced migration and invasive growth of gastric epithelial cells. Cell Commun Signal 2011; 9:27. [PMID: 22044652 PMCID: PMC3214149 DOI: 10.1186/1478-811x-9-27] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2011] [Accepted: 11/01/2011] [Indexed: 02/08/2023] Open
Abstract
Dynamic rearrangement of the actin cytoskeleton is a significant hallmark of Helicobacter pylori (H. pylori) infected gastric epithelial cells leading to cell migration and invasive growth. Considering the cellular mechanisms, the type IV secretion system (T4SS) and the effector protein cytotoxin-associated gene A (CagA) of H. pylori are well-studied initiators of distinct signal transduction pathways in host cells targeting kinases, adaptor proteins, GTPases, actin binding and other proteins involved in the regulation of the actin lattice. In this review, we summarize recent findings of how H. pylori functionally interacts with the complex signaling network that controls the actin cytoskeleton of motile and invasive gastric epithelial cells.
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Affiliation(s)
- Silja Wessler
- Division of Molecular Biology, Department of Microbiology, University of Salzburg, Salzburg, Austria.
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