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1
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Zou Y, Yuan Y, Zhou Q, Yue Z, Liu J, Fan L, Xu H, Xin L. The Role of Methionine Restriction in Gastric Cancer: A Summary of Mechanisms and a Discussion on Tumor Heterogeneity. Biomolecules 2024; 14:161. [PMID: 38397398 PMCID: PMC10887009 DOI: 10.3390/biom14020161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2023] [Revised: 01/18/2024] [Accepted: 01/24/2024] [Indexed: 02/25/2024] Open
Abstract
Gastric cancer is ranked as the fifth most prevalent cancer globally and has long been a topic of passionate discussion among numerous individuals. However, the incidence of gastric cancer in society has not decreased, but instead has shown a gradual increase in recent years. For more than a decade, the treatment effect of gastric cancer has not been significantly improved. This is attributed to the heterogeneity of cancer, which makes popular targeted therapies ineffective. Methionine is an essential amino acid, and many studies have shown that it is involved in the development of gastric cancer. Our study aimed to review the literature on methionine and gastric cancer, describing its mechanism of action to show that tumor heterogeneity in gastric cancer does not hinder the effectiveness of methionine-restricted therapies. This research also aimed to provide insight into the inhibition of gastric cancer through metabolic reprogramming with methionine-restricted therapies, thereby demonstrating their potential as adjuvant treatments for gastric cancer.
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Affiliation(s)
| | | | | | | | | | | | | | - Lin Xin
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Donghu District, Nanchang 330006, China; (Y.Z.); (Y.Y.); (Q.Z.); (Z.Y.); (J.L.); (L.F.); (H.X.)
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2
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Wrede D, Bordak M, Abraham Y, Mehedi M. Pulmonary Pathogen-Induced Epigenetic Modifications. EPIGENOMES 2023; 7:13. [PMID: 37489401 PMCID: PMC10366755 DOI: 10.3390/epigenomes7030013] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 06/27/2023] [Accepted: 07/03/2023] [Indexed: 07/26/2023] Open
Abstract
Epigenetics generally involves genetic control by factors other than our own DNA sequence. Recent research has focused on delineating the mechanisms of two major epigenetic phenomena: DNA methylation and histone modification. As epigenetics involves many cellular processes, it is no surprise that it can also influence disease-associated gene expression. A direct link between respiratory infections, host cell epigenetic regulations, and chronic lung diseases is still unknown. Recent studies have revealed bacterium- or virus-induced epigenetic changes in the host cells. In this review, we focused on respiratory pathogens (viruses, bacteria, and fungi) induced epigenetic modulations (DNA methylation and histone modification) that may contribute to lung disease pathophysiology by promoting host defense or allowing pathogen persistence.
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Affiliation(s)
| | | | | | - Masfique Mehedi
- School of Medicine & Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA; (D.W.); (M.B.); (Y.A.)
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3
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Yang J, Hu Y, Zhang B, Liang X, Li X. The JMJD Family Histone Demethylases in Crosstalk Between Inflammation and Cancer. Front Immunol 2022; 13:881396. [PMID: 35558079 PMCID: PMC9090529 DOI: 10.3389/fimmu.2022.881396] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 03/23/2022] [Indexed: 02/05/2023] Open
Abstract
Inflammation has emerged as a key player in regulating cancer initiation, progression, and therapeutics, acting as a double edged sword either facilitating cancer progression and therapeutic resistance or inducing anti-tumor immune responses. Accumulating evidence has linked the epigenetic modifications of histones to inflammation and cancer, and histone modifications-based strategies have shown promising therapeutic potentials against cancer. The jumonji C domain-containing (JMJD) family histone demethylases have exhibited multiple regulator functions in inflammatory processes and cancer development, and a number of therapeutic strategies targeting JMJD histone demethylases to modulate inflammatory cells and their products have been successfully evaluated in clinical or preclinical tumor models. This review summarizes current understanding of the functional roles and mechanisms of JMJD histone demethylases in crosstalk between inflammation and cancer, and highlights recent clinical and preclinical progress on harnessing the JMJD histone demethylases to regulate cancer-related inflammation for future cancer therapeutics.
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Affiliation(s)
- Jia Yang
- Department of Gynecology and Obstetrics and Pediatric Nephrology Nursing, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, China
| | - Yuan Hu
- Department of Gynecology and Obstetrics and Pediatric Nephrology Nursing, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, China
| | - Binjing Zhang
- State Key Laboratory of Oral Disease, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xiao Liang
- Department of Gynecology and Obstetrics and Pediatric Nephrology Nursing, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, China
| | - Xin Li
- State Key Laboratory of Oral Disease, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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4
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Bryan ER, Barrero RA, Cheung E, Tickner JAD, Trim LK, Richard D, McLaughlin EA, Beagley KW, Carey AJ. DNA damage contributes to transcriptional and immunological dysregulation of testicular cells during Chlamydia infection. Am J Reprod Immunol 2021; 86:e13400. [PMID: 33565167 DOI: 10.1111/aji.13400] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 09/23/2020] [Accepted: 02/06/2021] [Indexed: 01/17/2023] Open
Abstract
Chlamydia is the most commonly reported sexually transmitted bacterial infection, with 127 million notifications worldwide each year. Both males and females are susceptible to the pathological impacts on fertility that Chlamydia infections can induce. However, male chlamydial infections, particularly within the upper reproductive tract, including the testis, are not well characterized. In this study, using mouse testicular cell lines, we examined the impact of infection on testicular cell lineage transcriptomes and potential mechanisms for this impact. The somatic cell lineages exhibited significantly fragmented genomes during infection. Likely resulting from this, each of the Leydig, Sertoli and germ cell lineages experienced extensive transcriptional dysregulation, leading to significant changes in cellular biological pathways, including interferon and germ-Sertoli cell signalling. The cell lineages, as well as isolated spermatozoa from infected mice, also contained globally hypomethylated DNA. Cumulatively, the DNA damage and epigenetic-mediated transcriptional dysregulation observed within testicular cells during chlamydial infection could result in the production of spermatozoa with abnormal epigenomes, resulting in previously observed subfertility in infected animals and congenital defects in their offspring.
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Affiliation(s)
- Emily R Bryan
- School of Biomedical Sciences and Centre for Immunology and Infection Control, Queensland University of Technology, Herston, QLD, Australia
| | - Roberto A Barrero
- eResearch Office and Division of Research & Innovation, Queensland University of Technology, Brisbane City, QLD, Australia
| | - Eddie Cheung
- School of Biomedical Sciences and Centre for Immunology and Infection Control, Queensland University of Technology, Herston, QLD, Australia
| | - Jacob A D Tickner
- School of Biomedical Sciences and Genomics and Precision Health Centre, Queensland University of Technology, Woolloongabba, QLD, Australia
| | - Logan K Trim
- School of Biomedical Sciences and Centre for Immunology and Infection Control, Queensland University of Technology, Herston, QLD, Australia
| | - Derek Richard
- School of Biomedical Sciences and Genomics and Precision Health Centre, Queensland University of Technology, Woolloongabba, QLD, Australia
| | - Eileen A McLaughlin
- School of Environmental and Life Sciences, Faculty of Science, The University of Newcastle, Callaghan, NSW, Australia.,School of Science, Western Sydney University, Penrith, NSW, Australia
| | - Kenneth W Beagley
- School of Biomedical Sciences and Centre for Immunology and Infection Control, Queensland University of Technology, Herston, QLD, Australia
| | - Alison J Carey
- School of Biomedical Sciences and Centre for Immunology and Infection Control, Queensland University of Technology, Herston, QLD, Australia
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5
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Denzer L, Schroten H, Schwerk C. From Gene to Protein-How Bacterial Virulence Factors Manipulate Host Gene Expression During Infection. Int J Mol Sci 2020; 21:ijms21103730. [PMID: 32466312 PMCID: PMC7279228 DOI: 10.3390/ijms21103730] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 05/19/2020] [Accepted: 05/20/2020] [Indexed: 02/06/2023] Open
Abstract
Bacteria evolved many strategies to survive and persist within host cells. Secretion of bacterial effectors enables bacteria not only to enter the host cell but also to manipulate host gene expression to circumvent clearance by the host immune response. Some effectors were also shown to evade the nucleus to manipulate epigenetic processes as well as transcription and mRNA procession and are therefore classified as nucleomodulins. Others were shown to interfere downstream with gene expression at the level of mRNA stability, favoring either mRNA stabilization or mRNA degradation, translation or protein stability, including mechanisms of protein activation and degradation. Finally, manipulation of innate immune signaling and nutrient supply creates a replicative niche that enables bacterial intracellular persistence and survival. In this review, we want to highlight the divergent strategies applied by intracellular bacteria to evade host immune responses through subversion of host gene expression via bacterial effectors. Since these virulence proteins mimic host cell enzymes or own novel enzymatic functions, characterizing their properties could help to understand the complex interactions between host and pathogen during infections. Additionally, these insights could propose potential targets for medical therapy.
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6
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Wisnieski F, Santos LC, Calcagno DQ, Geraldis JC, Gigek CO, Anauate AC, Chen ES, Rasmussen LT, Payão SLM, Artigiani R, Demachki S, Assumpção PP, Lourenço LG, Arasaki CH, Pabinger S, Krainer J, Leal MF, Burbano RR, Arruda Cardoso Smith M. The impact of DNA demethylation on the upregulation of the NRN1 and TNFAIP3 genes associated with advanced gastric cancer. J Mol Med (Berl) 2020; 98:707-717. [PMID: 32285140 DOI: 10.1007/s00109-020-01902-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 03/10/2020] [Accepted: 03/18/2020] [Indexed: 12/24/2022]
Abstract
Gastric cancer (GC) is the third leading cause of cancer-related death worldwide. Very few therapeutic options are currently available in this neoplasia. The use of 5-Aza-2'-deoxycytidine (5-AZAdC) was approved for the treatment of myelodysplastic syndromes, and this drug can treat solid tumours at low doses. Epigenetic manipulation of GC cell lines is a useful tool to better understand gene expression regulatory mechanisms for clinical applications. Therefore, we compared the gene expression profile of 5-AZAdC-treated and untreated GC cell lines by a microarray assay. Among the genes identified in this analysis, we selected NRN1 and TNFAIP3 to be evaluated for gene expression by RT-qPCR and DNA methylation by bisulfite DNA next-generation sequencing in 43 and 52 pairs of GC and adjacent non-neoplastic tissue samples, respectively. We identified 83 candidate genes modulated by DNA methylation in GC cell lines. Increased expression of NRN1 and TNFAIP3 was associated with advanced tumours (P < 0.05). We showed that increased NRN1 and TNFAIP3 expression seems to be regulated by DNA demethylation in GC samples: inverse correlations between the mRNA and DNA methylation levels in the promoter of NRN1 (P < 0.05) and the intron of TNFAIP3 (P < 0.05) were detected. Reduced NRN1 promoter methylation was associated with III/IV TNM stage tumours (P = 0.03) and the presence of Helicobacter pylori infection (P = 0.02). The identification of demethylated activated genes in GC may be useful in clinical practice, stratifying patients who are less likely to benefit from 5-AZAdC-based therapies. KEY MESSAGES: Higher expression of NRN1 and TNFAIP3 is associated with advanced gastric cancer (GC). NRN1 promoter hypomethylation contributes to gene upregulation in advanced GC. TNFAIP3 intronic-specific CpG site demethylation contributes to gene upregulation in GC. These findings may be useful to stratify GC patients who are less likely to benefit from DNA demethylating-based therapies.
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Affiliation(s)
- Fernanda Wisnieski
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, Rua Botucatu, 740, São Paulo, São Paulo, 04023900, Brazil. .,Disciplina de Gastroenterologia, Departamento de Medicina, Universidade Federal de São Paulo, Rua Loefgreen, 1726, São Paulo, São Paulo, 04040002, Brazil.
| | - Leonardo Caires Santos
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, Rua Botucatu, 740, São Paulo, São Paulo, 04023900, Brazil
| | - Danielle Queiroz Calcagno
- Programa de Pós-graduação em Oncologia e Ciências Médicas, Universidade Federal do Pará, Rua dos Mundurucus, 4487, Belém, Pará, 66073-000, Brazil
| | - Jaqueline Cruz Geraldis
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, Rua Botucatu, 740, São Paulo, São Paulo, 04023900, Brazil
| | - Carolina Oliveira Gigek
- Departamento de Patologia, Universidade Federal de São Paulo, Rua Botucatu, 740, São Paulo, São Paulo, 04023900, Brazil
| | - Ana Carolina Anauate
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, Rua Botucatu, 740, São Paulo, São Paulo, 04023900, Brazil
| | - Elizabeth Suchi Chen
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, Rua Botucatu, 740, São Paulo, São Paulo, 04023900, Brazil
| | - Lucas Trevizani Rasmussen
- Disciplina de Genética, Hemocentro da Faculdade de Medicina de Marília, Rua Lourival Freire, 240, Marília, São Paulo, 17519-050, Brazil
| | - Spencer Luiz Marques Payão
- Disciplina de Genética, Hemocentro da Faculdade de Medicina de Marília, Rua Lourival Freire, 240, Marília, São Paulo, 17519-050, Brazil
| | - Ricardo Artigiani
- Departamento de Patologia, Universidade Federal de São Paulo, Rua Botucatu, 740, São Paulo, São Paulo, 04023900, Brazil
| | - Samia Demachki
- Programa de Pós-graduação em Oncologia e Ciências Médicas, Universidade Federal do Pará, Rua dos Mundurucus, 4487, Belém, Pará, 66073-000, Brazil
| | - Paulo Pimentel Assumpção
- Programa de Pós-graduação em Oncologia e Ciências Médicas, Universidade Federal do Pará, Rua dos Mundurucus, 4487, Belém, Pará, 66073-000, Brazil
| | - Laercio Gomes Lourenço
- Disciplina de Gastroenterologia Cirúrgica, Departamento de Cirurgia, Universidade Federal de São Paulo, R. Napoleão de Barros, 715, São Paulo, 04024002, Brazil
| | - Carlos Haruo Arasaki
- Disciplina de Gastroenterologia Cirúrgica, Departamento de Cirurgia, Universidade Federal de São Paulo, R. Napoleão de Barros, 715, São Paulo, 04024002, Brazil
| | - Stephan Pabinger
- Austrian Institute of Technology, Center for Health & Bioresources, Molecular Diagnostics, Giefinggasse 4, 1210, Vienna, Austria
| | - Julie Krainer
- Austrian Institute of Technology, Center for Health & Bioresources, Molecular Diagnostics, Giefinggasse 4, 1210, Vienna, Austria
| | - Mariana Ferreira Leal
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, Rua Botucatu, 740, São Paulo, São Paulo, 04023900, Brazil.,Programa de Pós-graduação em Oncologia e Ciências Médicas, Universidade Federal do Pará, Rua dos Mundurucus, 4487, Belém, Pará, 66073-000, Brazil
| | - Rommel Rodriguez Burbano
- Programa de Pós-graduação em Oncologia e Ciências Médicas, Universidade Federal do Pará, Rua dos Mundurucus, 4487, Belém, Pará, 66073-000, Brazil.,Laboratório de Biologia Molecular, Hospital Ophir Loyola, Avenida Governador Magalhães, 992, Belém, 66063-240, Brazil
| | - Marilia Arruda Cardoso Smith
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, Rua Botucatu, 740, São Paulo, São Paulo, 04023900, Brazil.
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7
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Yousefi B, Mohammadlou M, Abdollahi M, Salek Farrokhi A, Karbalaei M, Keikha M, Kokhaei P, Valizadeh S, Rezaiemanesh A, Arabkari V, Eslami M. Epigenetic changes in gastric cancer induction by Helicobacter pylori. J Cell Physiol 2019; 234:21770-21784. [PMID: 31169314 DOI: 10.1002/jcp.28925] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Revised: 05/06/2019] [Accepted: 05/07/2019] [Indexed: 02/05/2023]
Abstract
Epigenetic disorder mechanisms are one of the causes of cancer. The most important of these changes is the DNA methylation, which leads to the spread of Helicobacter pylori and inflammatory processes followed by induction of DNA methylation disorder. Mutations and epigenetic changes are the two main agents of neoplasia. Epithelial cells infection by H. pylori associated with activating several intracellular pathways including: MAPK, NF-κB, Wnt/β-catenin, and PI3K are affects a variety of cells and caused to an increase in the production of inflammatory cytokines, changes in apoptosis, proliferation, differentiation, and ultimately leads to the transformation of epithelial cells into oncogenic. The arose of free radicals impose the DNA cytosine methylation, and NO can increase the activity of DNA methyltransferase. H. pylori infection causes an environment that mediates inflammation and signaling pathways that probably caused to stomach tumorigenicity. The main processes that change by decreasing or increasing the expression of various microRNAs expressions include immune responses, apoptosis, cell cycle, and autophagy. In this review will be describe a probably H. pylori roles in infection and mechanisms that have contribution in epigenetic changes in the promoter of genes.
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Affiliation(s)
- Bahman Yousefi
- Department of Immunology, Semnan University of Medical Sciences, Semnan, Iran
| | - Maryam Mohammadlou
- Department of Immunology, Semnan University of Medical Sciences, Semnan, Iran
| | - Maryam Abdollahi
- Department of Immunology, Semnan University of Medical Sciences, Semnan, Iran
| | - Amir Salek Farrokhi
- Department of Immunology, Semnan University of Medical Sciences, Semnan, Iran
| | - Mohsen Karbalaei
- Department of Microbiology and Virology, School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran
| | - Masoud Keikha
- Department of Microbiology and Virology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Parviz Kokhaei
- Department of Immunology, Semnan University of Medical Sciences, Semnan, Iran
- Immune and Gene Therapy Lab, Cancer Centre Karolinska, Karolinska University Hospital, Stockholm, Sweden
| | - Saeid Valizadeh
- Department of Bacteriology and Virology, Semnan University of Medical Sciences, Semnan, Iran
| | - Alireza Rezaiemanesh
- Department of Immunology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Vahid Arabkari
- Centre for BioNano Interactions, School of Chemistry and Chemical Biology, University College Dublin, Dublin, Ireland
| | - Majid Eslami
- Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran
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8
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Bravo J, Díaz P, Corvalán AH, Quest AFG. A Novel Role for Helicobacter pylori Gamma-Glutamyltranspeptidase in Regulating Autophagy and Bacterial Internalization in Human Gastric Cells. Cancers (Basel) 2019; 11:cancers11060801. [PMID: 31185677 PMCID: PMC6627848 DOI: 10.3390/cancers11060801] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 04/23/2019] [Accepted: 04/26/2019] [Indexed: 12/12/2022] Open
Abstract
The risk of developing gastric cancer is strongly linked to Helicobacter pylori (H. pylori) infection. Alternatively, autophagy is a conserved response that is important in cellular homeostasis and provides protection against bacterial infections. Although H. pylori is typically considered an extracellular bacterium, several reports indicate that it internalizes, possibly to avoid exposure to antibiotics. Mechanisms by which H. pylori manipulates host cell autophagic processes remain unclear and, importantly, none of the available studies consider a role for the secreted H. pylori virulence factor gamma-glutamyltranspeptidase (HpGGT) in this context. Here, we identify HpGGT as a novel autophagy inhibitor in gastric cells. Our experiments revealed that deletion of HpGGT increased autophagic flux following H. pylori infection of AGS and GES-1 gastric cells. In AGS cells, HpGGT disrupted the late stages of autophagy by preventing degradation in lysosomes without affecting lysosomal acidification. Specifically, HpGGT impaired autophagic flux by disrupting lysosomal membrane integrity, which leads to a decrease in lysosomal cathepsin B activity. Moreover, HpGGT was necessary for efficient internalization of the bacteria into gastric cells. This important role of HpGGT in internalization together with the ability to inhibit autophagy posits HpGGT as a key virulence factor in the development of gastric cancer.
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Affiliation(s)
- Jimena Bravo
- Laboratory of Cellular Communication, Center for the Study of Exercise, Metabolism and Cancer (CEMC), Program in Cell and Molecular Biology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile.
- Advanced Center for Chronic Diseases (ACCDiS), Santiago 8380492, Chile.
| | - Paula Díaz
- Laboratory of Cellular Communication, Center for the Study of Exercise, Metabolism and Cancer (CEMC), Program in Cell and Molecular Biology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile.
- Advanced Center for Chronic Diseases (ACCDiS), Santiago 8380492, Chile.
| | - Alejandro H Corvalán
- Advanced Center for Chronic Diseases (ACCDiS), Santiago 8380492, Chile.
- Laboratory of Oncology, Department of Hematology and Oncology, Pontificia Universidad Católica de Chile, Santiago 8330034, Chile.
| | - Andrew F G Quest
- Laboratory of Cellular Communication, Center for the Study of Exercise, Metabolism and Cancer (CEMC), Program in Cell and Molecular Biology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile.
- Advanced Center for Chronic Diseases (ACCDiS), Santiago 8380492, Chile.
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9
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Vaziri F, Tarashi S, Fateh A, Siadat SD. New insights of Helicobacter pylori host-pathogen interactions: The triangle of virulence factors, epigenetic modifications and non-coding RNAs. World J Clin Cases 2018; 6:64-73. [PMID: 29774218 PMCID: PMC5955730 DOI: 10.12998/wjcc.v6.i5.64] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2018] [Revised: 02/09/2018] [Accepted: 03/07/2018] [Indexed: 02/05/2023] Open
Abstract
Helicobacter pylori (H. pylori) is a model organism for understanding host-pathogen interactions and infection-mediated carcinogenesis. Gastric cancer and H. pylori colonization indicates the strong correlation. The progression and exacerbation of H. pylori infection are influenced by some factors of pathogen and host. Several virulence factors involved in the proper adherence and attenuation of immune defense to contribute the risk of emerging gastric cancer, therefore analysis of them is very important. H. pylori also modulates inflammatory and autophagy process to intensify its pathogenicity. From the host regard, different genetic factors particularly affect the development of gastric cancer. Indeed, epigenetic modifications, MicroRNA and long non-coding RNA received more attention. Generally, various factors related to pathogen and host that modulate gastric cancer development in response to H. pylori need more attention due to develop an efficacious therapeutic intervention. Therefore, this paper will present a brief overview of host-pathogen interaction especially emphases on bacterial virulence factors, interruption of host cellular signaling, the role of epigenetic modifications and non-coding RNAs.
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Affiliation(s)
- Farzam Vaziri
- Microbiology Research Center, Pasteur Institute of Iran, Tehran 1316943551, Iran
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran 1316943551, Iran
| | - Samira Tarashi
- Microbiology Research Center, Pasteur Institute of Iran, Tehran 1316943551, Iran
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran 1316943551, Iran
| | - Abolfazl Fateh
- Microbiology Research Center, Pasteur Institute of Iran, Tehran 1316943551, Iran
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran 1316943551, Iran
| | - Seyed Davar Siadat
- Microbiology Research Center, Pasteur Institute of Iran, Tehran 1316943551, Iran
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran 1316943551, Iran
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10
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Modulation of gene transcription and epigenetics of colon carcinoma cells by bacterial membrane vesicles. Sci Rep 2018; 8:7434. [PMID: 29743643 PMCID: PMC5943334 DOI: 10.1038/s41598-018-25308-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Accepted: 04/12/2018] [Indexed: 12/18/2022] Open
Abstract
Interactions between bacteria and colon cancer cells influence the transcription of the host cell. Yet is it undetermined whether the bacteria itself or the communication between the host and bacteria is responsible for the genomic changes in the eukaryotic cell. Now, we have investigated the genomic and epigenetic consequences of co-culturing colorectal carcinoma cells with membrane vesicles from pathogenic bacteria Vibrio cholerae and non-pathogenic commensal bacteria Escherichia coli. Our study reveals that membrane vesicles from pathogenic and commensal bacteria have a global impact on the gene expression of colon-carcinoma cells. The changes in gene expression correlate positively with both epigenetic changes and chromatin accessibility of promoters at transcription start sites of genes induced by both types of membrane vesicles. Moreover, we have demonstrated that membrane vesicles obtained only from V. cholerae induced the expression of genes associated with epithelial cell differentiation. Altogether, our study suggests that the observed genomic changes in host cells might be due to specific components of membrane vesicles and do not require communication by direct contact with the bacteria.
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11
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Han F, Ren J, Zhang J, Sun Y, Ma F, Liu Z, Yu H, Jia J, Li W. JMJD2B is required for Helicobacter pylori-induced gastric carcinogenesis via regulating COX-2 expression. Oncotarget 2018; 7:38626-38637. [PMID: 27232941 PMCID: PMC5122416 DOI: 10.18632/oncotarget.9573] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2015] [Accepted: 05/05/2016] [Indexed: 12/11/2022] Open
Abstract
Helicobacter pylori (H. pylori) infection is the strongest risk factor for the initiation and progression of gastric cancer. However, the mechanism of H. pylori-induced pathogenesis remains unclear. In this study, we investigate the role of H. pylori infection in JMJD2B upregulation and the mechanism underlying gastric carcinogenesis. We find that JMJD2B can be induced by H. pylori infection via β-catenin pathway. β-catenin directly binds to JMJD2B promoter and stimulates JMJD2B expression following H. pylori infection. Increased JMJD2B, together with NF-κB, binds to COX-2 promoter to enhance its transcription by demethylating H3K9me3 locally. JMJD2B and COX-2 expression is upregulated in H. pylori infected mice in vivo. Furthermore, JMJD2B and COX-2 expression is gradually increased in human gastric tissues from gastritis to gastric cancer. The level of JMJD2B and COX-2 in H. pylori-positive gastritis tissues is significantly higher than that in H. pylori-negative tissues. Moreover, a positive correlation between JMJD2B and COX-2 expression is found in both gastritis and gastric cancer tissues. Therefore, JMJD2B is a crucial factor in triggering H. pylori-induced chronic inflammation and progression of gastric carcinogenesis and it may serve as a novel target for the intervention of gastric cancer.
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Affiliation(s)
- Fengjuan Han
- Department of Microbiology, Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan, PR China
| | - Juchao Ren
- Department of Microbiology, Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan, PR China.,Department of Urology, Qilu Hospital, Shandong University, Jinan, PR China
| | - Jinjin Zhang
- Department of Microbiology, Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan, PR China
| | - Yundong Sun
- Department of Microbiology, Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan, PR China
| | - Fang Ma
- Department of Microbiology, Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan, PR China
| | - Zhifang Liu
- Department of Biochemistry and Molecular Biology, School of Medicine, Shandong University, Jinan, PR China
| | - Han Yu
- Department of Microbiology, Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan, PR China
| | - Jihui Jia
- Department of Microbiology, Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan, PR China
| | - Wenjuan Li
- Department of Microbiology, Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan, PR China
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Devanand P, Oya Y, Sundaramoorthy S, Song KY, Watanabe T, Kobayashi Y, Shimizu Y, Hong SA, Suganuma M, Lim IK. Inhibition of TNFα-interacting protein α (Tipα)-associated gastric carcinogenesis by BTG2 /TIS21 via downregulating cytoplasmic nucleolin expression. Exp Mol Med 2018; 50:e449. [PMID: 29472702 PMCID: PMC5903828 DOI: 10.1038/emm.2017.281] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Revised: 09/06/2017] [Accepted: 09/26/2017] [Indexed: 02/07/2023] Open
Abstract
To understand the regulation of Helicobacter pylori (H. pylori)-associated gastric carcinogenesis, we examined the effect of B-cell translocation gene 2 (BTG2) expression on the biological activity of Tipα, an oncoprotein secreted from H. pylori. BTG2, the human ortholog of mouse TIS21 (BTG2/TIS21), has been reported to be a primary response gene that is transiently expressed in response to various stimulations. Here, we report that BTG2 is constitutively expressed in the mucous epithelium and parietal cells of the gastric gland in the stomach. Expression was increased in the mucous epithelium following H. pylori infection in contrast to its loss in human gastric adenocarcinoma. Indeed, adenoviral transduction of BTG2/TIS21 significantly inhibited Tipα activity in MKN-1 and MGT-40, human and mouse gastric cancer cells, respectively, thereby downregulating tumor necrosis factor-α (TNFα) expression and Erk1/2 phosphorylation by reducing expression of nucleolin, a Tipα receptor. Chromatin immunoprecipitation proved that BTG2/TIS21 inhibited Sp1 expression and its binding to the promoter of the nucleolin gene. In addition, BTG2/TIS21 expression significantly reduced membrane-localized nucleolin expression in cancer cells, and the loss of BTG2/TIS21 expression induced cytoplasmic nucleolin availability in gastric cancer tissues, as evidenced by immunoblotting and immunohistochemistry. Higher expression of BTG2 and lower expression of nucleolin were accompanied with better overall survival of poorly differentiated gastric cancer patients. This is the first report showing that BTG2/TIS21 inhibits nucleolin expression via Sp1 binding, which might be associated with the inhibition of H. pylori-induced carcinogenesis. We suggest that BTG2/TIS21 is a potential inhibitor of nucleolin in the cytoplasm, leading to inhibition of carcinogenesis after H. pylori infection.
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Affiliation(s)
- Preethi Devanand
- Division of Medical Sciences, Graduate School of Ajou University, Gyeonggi-do, Republic of Korea
- Department of Biochemistry and Molecular Biology, Ajou University, School of Medicine, Gyeonggi-do, Republic of Korea
| | - Yukiko Oya
- Graduate School of Science and Engineering, Saitama University, Saitama, Japan
| | - Santhoshkumar Sundaramoorthy
- Division of Medical Sciences, Graduate School of Ajou University, Gyeonggi-do, Republic of Korea
- Department of Biochemistry and Molecular Biology, Ajou University, School of Medicine, Gyeonggi-do, Republic of Korea
| | - Kye Yong Song
- Department of Pathology, Chung-Ang University College of Medicine, Seoul, Republic of Korea
| | - Tatsuro Watanabe
- Department of Clinical Laboratory of Medicine, Faculty of Medicine, Saga University, Saga, Japan
| | | | | | - Soon Auck Hong
- Department of Pathology, Soonchunhyang Cheonan hospital, Soonchunhyang University, College of Medicine, Cheonan, Republic of Korea
| | - Masami Suganuma
- Graduate School of Science and Engineering, Saitama University, Saitama, Japan
| | - In Kyoung Lim
- Division of Medical Sciences, Graduate School of Ajou University, Gyeonggi-do, Republic of Korea
- Department of Biochemistry and Molecular Biology, Ajou University, School of Medicine, Gyeonggi-do, Republic of Korea
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Xie Y, Zhou JJ, Zhao Y, Zhang T, Mei LZ. H. pylori modifies methylation of global genomic DNA and the gastrin gene promoter in gastric mucosal cells and gastric cancer cells. Microb Pathog 2017; 108:129-136. [PMID: 28478202 DOI: 10.1016/j.micpath.2017.05.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Revised: 05/02/2017] [Accepted: 05/02/2017] [Indexed: 01/26/2023]
Abstract
AIMS The aim of this study was to evaluate the correlation between H. pylori infection and global DNA methylation, as well as the methylation levels of the gastrin promoters. MATERIALS AND METHODS We constructed a eukaryotic expression vector, pcDNA3.1::cagA, and transfected it into GES-1 gastric mucosal cells and SGC-7901 gastric cancer cells. Both cell lines were infected with the H. pylori/CagA+ strain NCTC11637. Then, we detected global DNA methylation by capture and detection antibodies, followed by colorimetric quantification. The methylation levels of the gastrin promoter were evaluated by base-specific cleavage and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. RESULTS In H. pylori/CagA+-infected GES-1 and SGC-7901 cells, the methylation levels of genomic DNA decreased by 49.4% and 18.8%, and in GES-1 and SGC-7901 cells transfected with pcDNA3.1::cagA, the methylation levels of genomic DNA decreased by 17.05% and 25.6%, respectively. Among 24 methylation sites detected in the gastrin promoter region, the methylation levels of 9 CpG sites were significantly decreased in H. pylori/CagA+-infected and pcDNA3.1:: cagA-transfected cells in comparison to corresponding control cells. CONCLUSION These results indicate that H. pylori/CagA+ decreases the methylation of the genome and the gastrin promoter at some CpG sites in gastric mucosal and gastric cancer cells.
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Affiliation(s)
- Yuan Xie
- Key Laboratory of Endemic and Ethnic Diseases, Guizhou Medical University, Ministry of Education, China; Key Laboratory of Medical Molecular Biology, Guizhou Medical University, Guizhou Province, China
| | - Jian Jiang Zhou
- Key Laboratory of Endemic and Ethnic Diseases, Guizhou Medical University, Ministry of Education, China; Key Laboratory of Medical Molecular Biology, Guizhou Medical University, Guizhou Province, China; Affiliated Hospital, Guiyang Medical University, No. 9, Beijing Road, Guiyang 550004, China.
| | - Yan Zhao
- Key Laboratory of Endemic and Ethnic Diseases, Guizhou Medical University, Ministry of Education, China; Key Laboratory of Medical Molecular Biology, Guizhou Medical University, Guizhou Province, China
| | - Ting Zhang
- Key Laboratory of Endemic and Ethnic Diseases, Guizhou Medical University, Ministry of Education, China; Key Laboratory of Medical Molecular Biology, Guizhou Medical University, Guizhou Province, China
| | - Liu Zheng Mei
- Key Laboratory of Endemic and Ethnic Diseases, Guizhou Medical University, Ministry of Education, China; Key Laboratory of Medical Molecular Biology, Guizhou Medical University, Guizhou Province, China
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MIFTAHUSSURUR MUHAMMAD, YAMAOKA YOSHIO, GRAHAM DAVIDY. Helicobacter pylori as an oncogenic pathogen, revisited. Expert Rev Mol Med 2017; 19:e4. [PMID: 28322182 PMCID: PMC6905048 DOI: 10.1017/erm.2017.4] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Gastric cancer is an inflammation-associated malignancy aetiologically related to infection with the bacterium, Helicobacter pylori, which is considered a necessary but insufficient cause. Unless treated, H. pylori causes life-long acute and chronic gastric inflammation resulting in progressive gastric mucosal damage that may result in gastric cancer. The rate of progression from superficial gastritis, to an atrophic metaplastic mucosa, and ultimately to cancer relates to the virulence of the infecting H. pylori as well as host and environmental factors. H. pylori virulence is a reflection of its propensity to cause severe gastric inflammation. Both mucosal inflammation and H. pylori can cause host genomic instability, including dysregulation of DNA mismatch repair, stimulation of expression of activation-induced cytidine deaminase, abnormal DNA methylation and dysregulation of micro RNAs, which may result in an accumulation of mutations and loss of normal regulation of cell growth. The difference in cancer risk between the most and least virulent H. pylori strain is only approximately 2-fold. Overall, none of the putative virulence factors identified to date have proved to be disease-specific. The presence, severity, extent and duration of inflammation appear to be the most important factors and current evidence suggests that any host, environmental or bacterial factor that reliably enhances the inflammatory response to the H. pylori infection increases the risk of gastric cancer.
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Affiliation(s)
- MUHAMMAD MIFTAHUSSURUR
- Department of Medicine, Gastroenterology and Hepatology Section, Baylor College of Medicine, Houston, Texas 77030, USA
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu 879-5593, Japan
- Gastroentero-Hepatology Division, Department of Internal Medicine, Faculty of Medicine – Dr Soetomo Teaching Hospital – Institute of Tropical Disease, Universitas Airlangga, Surabaya 60115, Indonesia
| | - YOSHIO YAMAOKA
- Department of Medicine, Gastroenterology and Hepatology Section, Baylor College of Medicine, Houston, Texas 77030, USA
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu 879-5593, Japan
| | - DAVID Y. GRAHAM
- Department of Medicine, Gastroenterology and Hepatology Section, Baylor College of Medicine, Houston, Texas 77030, USA
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Sabry D, Ahmed R, Abdalla S, Fathy W, Eldemery A, Elamir A. Braf, Kras and Helicobacter pylori epigenetic changes-associated chronic gastritis in Egyptian patients with and without gastric cancer. World J Microbiol Biotechnol 2016; 32:92. [PMID: 27116958 DOI: 10.1007/s11274-016-2048-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2015] [Accepted: 03/08/2016] [Indexed: 12/15/2022]
Abstract
UNLABELLED We aimed to study MLH1 and MGMT methylation status in Helicobacter pylori-associated chronic gastritis in Egyptian patients with and without gastric cancer. 39 patients were included in our study. They were divided into 2 groups; patients without (group I) and with gastric adenocarcinoma (group II). Patients were subjected to clinical examination, abdominal ultrasound and upper endoscopy for gastric biopsy. Biopsies were subjected to urease test, histological examination, and DNA purification. H. pylori, Braf, Kras, MLH1 and MGMT methylation were assessed by quantitative PCR. DNA sequencing was performed to assess Braf and Kras genes mutation. qPCR of H. pylori was significantly higher in patients with adenocarcinoma (group II) than those without adenocarcinoma (group I); with a p < 0.001 as well as in patients with age above 50 years with a p value = 0.008. By applying logistic regression analysis it was reported that the H. pylori qPCR is a significant predictor to the adenocarcinoma with OR = 1.025 (95 % CI: 1. 002-1.048), with sensitivity of 90 % and specificity of 100 %. Adenocarcinoma patients had a significantly higher mean age and levels of H. Pylori, Braf, K-ras, methylated MGMT and methylated MLH1 than those of gastritis patients. DNA sequence analysis of Braf (codon 12) and Kras (codon 600) had genes mutation in gastric adenocarcinoma versus chronic gastritis. CONCLUSION H. pylori may cause epigenetic changes predisposing the patients to cancer stomach. Estimation of H. pylori by qPCR can be a good predictor to adenocarcinoma. Braf and Kras genes mutation were reveled in gastritis and adenocarcinoma patients.
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Affiliation(s)
- Dina Sabry
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Giza, Egypt.
| | - Rasha Ahmed
- Endemic Medicine & Hepatology Department, Faculty of Medicine, Cairo University, Giza, Egypt
| | - Sayed Abdalla
- Internal Medicine Department, Faculty of Medicine, Cairo University, Giza, Egypt
| | - Wael Fathy
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Giza, Egypt
| | - Ahmed Eldemery
- Medical Biochemistry Department, Faculty of Medicine, October 6 University, Giza, Egypt
| | - Azza Elamir
- Medical Biochemistry Department, Faculty of Medicine, El Fayoum University, Al Fayoum, Egypt
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Valenzuela MA, Canales J, Corvalán AH, Quest AFG. Helicobacter pylori-induced inflammation and epigenetic changes during gastric carcinogenesis. World J Gastroenterol 2015; 21:12742-12756. [PMID: 26668499 PMCID: PMC4671030 DOI: 10.3748/wjg.v21.i45.12742] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Revised: 08/08/2015] [Accepted: 10/13/2015] [Indexed: 02/06/2023] Open
Abstract
The sequence of events associated with the development of gastric cancer has been described as “the gastric precancerous cascade”. This cascade is a dynamic process that includes lesions, such as atrophic gastritis, intestinal metaplasia and dysplasia. According to this model, Helicobacter pylori (H. pylori) infection targets the normal gastric mucosa causing non-atrophic gastritis, an initiating lesion that can be cured by clearing H. pylori with antibiotics or that may then linger in the case of chronic infection and progress to atrophic gastritis. The presence of virulence factors in the infecting H. pylori drives the carcinogenesis process. Independent epidemiological and animal studies have confirmed the sequential progression of these precancerous lesions. Particularly long-term follow-up studies estimated a risk of 0.1% for atrophic gastritis/intestinal metaplasia and 6% in case of dysplasia for the long-term development of gastric cancer. With this in mind, a better understanding of the genetic and epigenetic changes associated with progression of the cascade is critical in determining the risk of gastric cancer associated with H. pylori infection. In this review, we will summarize some of the most relevant mechanisms and focus predominantly but not exclusively on the discussion of gene promoter methylation and miRNAs in this context.
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17
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Qing Y, Hu H, Liu Y, Feng T, Meng W, Jiang L, Sun Y, Yao Y. Berberine induces apoptosis in human multiple myeloma cell line U266 through hypomethylation of p53 promoter. Cell Biol Int 2015; 38:563-70. [PMID: 24843889 DOI: 10.1002/cbin.10206] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Berberine has multiple pharmacological activities, such as anti-oxidative, anti-inflammation and anticancer activity. It reduces the proliferation and induces apoptosis in the multiple myeloma cell line, U266. Here we explored the detailed mechanism by analysing the gene expression profiles in U266 treated with or without berberine. DNMT1 andDNMT3B, encoding for a highly conserved member of the DNA methyltransferases, decreased significantly. By dissection of biochemical network database (BNDB) with Kyoto Encyclopaedia of Genes and Genomes (KEGG) annotation, the p53 signalling pathway related genes were altered. By using epigenetic chromatin modification enzymes PCR Array, gene expression microarray, RT-PCR and Bisulphite sequencing, the results show that berberine can repress the expression of DNMT1 and DNMT3B, which triggers hypomethylation of TP53 by changing the DNA methylation level and the alteration of p53 dependent signal pathway in human multiple melanoma cell U266.
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Toiyama Y, Okugawa Y, Goel A. DNA methylation and microRNA biomarkers for noninvasive detection of gastric and colorectal cancer. Biochem Biophys Res Commun 2014; 455:43-57. [PMID: 25128828 DOI: 10.1016/j.bbrc.2014.08.001] [Citation(s) in RCA: 125] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2014] [Revised: 07/22/2014] [Accepted: 08/01/2014] [Indexed: 02/06/2023]
Abstract
Cancer initiation and progression is controlled by both genetic and epigenetic events. Epigenetics refers to the study of mechanisms that alter gene expression without permanently altering the DNA sequence. Epigenetic alterations are reversible and heritable, and include changes in histone modifications, DNA methylation, and non-coding RNA-mediated gene silencing. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Aberrant epigenetic modifications occur at the earliest stages of neoplastic transformation and are now believed to be essential players in cancer initiation and progression. Recent advances in epigenetics have not only offered a deeper understanding of the underlying mechanism(s) of carcinogenesis, but have also allowed identification of clinically relevant putative biomarkers for the early detection, disease monitoring, prognosis and risk assessment of cancer patients. At this moment, DNA methylation and non-coding RNA including with microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) represent the largest body of available literature on epigenetic biomarkers with the highest potential for cancer diagnosis. Following identification of cell-free nucleic acids in systematic circulation, increasing evidence has demonstrated the potential of cell-free epigenetic biomarkers in the blood or other body fluids for cancer detection. In this article, we summarize the current state of knowledge on epigenetic biomarkers - primarily DNA methylation and non-coding RNAs - as potential substrates for cancer detection in gastric and colorectal cancer, the two most frequent cancers within the gastrointestinal tract. We also discuss the obstacles that have limited the routine use of epigenetic biomarkers in the clinical settings and provide our perspective on approaches that might help overcome these hurdles, so that these biomarkers can be readily developed for clinical management of cancer patients.
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Affiliation(s)
- Yuji Toiyama
- Gastrointestinal Cancer Research Laboratory, Department of Internal Medicine, Charles A. Sammons Cancer Center and Baylor Research Institute, Baylor University Medical Center, 3500 Gaston Avenue, Dallas, TX 75246, USA; Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Graduate School of Medicine, Mie University, Mie 514-8507, Japan
| | - Yoshinaga Okugawa
- Gastrointestinal Cancer Research Laboratory, Department of Internal Medicine, Charles A. Sammons Cancer Center and Baylor Research Institute, Baylor University Medical Center, 3500 Gaston Avenue, Dallas, TX 75246, USA; Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Graduate School of Medicine, Mie University, Mie 514-8507, Japan
| | - Ajay Goel
- Gastrointestinal Cancer Research Laboratory, Department of Internal Medicine, Charles A. Sammons Cancer Center and Baylor Research Institute, Baylor University Medical Center, 3500 Gaston Avenue, Dallas, TX 75246, USA.
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Hanada K, Graham DY. Helicobacter pylori and the molecular pathogenesis of intestinal-type gastric carcinoma. Expert Rev Anticancer Ther 2014; 14:947-54. [PMID: 24802804 DOI: 10.1586/14737140.2014.911092] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Gastric carcinoma is an inflammation-related cancer caused by long-term infection with the human bacterial pathogen, Helicobacter pylori. The pattern of acute-on-chronic inflammation causes progressive mucosal damage which may result in atrophy with metaplastic epithelia and eventually gastric cancer. Recently, it has been recognized that H. pylori can also cause genetic instability such as double-stranded DNA breaks and can produce gene activation and silencing via epigenetic pathways. As genetic instability is the hallmark of cancer, we highlight recent progress in understanding the gastric carcinogenesis in relation to H. pylori-related inflammation, H. pylori-induced double-stranded DNA breakage and aberrant gene expression as well as the mechanisms and role of H. pylori-associated epigenetic change in gene expression.
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Affiliation(s)
- Katsuhiro Hanada
- Department of Environmental and Preventive Medicine, Faculty of Medicine, Oita University, Yufu, Japan
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20
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Stein M, Ruggiero P, Rappuoli R, Bagnoli F. Helicobacter pylori CagA: From Pathogenic Mechanisms to Its Use as an Anti-Cancer Vaccine. Front Immunol 2013; 4:328. [PMID: 24133496 PMCID: PMC3796731 DOI: 10.3389/fimmu.2013.00328] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2013] [Accepted: 09/25/2013] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori colonizes the gastric mucosa of more than 50% of the human population, causing chronic inflammation, which however is largely asymptomatic. Nevertheless, H. pylori-infected subjects can develop chronic gastritis, peptic ulcer, gastric mucosa-associated lymphoid tissue lymphoma, and gastric cancer. Chronic exposure to the pathogen and its ability to induce epithelial to mesenchymal transition (EMT) through the injection of cytotoxin-associated gene A into gastric epithelial cells may be key triggers of carcinogenesis. By deregulating cell-cell and cell-matrix interactions as well as DNA methylation, histone modifications, expression of micro RNAs, and resistance to apoptosis, EMT can actively contribute to early stages of the cancer formation. Host response to the infection significantly contributes to disease development and the concomitance of particular genotypes of both pathogen and host may turn into the most severe outcomes. T regulatory cells (Treg) have been recently demonstrated to play an important role in H. pylori-related disease development and at the same time the Treg-induced tolerance has been proposed as a possible mechanism that leads to less severe disease. Efficacy of antibiotic therapies of H. pylori infection has significantly dropped. Unfortunately, no vaccine against H. pylori is currently licensed, and protective immunity mechanisms against H. pylori are only partially understood. In spite of promising results obtained in animal models of infection with a number of vaccine candidates, few clinical trials have been conducted so far and with no satisfactory outcomes. However, prophylactic vaccination may be the only means to efficiently prevent H. pylori-associated cancers.
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Affiliation(s)
- Markus Stein
- Albany College of Pharmacy and Health Sciences, Albany, NY, USA
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22
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Moon DC, Choi CH, Lee SM, Lee JH, Kim SI, Kim DS, Lee JC. Nuclear translocation of Acinetobacter baumannii transposase induces DNA methylation of CpG regions in the promoters of E-cadherin gene. PLoS One 2012; 7:e38974. [PMID: 22685614 PMCID: PMC3369853 DOI: 10.1371/journal.pone.0038974] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2012] [Accepted: 05/14/2012] [Indexed: 12/18/2022] Open
Abstract
Nuclear targeting of bacterial proteins has emerged as a pathogenic mechanism whereby bacterial proteins induce host cell pathology. In this study, we examined nuclear targeting of Acinetobacter baumannii transposase (Tnp) and subsequent epigenetic changes in host cells. Tnp of A. baumannii ATCC 17978 possesses nuclear localization signals (NLSs), 225RKRKRK230. Transient expression of A. baumannii Tnp fused with green fluorescent protein (GFP) resulted in the nuclear localization of these proteins in COS-7 cells, whereas the truncated Tnp without NLSs fused with GFP were exclusively localized in the cytoplasm. A. baumannii Tnp was found in outer membrane vesicles, which delivered this protein to the nucleus of host cells. Nuclear expression of A. baumannii Tnp fused with GFP in A549 cells induced DNA methylation of CpG regions in the promoters of E-cadherin (CDH1) gene, whereas the cytoplasmic localization of the truncated Tnp without NLSs fused with GFP did not induce DNA methylation. DNA methylation in the promoters of E-cadherin gene induced by nuclear targeting of A. baumannii Tnp resulted in down-regulation of gene expression. In conclusion, our data show that nuclear traffic of A. baumannii Tnp induces DNA methylation of CpG regions in the promoters of E-cadherin gene, which subsequently down-regulates gene expression. This study provides a new insight into the epigenetic control of host genes by bacterial proteins.
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Affiliation(s)
- Dong Chan Moon
- Department of Microbiology, Kyungpook National University School of Medicine, Daegu, Korea
| | - Chul Hee Choi
- Department of Periodontology, University of Florida, Gainesville, Florida, United States of America
| | - Su Man Lee
- Department of Anatomy, Kyungpook National University School of Medicine, Daegu, Korea
| | - Jung Hwa Lee
- Department of Microbiology, Kyungpook National University School of Medicine, Daegu, Korea
| | - Seung Il Kim
- Division of Life Science, Korea Basic Science Institute, Daejeon, Korea
| | - Dong Sun Kim
- Department of Anatomy, Kyungpook National University School of Medicine, Daegu, Korea
- * E-mail: (JCL); (DSK)
| | - Je Chul Lee
- Department of Microbiology, Kyungpook National University School of Medicine, Daegu, Korea
- * E-mail: (JCL); (DSK)
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Abstract
Although development leads unidirectionally toward more restricted cell fates, recent work in cellular reprogramming has proven that one cellular identity can strikingly convert into another, promising countless applications in biomedical research and paving the way for modeling diseases with patient-derived stem cells. To date, there has been little discussion of which disease models are likely to be most informative. Here, we review evidence demonstrating that, because environmental influences and epigenetic signatures are largely erased during reprogramming, patient-specific models of diseases with strong genetic bases and high penetrance are likely to prove most informative in the near term. We also discuss the implications of the new reprogramming paradigm in biomedicine and outline how reprogramming of cell identities is enhancing our understanding of cell differentiation and prospects for cellular therapies and in vivo regeneration.
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Sapari NS, Loh M, Vaithilingam A, Soong R. Clinical potential of DNA methylation in gastric cancer: a meta-analysis. PLoS One 2012; 7:e36275. [PMID: 22558417 PMCID: PMC3338684 DOI: 10.1371/journal.pone.0036275] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2011] [Accepted: 03/31/2012] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Accumulating evidence indicates aberrant DNA methylation is involved in gastric tumourigenesis, suggesting it may be a useful clinical biomarker for the disease. The aim of this study was to consolidate and summarize published data on the potential of methylation in gastric cancer (GC) risk prediction, prognostication and prediction of treatment response. METHODS Relevant studies were identified from PubMed using a systematic search approach. Results were summarized by meta-analysis. Mantel-Haenszel odds ratios were computed for each methylation event assuming the random-effects model. RESULTS A review of 589 retrieved publications identified 415 relevant articles, including 143 case-control studies on gene methylation of 142 individual genes in GC clinical samples. A total of 77 genes were significantly differentially methylated between tumour and normal gastric tissue from GC subjects, of which data on 62 was derived from single studies. Methylation of 15, 4 and 7 genes in normal gastric tissue, plasma and serum respectively was significantly different in frequency between GC and non-cancer subjects. A prognostic significance was reported for 18 genes and predictive significance was reported for p16 methylation, although many inconsistent findings were also observed. No bias due to assay, use of fixed tissue or CpG sites analysed was detected, however a slight bias towards publication of positive findings was observed. CONCLUSIONS DNA methylation is a promising biomarker for GC risk prediction and prognostication. Further focused validation of candidate methylation markers in independent cohorts is required to develop its clinical potential.
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Affiliation(s)
- Nur Sabrina Sapari
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Marie Loh
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
- School of Surgery, University of Western Australia, Crawley, Australia
| | - Aparna Vaithilingam
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Richie Soong
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
- Department of Pathology, National University of Singapore, Singapore, Singapore
- * E-mail:
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25
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Abstract
Gastric cancer is a main cause of cancer death worldwide. Despite the knowledge that Helicobacter pylori constitutes the main cause of gastric cancer, the mechanisms for gastric carcinogenesis are still elucidated. Cancer development and progression depend on the balance between cell survival and death signals. Common cell survival signaling pathways are activated by carcinogens as well as by inflammatory cytokines, which contribute substantially to tumorigenesis. Nuclear factor-kappaB (NF-κB) is a major cell survival signal. Recent studies with cell culture systems and animal models have certified the links between NF-κB and gastric carcinogenesis and resistance to chemotherapy. Inhibition of NF-κB activation can enhance the sensitivity of cancer cells to chemotherapeutic drugs. In this review, we summarize recent progress in understanding the role of the NF-κB pathway in gastric cancer development as well as in modulating NF-κB for gastric cancer prevention and therapy.
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Niller HH, Banati F, Ay E, Minarovits J. Microbe-Induced Epigenetic Alterations. PATHO-EPIGENETICS OF DISEASE 2012:419-455. [DOI: 10.1007/978-1-4614-3345-3_14] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Neves Filho EHC, Alves MKS, Lima VP, Rabenhorst SHB. MTHFR C677T polymorphism and differential methylation status in gastric cancer: an association with Helicobacter pylori infection. Virchows Arch 2010; 457:627-33. [DOI: 10.1007/s00428-010-0996-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2010] [Revised: 10/01/2010] [Accepted: 10/05/2010] [Indexed: 12/11/2022]
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28
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Touati E. When bacteria become mutagenic and carcinogenic: lessons from H. pylori. Mutat Res 2010; 703:66-70. [PMID: 20709622 DOI: 10.1016/j.mrgentox.2010.07.014] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2010] [Accepted: 07/30/2010] [Indexed: 12/24/2022]
Abstract
More and more convincing data link bacteria to the development of cancers. How bacteria act as mutagens by altering host genomes, what are the different strategies they develop and what consequences do they have on infection-associated pathogenesis are the main questions addressed in this review, which focuses in particular on Helicobacter pylori infection. H. pylori is a major risk factor for gastric cancer development. Its oncogenic role is mediated by the chronic active inflammation it elicits in the gastric mucosa, associated with its capacity to persistently colonize the human stomach. However, direct genotoxicity of H. pylori through the action of bacterial cytotoxin or resulting from a DNA damaging effect of its metabolic derivatives as nitroso compounds cannot be excluded. Numerous studies have investigated inflammation-associated DNA damaging activity and mutagenic response due to H. pylori infection in both human and animal models. Recent findings on its mutagenic effects at the nuclear and mitochondrial genome and related DNA damage are reviewed. This genotoxic activity associated with oxidative species produced during inflammation is linked to the decreased efficiency of DNA repair systems. DNA methylation, which plays an important role in the regulation of the host response to H. pylori infection, is also documented. Furthermore, H. pylori affects genome integrity by increasing activation-induced cytidine deaminase (AID), a DNA/RNA editing cytidine deaminase linking mutagenesis and tumorigenesis. These different strategies occurring during bacteria-host cell interaction, lead to nucleotide modifications and genome instabilities recognized as early events in the carcinogenesis process and contribute to the oncogenic properties of H. pylori infection.
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Affiliation(s)
- Eliette Touati
- Institut Pasteur, Unité de Pathogenèse de Helicobacter, 28 Rue du Dr Roux, 75724 Paris Cedex 15, France.
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Ding SZ, Goldberg JB, Hatakeyama M. Helicobacter pylori infection, oncogenic pathways and epigenetic mechanisms in gastric carcinogenesis. Future Oncol 2010; 6:851-62. [PMID: 20465395 PMCID: PMC2882595 DOI: 10.2217/fon.10.37] [Citation(s) in RCA: 126] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Chronic colonization of the human stomach by Helicobacter pylori, a Gram-negative bacterium, is the major cause of chronic gastritis, peptic ulcers and gastric cancer. Recent progress has elucidated important bacterial and host factors that are responsible for H. pylori-induced gastric inflammation and gastric malignancy. H. pylori cytotoxin-associated antigen A is the major oncogenic factor injected into host cells from bacteria and it disrupts epithelial cell functions. Together with H. pylori cag pathogenicity island, it causes general inflammatory stress within gastric mucosa and activates multiple oncogenic pathways in epithelial cells. A growing list of these pathways includes NF-kappaB, activator protein-1, PI3K, signal transducers and activators of transcription 3, Wnt/beta-catenin and cyclooxygenase 2. H. pylori induces epigenetic alterations, such as DNA methylation and histone modification, which play critical roles in oncogenic transformation. In addition, investigations into gastric stem cell or progenitor cell biology have shed light on the mechanisms through which gastric cancer may originate. Continued investigation in these areas will yield novel insights and help to elucidate the mechanisms of bacteria-induced carcinogenesis.
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Affiliation(s)
- Song-Ze Ding
- Department of Microbiology, University of Virginia Health System, Charlottesville, VA 22908, USA.
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30
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Abstract
Epigenetic silencing of tumor suppressor genes is a salient feature of tumor cells. Re-expression of epigenetically silenced genes is a feasible and achievable strategy for cancer treatment. DNA methylation is the most characterized epigenetic silencing mechanism and the reversal of DNA methylation, genetically or pharmacologically, induces gene re-expression and proliferation arrest in tumor cells. Other epigenetic targets, such as histone acetylation and methylation, are also rational drug targets, and several small-molecule modulators of histone acetylation and methylation are currently under development or already in clinical trials. Epigenetic deregulation of miRNAs induces aberrant expression of miRNAs, which have been associated with the development and progression of cancer. The reversal of DNA methylation can induce the re-expression of miRNAs, and oligonucleotides can silence aberrantly expressed miRNAs. Evaluating the combination of different epigenetic modifiers and ensuring their optimization are the next challenges towards the establishment of epigenetic therapy.
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Affiliation(s)
| | - Steven D Gore
- Division of Hematologic Malignancies, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, 1650 Orleans St, Cancer Research Building 1, Room 288, Baltimore, MD 21231, USA
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31
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The presence of JC virus in gastric carcinomas correlates with patient's age, intestinal histological type and aberrant methylation of tumor suppressor genes. Mod Pathol 2010; 23:522-30. [PMID: 20081806 DOI: 10.1038/modpathol.2009.184] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
JC virus (JCV) is a neurotropic polyomavirus and the causative agent of progressive multifocal leukoencephalopathy. A role for JCV in gastrointestinal malignancies has been recently suggested. This study was carried out to determine the prevalence of polyomaviruses including JCV, BKV and SV40 in gastric cancers in Tunisia and to determine the clinicopathological characteristics of virus-associated gastric carcinomas. The presence of polyomaviruses DNA sequences was surveyed in 61 cases of primary gastric carcinomas and in 53 paired non-tumor gastric mucosa by PCR. Findings were correlated to clinicopathological parameters, p53 expression and methylation status of 11 tumor-related genes. Using PCR assays, JCV T-antigen sequence was more frequently detected in gastric carcinomas than in non-tumor gastric mucosa (26 vs 6%, P=0.03), while those of SV40 and BKV were not detected in any cases. Correlation analysis showed that JCV had higher frequency in patients older than 55 years (P=0.034) and in the intestinal histological type (P=0.04). With regard to methylation status, P16 and P14 showed significantly higher methylation frequencies in JCV-positive gastric carcinomas than in JCV-negative cases (P=0.007 and P=0.003, respectively). Moreover, the mean of the methylation index was significantly higher in JCV-positive than in JCV-negative cases (P=0.024). In multivariate logistic regression analysis, age of patients and the methylation index are only the two independent factors associated with JCV infection. Kaplan-Meier survival analysis showed a trend toward better survival for JCV-associated gastric carcinomas patients (log-rank, P=0.11). Our study suggests a role of JCV as cofactor in the pathogenesis of the intestinal type of gastric carcinomas in older persons.
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32
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Kabir S. Effect of Helicobacter pylori eradication on incidence of gastric cancer in human and animal models: underlying biochemical and molecular events. Helicobacter 2009; 14:159-71. [PMID: 19702845 DOI: 10.1111/j.1523-5378.2009.00677.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Gastric cancer remains one of the most common cancers worldwide. A strong association exists between Helicobacter pylori infection and the risk of developing noncardia gastric cancer. H. pylori eradication by antibiotic treatment is regarded as a primary chemoprevention strategy to reduce gastric cancer incidence. AIM To analyze the efficacy of H. pylori eradication in preventing gastric cancer in human and animal models, and to discuss whether biochemical, genetic, and epigenetic changes associated with H. pylori infection are reversible after curing the infection. RESULTS Several intervention trials have indicated that in some patients, H. pylori eradication leads to regression and prevents the progression of precancerous lesions. The eradication therapy reduces gastric cancer incidence in patients without any precancerous lesions at the baseline and is most effective before the development of atrophic gastritis. A few recent intervention studies in Japan have demonstrated significant prophylactic effects of eradication therapy on the development of gastric cancer, suggesting the use of eradication therapy in high-risk populations as a gastric cancer reduction strategy. However, gastric cancer may still develop despite successful eradication therapy. Studies in animal models have confirmed the use of eradication therapy at an early point of infection to prevent gastric cancer development. CONCLUSION H. pylori eradication may not completely abolish the risk of gastric cancer. However, eradication therapy may be used in high-risk populations to reduce gastric cancer incidence. It can reverse many biochemical, genetic, and epigenetic changes that H. pylori infection induces in the stomach.
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Affiliation(s)
- Shahjahan Kabir
- Academic Research and Information Management, Uppsala, Sweden.
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Vuillermin PJ, Ponsonby AL, Saffery R, Tang ML, Ellis JA, Sly P, Holt P. Microbial exposure, interferon gamma gene demethylation in naïve T-cells, and the risk of allergic disease. Allergy 2009; 64:348-53. [PMID: 19210359 DOI: 10.1111/j.1398-9995.2009.01970.x] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
The period of immune programming during early life presents a critical window of opportunity for the prevention of allergic diseases. There is mounting evidence that inappropriate immune programming may involve disruption of specific epigenetic modifications (switches) at immune-related genes. This novel area of research has great potential, as epigenetic changes are known to be sensitive to environmental factors and may therefore provide a mechanistic link for the observed association between specific environmental cues, faulty immune development, and the risk of allergic disease. In addition, the dynamic and potentially reversible nature of epigenetic modifications offers potentially novel targets for therapeutic and/or preventative interventions. We review the evidence that (1) failure to up-regulate the interferon gamma (IFNgamma) response during infancy is an important determinant of the risk of allergic disease, (2) expression of the IFNgamma gene in naïve T-cells is regulated by epigenetic mechanisms, and (3) failure to up-regulate IFNgamma gene expression of naïve T-cells associated with low early life microbial exposure. Taken together, these lines of evidence suggest that low microbial exposure during early life increases the risk of allergic disease by reducing demethylation (activation) of the IFNgamma gene of naive T-cells.
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Affiliation(s)
- P J Vuillermin
- Child Health Research Unit, Barwon Health, Geelong, Victoria, Australia
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Nardone G, Compare D. Epigenetic alterations due to diet and Helicobacter pylori infection in gastric carcinogenesis. Expert Rev Gastroenterol Hepatol 2008; 2:243-8. [PMID: 19072359 DOI: 10.1586/17474124.2.2.243] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Sporadic gastric cancer is considered to be the result of a progressive accumulation of genotypic changes due to an adverse environment (i.e., diet and Helicobacter pylori infection). The main molecular mechanism implicated in cancer-related molecular alterations is of epigenetic nature, which includes DNA methylation and histone modification. Diet may influence the methylation status supplying methyl groups S-adenosyl-methionine formation, modifying DNA methyltransferase activity and influencing DNA demethylation activity. H. pylori may affect DNA methyltransferase directly or through inflammatory mediators (e.g., reactive oxygen species or nitric oxide). In conclusion, gastric cancer is a multistep process due to an adverse environment over a long period of time. Dietary habit and H. pylori infection can induce epigenetic alterations that, in turn, trigger gastric carcinogenesis.
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Affiliation(s)
- Gerardo Nardone
- Dipartimento di Medicina Clinica e Sperimentale, Unità di Gastroenterologia, Università degli Studi di Napoli "Federico II", Via Pansini N degrees 5, 80131 Napoli, Italy.
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Lafon-Hughes L, Di Tomaso MV, Méndez-Acuña L, Martínez-López W. Chromatin-remodelling mechanisms in cancer. Mutat Res 2008; 658:191-214. [PMID: 18403253 DOI: 10.1016/j.mrrev.2008.01.008] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2007] [Revised: 01/29/2008] [Accepted: 01/29/2008] [Indexed: 02/06/2023]
Abstract
Chromatin-remodelling mechanisms include DNA methylation, histone-tail acetylation, poly-ADP-ribosylation, and ATP-dependent chromatin-remodelling processes. Some epigenetic modifications among others have been observed in cancer cells, namely (1) local DNA hypermethylation and global hypomethylation, (2) alteration in histone acetylation/deacetylation balance, (3) increased or decreased poly-ADP-ribosylation, and (4) failures in ATP-dependent chromatin-remodelling mechanisms. Moreover, these alterations can influence the response to classical anti-tumour treatments. Drugs targeting epigenetic alterations are under development. Currently, DNA methylation and histone deacetylase inhibitors are in use in cancer therapy, and poly-ADP-ribosylation inhibitors are undergoing clinical trials. Epigenetic therapy is gaining in importance in pharmacology as a new tool to improve anti-cancer therapies.
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Affiliation(s)
- Laura Lafon-Hughes
- Genetic Toxicology Department, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay
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