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Sgamato C, Rocco A, Compare D, Priadko K, Romano M, Nardone G. Exploring the Link between Helicobacter pylori, Gastric Microbiota and Gastric Cancer. Antibiotics (Basel) 2024; 13:484. [PMID: 38927151 PMCID: PMC11201017 DOI: 10.3390/antibiotics13060484] [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: 04/26/2024] [Revised: 05/20/2024] [Accepted: 05/21/2024] [Indexed: 06/28/2024] Open
Abstract
Gastric cancer (GC) still represents one of the leading causes of cancer-related mortality and is a major public health issue worldwide. Understanding the etiopathogenetic mechanisms behind GC development holds immense potential to revolutionize patients' treatment and prognosis. Within the complex web of genetic predispositions and environmental factors, the connection between Helicobacter pylori (H. pylori) and gastric microbiota emerges as a focus of intense research investigation. According to the most recent hypotheses, H. pylori triggers inflammatory responses and molecular alterations in gastric mucosa, while non-Helicobacter microbiota modulates disease progression. In this review, we analyze the current state of the literature on the relationship between H. pylori and non-Helicobacter gastric microbiota in gastric carcinogenesis, highlighting the mechanisms by which microecological dysbiosis can contribute to the malignant transformation of the mucosa.
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Affiliation(s)
- Costantino Sgamato
- Gastroenterology Unit, Department of Clinical Medicine and Surgery, University Federico II of Naples, 80131 Naples, Italy; (C.S.); (D.C.); (G.N.)
| | - Alba Rocco
- Gastroenterology Unit, Department of Clinical Medicine and Surgery, University Federico II of Naples, 80131 Naples, Italy; (C.S.); (D.C.); (G.N.)
| | - Debora Compare
- Gastroenterology Unit, Department of Clinical Medicine and Surgery, University Federico II of Naples, 80131 Naples, Italy; (C.S.); (D.C.); (G.N.)
| | - Kateryna Priadko
- Hepatogastroenterology Unit, Department of Precision Medicine, University of Campania “L. Vanvitelli”, 80138 Naples, Italy; (K.P.); (M.R.)
| | - Marco Romano
- Hepatogastroenterology Unit, Department of Precision Medicine, University of Campania “L. Vanvitelli”, 80138 Naples, Italy; (K.P.); (M.R.)
| | - Gerardo Nardone
- Gastroenterology Unit, Department of Clinical Medicine and Surgery, University Federico II of Naples, 80131 Naples, Italy; (C.S.); (D.C.); (G.N.)
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Žilienė E, Inčiūra A, Ugenskienė R, Juozaitytė E. Pathomorphological Manifestations and the Course of the Cervical Cancer Disease Determined by Variations in the TLR4 Gene. Diagnostics (Basel) 2023; 13:1999. [PMID: 37370894 DOI: 10.3390/diagnostics13121999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 05/31/2023] [Accepted: 06/03/2023] [Indexed: 06/29/2023] Open
Abstract
Cervical cancer (CC) is often associated with human papillomavirus (HPV). Chronic inflammation has been described as one of the triggers of cancer. The immune system fights diseases, including cancer. The genetic polymorphism of pathogen recognition receptors potentially influences the infectious process, development, and disease progression. Many candidate genes SNPs have been contradictory demonstrated to be associated with cervical cancer by association studies, GWAS. TLR4 gene activation can promote antitumor immunity. It can also result in immunosuppression and tumor growth. Our study aimed to investigate eight selected polymorphisms of the TLR4 gene (rs10759932, rs1927906, rs11536898, rs11536865, rs10983755, rs4986790, rs4986791, rs11536897) and to determine the impact of polymorphisms in genotypes and alleles on the pathomorphological characteristics and progression in a group of 172 cervical cancer subjects with stage I-IV. Genotyping was performed by RT-PCR assay. We detected that the CA genotype and A allele of rs11536898 were significantly more frequent in patients with metastases (p = 0.026; p = 0.008). The multivariate logistic regression analysis confirmed this link to be significant. The effect of rs10759932 and rs11536898 on progression-free survival (PFS) and overall survival (OS) has been identified as important. In univariate and multivariate Cox analyses, AA genotype of rs11536898 was a negative prognostic factor for PFS (p = 0.024; p = 0.057, respectively) and OS (p = 0.008; p = 0.042, respectively). Rs11536898 C allele predisposed for longer PFS (univariate and multivariate: p = 0.025; p = 0.048, respectively) and for better OS (univariate and multivariate: p = 0.010; p = 0.043). The worse prognostic factor of rs10759932 in a univariate and multivariate Cox analysis for survival was CC genotype: shorter PFS (p = 0.032) and increased risk of death (p = 0.048; p = 0.015, respectively). The T allele of rs10759932 increased longer PFS (univariate and multivariate: p = 0.048; p = 0.019, respectively) and longer OS (univariate and multivariate: p = 0.037; p = 0.009, respectively). Our study suggests that SNPs rs10759932 and rs11536898 may have the potential to be markers contributing to the assessment of the cervical cancer prognosis. Further studies, preferably with larger groups of different ethnic backgrounds, are needed to confirm the results of the current study.
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Affiliation(s)
- Eglė Žilienė
- Institute of Oncology, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
| | - Arturas Inčiūra
- Institute of Oncology, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
| | - Rasa Ugenskienė
- Institute of Oncology, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
- Department of Genetics and Molecular Medicine, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
| | - Elona Juozaitytė
- Institute of Oncology, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
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Wang F, Wen X, Wen T, Liu Z. Association of TLR4 gene 2026A/G (rs1927914), 896A/G (rs4986790), and 1196C/T (rs4986791) polymorphisms and cancer susceptibility: Meta-analysis and trial sequential analysis. Medicine (Baltimore) 2023; 102:e33040. [PMID: 36827055 PMCID: PMC11309699 DOI: 10.1097/md.0000000000033040] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 01/31/2023] [Accepted: 01/31/2023] [Indexed: 02/25/2023] Open
Abstract
BACKGROUND This study was performed to assess the association of TLR4 gene 2026A/G (rs1927914), 896A/G (rs4986790), and 1196C/T (rs4986791) polymorphisms and cancer susceptibility based on published case-control studies. METHODS Web of Science, PubMed, Embase, CBM, WanFang Data, CNKI, and VIP database were used for article retrieving. Then, these articles were screened according to the study inclusion and exclusion criteria. The data was extracted, and the study quality was evaluated according to the principle of Newcastle-Ottawa Scale. Meta-analysis was performed by RevMan 5.4 and Stata MP-17 software. Trial sequential analysis was performed by TSA 0.9.5.10 Beta software. RESULTS Eighty-seven case-control studies including 25,969 cases and 32,119 controls were included in the meta-analysis. The diseases involved in case groups include prostate cancer, lung cancer, gastric cancer, hepatocellular carcinoma, colorectal cancer, etc. A versus G model of rs1927914, A versus G model of rs4986790 and C versus T model of rs4986791 showed that odds ratio (OR) = 1.08, OR = 0.85, and OR = 0.74 respectively. All the 3 comparisons were statistically significant. Sensitivity analysis showed that the results were stable. Publication bias analysis and trial sequential analysis showed that no significant publication bias was found in the results of the meta-analysis, and the probability of false positives was small. CONCLUSION People with A allele of rs1927914, G allele of rs4986790, or T allele of rs4986791 have higher risks of cancer. The results of meta-analysis are stable and have less probability of false positives.
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Affiliation(s)
- Fengzhen Wang
- Heart Medical Centre, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Xianming Wen
- Heart Medical Centre, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Ting Wen
- Department of physiology, Gannan Medical University, Ganzhou, China
| | - Ziyou Liu
- Heart Medical Centre, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
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Xiao Q, Chen J, Zeng S, Cai H, Zhu G. An updated systematic review of the association between the TLR4 polymorphism rs4986790 and cancers risk. Medicine (Baltimore) 2022; 101:e31247. [PMID: 36281200 PMCID: PMC9592503 DOI: 10.1097/md.0000000000031247] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND Toll-like receptor 4 (TLR4) is a lipopolysaccharide receptor that may influence tumor progression through inflammatory response and immune response. This complex process mainly occurs within cells. The correlation between TLR4 and neoplasms has been of great interest, but discrepancies remain. METHODS We analyze the literature retrieved from five databases (Web of Science, PubMed, Embase, CNKI, and Wan Fang) to assess the intensity of association using odds ratio (ORs) and 95% confidence intervals (95% CI). Meta-regression and subgroup analysis were utilized to find sources of heterogeneity. Publication bias is estimated using contour-enhanced funnel plots, Begg's test, and Egger's test, and we implemented sensitivity analysis to clarify the reliability of the outcomes. We also conducted an evaluation of the sample size using trial sequential analysis (TSA) method. RESULTS We found a significant association between rs4986790 and tumors (dominant model: OR [95% CI] = 1.25 [1.11-1.42]; heterozygous model OR [95% CI] = 1.25 [1.11-1.41]; and additive model: OR [95% CI] = 1.25 [1.10-1.41]. Specifically, the rs4986790 minor allele G may increase the risk of gastric cancer (dominant model: OR [95% CI] = 1.62 [1.3-2.03]; heterozygous model: OR [95% CI] = 1.57 [1.24-1.97]; additive model: OR [95% CI] = 1.64 [1.31-2.05] and other tumors (dominant model: OR [95% CI] = 1.36 [1.17-1.57]; heterozygous model: OR [95% CI] = 1.43 [1.25-1.63]; additive model: OR [95% CI] = 1.35 [1.18-1.55]. Further subgroup analysis showed that this association are both present in Caucasian and Asian. CONCLUSION The outcomes of our systemic review proved that the TLR4 polymorphism rs4986790 is associated with cancer, especially with gastric cancer, and this strong correlation are evident in Caucasians and Asian.
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Affiliation(s)
- Qiang Xiao
- General Surgery Department, First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jian Chen
- General Surgery Department, First Affiliated Hospital of Nanchang University, Nanchang, China
| | - ShuKun Zeng
- General Surgery Department, First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Hu Cai
- General Surgery Department, First Affiliated Hospital of Nanchang University, Nanchang, China
| | - GuoMin Zhu
- General Surgery Department, First Affiliated Hospital of Nanchang University, Nanchang, China
- *Correspondence: Guomin Zhu, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China (e-mail: )
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5
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Lam SY, Mommersteeg MC, Yu B, Broer L, Spaander MCW, Frost F, Weiss S, Völzke H, Lerch MM, Schöttker B, Zhang Y, Stocker H, Brenner H, Levy D, Hwang SJ, Wood AC, Rich SS, Rotter JI, Taylor KD, Tracy RP, Kabagambe EK, Leja M, Klovins J, Peculis R, Rudzite D, Nikitina-Zake L, Skenders G, Rovite V, Uitterlinden A, Kuipers EJ, Fuhler GM, Homuth G, Peppelenbosch MP. Toll-Like Receptor 1 Locus Re-examined in a Genome-Wide Association Study Update on Anti-Helicobacter pylori IgG Titers. Gastroenterology 2022; 162:1705-1715. [PMID: 35031300 PMCID: PMC11734630 DOI: 10.1053/j.gastro.2022.01.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 12/03/2021] [Accepted: 01/07/2022] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS A genome-wide significant association between anti-Helicobacter pylori (H pylori) IgG titers and Toll-like receptor (TLR1/6/10) locus on 4p14 was demonstrated for individuals of European ancestry, but not uniformly replicated. We re-investigated this association in an updated genome-wide association study (GWAS) meta-analysis for populations with low gastric cancer incidence, address potential causes of cohort heterogeneity, and explore functional implications of genetic variation at the TLR1/6/10 locus. METHODS The dichotomous GWAS (25% individuals exhibiting highest anti-H pylori IgG titers vs remaining 75%) included discovery and replication sampls of, respectively, n = 15,685 and n = 9676, all of European ancestry. Longitudinal analysis of serologic data was performed on H pylori-eradicated subjects (n = 132) and patients under surveillance for premalignant gastric lesions (n = 107). TLR1/6/10 surface expression, TLR1 mRNA, and cytokine levels were measured in leukocyte subsets of healthy subjects (n = 26) genotyped for TLR1/6/10 variants. RESULTS The association of the TLR1/6/10 locus with anti-H pylori IgG titers (rs12233670; β = -0.267 ± SE 0.034; P = 4.42 × 10-15) presented with high heterogeneity and failed replication. Anti-H pylori IgG titers declined within 2-4 years after eradication treatment (P = 0.004), and decreased over time in patients with premalignant gastric lesions (P < 0.001). Variation at the TLR1/6/10 locus affected TLR1-mediated cytokine production and TLR1 surface expression on monocytes (P = 0.016) and neutrophils (P = 0.030), but not mRNA levels. CONCLUSIONS The association between anti-H pylori IgG titers and TLR1/6/10 locus was not replicated across cohorts, possibly owing to dependency of anti-H pylori IgG titers on therapy, clearance, and antibody decay. H pylori-mediated immune cell activation is partly mediated via TLR1 signaling, which in turn is affected by genetic variation.
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Affiliation(s)
- Suk Yee Lam
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Michiel C Mommersteeg
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Bingting Yu
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Linda Broer
- Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Manon C W Spaander
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Fabian Frost
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Stefan Weiss
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany; Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Henry Völzke
- Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Markus M Lerch
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Ben Schöttker
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany; Network Aging Research, Heidelberg University, Heidelberg, Germany
| | - Yan Zhang
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany
| | - Hannah Stocker
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany; Network Aging Research, Heidelberg University, Heidelberg, Germany
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany; Network Aging Research, Heidelberg University, Heidelberg, Germany
| | - Daniel Levy
- Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, Massachusetts, USA; Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA
| | - Shih-Jen Hwang
- Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, Massachusetts, USA; Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA
| | - Alexis C Wood
- USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas, USA
| | - Stephen S Rich
- Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA
| | - Jerome I Rotter
- Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, USA
| | - Kent D Taylor
- Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, USA
| | - Russell P Tracy
- Laboratory for Clinical Biochemistry Research, University of Vermont College of Medicine, Colchester, Vermont, USA
| | | | - Marcis Leja
- Institute of Clinical and Preventive Medicine, Faculty of Medicine, University of Latvia, Riga, Latvia
| | - Janis Klovins
- Latvian Biomedical Research and Study Center, Riga, Latvia
| | - Raitis Peculis
- Latvian Biomedical Research and Study Center, Riga, Latvia
| | - Dace Rudzite
- Institute of Clinical and Preventive Medicine, Faculty of Medicine, University of Latvia, Riga, Latvia
| | | | - Girts Skenders
- Institute of Clinical and Preventive Medicine, Faculty of Medicine, University of Latvia, Riga, Latvia
| | - Vita Rovite
- Latvian Biomedical Research and Study Center, Riga, Latvia
| | - André Uitterlinden
- Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Ernst J Kuipers
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Gwenny M Fuhler
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Georg Homuth
- Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Maikel P Peppelenbosch
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands.
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Li ZM, Zhuang X. Application of artificial intelligence in microbiome study promotes precision medicine for gastric cancer. Artif Intell Gastroenterol 2021; 2:105-110. [DOI: 10.35712/aig.v2.i4.105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 04/22/2021] [Accepted: 07/09/2021] [Indexed: 02/06/2023] Open
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Nasr R, Shamseddine A, Mukherji D, Nassar F, Temraz S. The Crosstalk between Microbiome and Immune Response in Gastric Cancer. Int J Mol Sci 2020; 21:ijms21186586. [PMID: 32916853 PMCID: PMC7556019 DOI: 10.3390/ijms21186586] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Revised: 08/04/2020] [Accepted: 08/12/2020] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is the end result of a complex interplay between host genetics, environmental factors, and microbial factors. The link between gut microbiome and gastric cancer has been attributed to persistent activation of the host's immune system by gut microbiota. The end result of this dysregulated interaction between host epithelium and microbes is a state of chronic inflammation. Gut bacteria can promote anti-tumor immune responses through several mechanisms. These include triggering T-cell responses to bacterial antigens that can cross-react with tumor antigens or cause tumor-specific antigen recognition; engagement of pattern recognition receptors that mediate pro-immune or anti-inflammatory effects or via small metabolites that mediate systemic effects on the host. Here we review the role of the gut microbiome including H. pylori and non-H. pylori gastric bacteria, the immune response, and immunotherapy using checkpoint inhibitors. We also review the evidence for cross talk between the gut microbiome and immune response in gastric cancer.
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Affiliation(s)
- Rihab Nasr
- Department of Anatomy, Cell Biology and Physiology, American University of Beirut Medical Center, Riad El Solh, Beirut 1107, Lebanon;
| | - Ali Shamseddine
- Department of Internal Medicine, Hematology/Oncology Division, American University of Beirut Medical Center, Riad El Solh, Beirut 1107, Lebanon; (A.S.); (D.M.); (F.N.)
| | - Deborah Mukherji
- Department of Internal Medicine, Hematology/Oncology Division, American University of Beirut Medical Center, Riad El Solh, Beirut 1107, Lebanon; (A.S.); (D.M.); (F.N.)
| | - Farah Nassar
- Department of Internal Medicine, Hematology/Oncology Division, American University of Beirut Medical Center, Riad El Solh, Beirut 1107, Lebanon; (A.S.); (D.M.); (F.N.)
| | - Sally Temraz
- Department of Internal Medicine, Hematology/Oncology Division, American University of Beirut Medical Center, Riad El Solh, Beirut 1107, Lebanon; (A.S.); (D.M.); (F.N.)
- Correspondence: ; Tel.: +961-137-4374
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de Almeida NM, Fernandes A, Romãozinho JM, Freire P, Donato MM, Cardoso O, Luxo C, Cipriano MA, Marinho C, Calhau C, Figueiredo P. Correlation of
NOD2
genotypes with
Helicobacter pylori
infection in a
South‐European
country. ADVANCES IN DIGESTIVE MEDICINE 2020. [DOI: 10.1002/aid2.13210] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Nuno Miguel de Almeida
- Gastroenterology Department Centro Hospitalar e Universitário de Coimbra Coimbra Portugal
- Faculty of Medicine University of Coimbra Coimbra Portugal
| | | | - José Manuel Romãozinho
- Gastroenterology Department Centro Hospitalar e Universitário de Coimbra Coimbra Portugal
- Faculty of Medicine University of Coimbra Coimbra Portugal
| | - Paulo Freire
- Faculty of Medicine University of Coimbra Coimbra Portugal
| | - Maria M. Donato
- CIMAGO, Faculty of Medicine University of Coimbra Coimbra Portugal
| | - Olga Cardoso
- Laboratory of Microbiology, Faculty of Pharmacy University of Coimbra Coimbra Portugal
- CIEPQPF, Faculty of Sciences and Technology University of Coimbra Coimbra Portugal
| | - Cristina Luxo
- Laboratory of Microbiology, Faculty of Pharmacy University of Coimbra Coimbra Portugal
- CIEPQPF, Faculty of Sciences and Technology University of Coimbra Coimbra Portugal
| | | | - Carol Marinho
- Pathology Department Centro Hospitalar e Universitário de Coimbra Coimbra Portugal
| | - Carlos Calhau
- Gastroenterology Department Centro Hospitalar e Universitário de Coimbra Coimbra Portugal
| | - Pedro Figueiredo
- Gastroenterology Department Centro Hospitalar e Universitário de Coimbra Coimbra Portugal
- Faculty of Medicine University of Coimbra Coimbra Portugal
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9
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Guan Y, Huang XF, Li PJ, Cao W, Gao XH, Guan X. Association of CD14 gene -260C>T and -561C>T polymorphisms with cancer susceptibility: A meta-analysis. J Gene Med 2020; 22:e3151. [PMID: 31826310 DOI: 10.1002/jgm.3151] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Revised: 11/12/2019] [Accepted: 12/07/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Two polymorphisms, -260C>T (rs2569190) and -561C>T (rs5744455), in the CD14 gene have been implicated in susceptibility to cancer. However, the results remain inconclusive. The current meta-analysis was carried out aiming to confirm the function of these two polymorphisms on the susceptibility of cancer. METHODS We collected eligible studies from databases, including PubMed, EMBASE, CNKI, Wanfang, and VIP (Weipu). We used logistic regression calculation to compute odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS After strict selection, 24 studies with 5854 cases and 10339 controls for -260C>T and seven studies with 1809 cases and 7289 controls for -561C>T were finally enlisted into our analysis reference material. Pool results revealed that neither -260C>T, nor -561C>T was found to have any association with overall cancer susceptibility. Nevertheless, when stratified by cancer type, we detected a decreased risk associated with other cancers in a heterozygous model (OR = 0.69, 95% CI = 0.51-0.93, p = 0.014) and a dominant model (OR = 0.70, 95% CI = 0.53-0.93, p = 0.012) for -561C>T. An increased risk was found in other cancers under an allele model (OR = 1.29, 95% CI = 1.03-1.62, p = 0.026), in laryngeal cancer under a dominant model (OR = 1.38, 95% CI = 1.11-1.71, p = 0.003) and for a score ≤ 9 under a recessive model (OR = 1.45, 95% CI = 1.09-1.91, p = 0.009) for -561C>T. CONCLUSIONS In the present study, we conclude that the CD14 -260C>T and -561C>T polymorphisms might not be associated with overall cancer risk. Further studies are encouraged to confirm this conclusion.
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Affiliation(s)
- Yin Guan
- Intensive Critical Care Unit, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Xiao-Feng Huang
- Intensive Critical Care Unit, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Pei-Jie Li
- Intensive Critical Care Unit, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Wen Cao
- Intensive Critical Care Unit, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Xue-Hua Gao
- Department of Anethesiology, Gansu Provincial Cancer Hospital, Lanzhou, Gansu, China
| | - Xia Guan
- Digestive Endoscopy Center, The Second Peoples Hospital of Lanzhou, Lanzhou, Gansu, China
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10
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Gentiluomo M, Peduzzi G, Lu Y, Campa D, Canzian F. Genetic polymorphisms in inflammatory genes and pancreatic cancer risk: a two-phase study on more than 14 000 individuals. Mutagenesis 2019; 34:395-401. [PMID: 31748817 DOI: 10.1093/mutage/gez040] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Accepted: 10/18/2019] [Indexed: 12/17/2023] Open
Abstract
There is overwhelming evidence that inflammation plays a key role in the pathogenesis of cancer and its progression. Inflammation is regulated through a complex network of genes and polymorphic variants in these genes have been found to be associated to risk of various human cancers, alone or in combination with environmental variables. Despite this, not much is known on the genetic variability of genes that regulate inflammation and risk of pancreatic ductal adenocarcinoma (PDAC). We performed a two-phase association study considering the genetic variability of 76 genes that are key players in inflammatory response. We analysed tagging single nucleotide polymorphisms (SNPs) and regulatory SNPs on 7207 PDAC cases and 7063 controls and observed several associations with PDAC risk. The most significant association was between the carriers of the A allele of the CCL4-rs1719217 polymorphism, which was reported to be also associated with the expression level of the CCL4 gene, and increased risk of developing PDAC (odds ratio = 1.12, 95% confidence interval = 1.06-1.18, P = 3.34 × 10-5). This association was significant also after correction for multiple testing, highlighting the importance of using potentially functional SNPs in order to discover more genetic variants associated with PDAC risk.
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Affiliation(s)
| | | | - Ye Lu
- Genomic Epidemiology Group, German Cancer Research Center, Heidelberg, Germany
| | - Daniele Campa
- Department of Biology, University of Pisa, Pisa, Italy
| | - Federico Canzian
- Genomic Epidemiology Group, German Cancer Research Center, Heidelberg, Germany
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Schulz C, Schütte K, Mayerle J, Malfertheiner P. The role of the gastric bacterial microbiome in gastric cancer: Helicobacter pylori and beyond. Therap Adv Gastroenterol 2019; 12:1756284819894062. [PMID: 31897087 PMCID: PMC6920592 DOI: 10.1177/1756284819894062] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Accepted: 11/11/2019] [Indexed: 02/04/2023] Open
Abstract
A link between chronic inflammation and carcinogenesis has been depicted in many organ systems. Helicobacter pylori is the most prevalent bacterial pathogen, induces chronic gastritis and is associated with more than 90% of cases of gastric cancer (GC). However, the introduction of nucleotide sequencing techniques and the development of biocomputional tools have surpassed traditional culturing techniques and opened a wide field for studying the mucosal and luminal composition of the bacterial gastric microbiota beyond H. pylori. In studies applying animal models, a potential role in gastric carcinogenesis for additional bacteria besides H. pylori has been demonstrated. At different steps of gastric carcinogenesis, changes in bacterial communities occur. Whether these microbial changes are a driver of malignant disease or a consequence of the histologic progression along the precancerous cascade, is not clear at present. It is hypothesized that atrophy, as a consequence of chronic gastric inflammation, alters the gastric niche for commensals that might further urge the development of H. pylori-induced GC. Here, we review the current state of knowledge on gastric bacteria other than H. pylori and on their synergism with H. pylori in gastric carcinogenesis.
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Affiliation(s)
| | - Kerstin Schütte
- Department of Internal Medicine and
Gastroenterology, Niels-Stensen-Kliniken, Marienhospital Osnabrück,
Osnabrück, Germany,Department of Gastroenterology, Hepatology and
Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany
| | - Julia Mayerle
- Department of Medicine II, University Hospital,
LMU Munich, Germany
| | - Peter Malfertheiner
- Department of Medicine II, University Hospital,
LMU Munich, Germany,Department of Gastroenterology, Hepatology and
Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany
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12
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Abstract
PURPOSE The role of Helicobacter pylori as key factor in gastric inflammation and the development of (pre-)cancerous lesions is undisputable. As an open system, the human upper gastrointestinal tract harbors a complex bacterial community which is highly impacted by the absence or presence of H. pylori. The interaction between other bacteria and H. pylori might impact on gastric carcinogenesis. RECENT FINDINGS Several studies demonstrated differences in the composition of the gastric bacterial community in different stages of gastritis and between samples from tumor and adjacent tissue. In addition, animal studies demonstrated an increased and accelerated development of precancerous lesions in mice colonized with intestinal flora and H. pylori compared with mice mono-infected with H. pylori. CONCLUSION Other bacteria beyond H. pylori enter the focus in research on gastric carcinogenesis. However, we are still far from a thorough understanding of the pathophysiology of host-microbiota interaction and its impact on the development of malignant and precancerous changes.
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Companioni O, Bonet C, García N, Ramírez-Lázaro MJ, Lario S, Mendoza J, Adrados MM, Poves E, Espinosa L, Pozo-Kreilinger JJ, Ortega L, Bujanda L, Cosme A, Ferrández A, Muñoz G, Cuatrecasas M, Elizalde I, Andreu V, Paules MJ, Madrigal B, Barrio J, Berdasco M, Calvet X, Sanz-Anquela JM, Gisbert JP, González CA, Sala N. Genetic variation analysis in a follow-up study of gastric cancer precursor lesions confirms the association of MUC2 variants with the evolution of the lesions and identifies a significant association with NFKB1 and CD14. Int J Cancer 2018; 143:2777-2786. [PMID: 30171605 DOI: 10.1002/ijc.31839] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Revised: 07/03/2018] [Accepted: 07/11/2018] [Indexed: 01/05/2023]
Abstract
Gastric carcinogenesis proceeds through a series of gastric cancer precursor lesions (GCPLs) leading to gastric cancer (GC) development. Although Helicobacter pylori infection initiates this process, genetic factors also play a role. We previously reported that genetic variability in MUC2 is associated with the evolution of GCPLs. In order to replicate previous results in an independent sample series and to explore whether genetic variability in other candidate genes plays a role in the evolution of GCPL, genomic DNA from 559 patients with GCPLs, recruited from 9 Spanish hospitals and followed for a mean of 12 years, was genotyped for 141 SNPs in 29 genes. After follow-up, 45.5% of the lesions remained stable, 37% regressed and 17.5% progressed to a more severe lesion. Genetic association with the evolution of the lesions (progression or regression) was analyzed by multinomial and binomial logistic regression. After correction for multiple comparisons, the results obtained confirmed the inverse association between MUC2 variants and the regression of the lesions. A significant association was also observed between NFKB1 and CD14 variants and the evolution of the lesions; interestingly, this association was with both progression and regression in the same direction, which could reflect the dual role of inflammation in cancer. Stratified analyses according to H. pylori virulence factors indicated some significant and differential effects but none of them passed the FDR test. These results confirm that genetic variability in MUC2, NFKB1 and CD14 may have a role in the evolution of the GCPLs along time and in gastric carcinogenesis.
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Affiliation(s)
- Osmel Companioni
- Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO)-IDIBELL, Barcelona, Spain
| | - Catalina Bonet
- Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO)-IDIBELL, Barcelona, Spain
| | - Nadia García
- Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO)-IDIBELL, Barcelona, Spain
- Translational Research Laboratory, Catalan Institute of Oncology (ICO)-IDIBELL, Barcelona, Spain
| | - María José Ramírez-Lázaro
- Departament of Medicine, Digestive Diseases Service, Institut Universitari Parc Taulí, Sabadell, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Spain
| | - Sergio Lario
- Departament of Medicine, Digestive Diseases Service, Institut Universitari Parc Taulí, Sabadell, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Spain
| | - Jorge Mendoza
- Department of Gastroenterology, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP) and CIBEREHD, Madrid, Spain
| | - Mª Magdalena Adrados
- Department of Pathology, Hospital Universitario de la Princesa, IIS-IP, Madrid, Spain
| | - Elvira Poves
- Department of Gastroenterology, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Spain
| | - Laura Espinosa
- Department of Gastroenterology, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Spain
| | | | - Luís Ortega
- Department of Pathology, Hospital Clínico San Carlos, Madrid, Spain
| | - Luis Bujanda
- Department of Pathology and Hospital Donostia/Instituto Biodonostia, Universidad del País Vasco (UPV/EHU), and CIBEREHD, San Sebastián, Spain
| | - Angel Cosme
- Department of Gastroenterology, Hospital Donostia/Instituto Biodonostia, Universidad del País Vasco (UPV/EHU), and CIBEREHD, San Sebastián, Spain
| | - Angel Ferrández
- Department of Gastroenterology and Hospital Clínico Universitario Lozano Blesa Zaragoza, and CIBEREHD, Spain
| | - Guillermo Muñoz
- Department of Pathology, Hospital Clínico Universitario Lozano Blesa, Zaragoza, and CIBEREHD, Spain
| | - Miriam Cuatrecasas
- Department of Pathology, Hospital Clínic de Barcelona, IDIBAPS and CIBEREHD, and Universitat de Barcelona, Spain
| | - Ignasi Elizalde
- Department of Gastroenterology, Hospital Clínic de Barcelona, IDIBAPS and CIBEREHD, Spain
| | - Victoria Andreu
- Department of Gastroenterology, Hospital de Viladecans, Spain
| | - Mª José Paules
- Department of Pathology, Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, Spain
| | - Beatriz Madrigal
- Department of Pathology, Hospital Universitario Río Hortega, Valladolid, Spain
| | - Jesús Barrio
- Department of Gastroenterology, Hospital Universitario Río Hortega, Valladolid, Spain
| | - María Berdasco
- Cancer Epigenetics and Biology Program, IDIBELL, Barcelona, Spain
| | - Xavier Calvet
- Departament of Medicine, Digestive Diseases Service, Institut Universitari Parc Taulí, Sabadell, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Spain
| | - José Miguel Sanz-Anquela
- Department of Pathology, Hospital "Principe de Asturias" and University of Alcalá, Alcalá de Henares, Spain
| | - Javier P Gisbert
- Department of Gastroenterology, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP) and CIBEREHD, Madrid, Spain
| | - Carlos A González
- Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO)-IDIBELL, Barcelona, Spain
| | - Núria Sala
- Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO)-IDIBELL, Barcelona, Spain
- Translational Research Laboratory, Catalan Institute of Oncology (ICO)-IDIBELL, Barcelona, Spain
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Mommersteeg MC, Yu J, Peppelenbosch MP, Fuhler GM. Genetic host factors in Helicobacter pylori-induced carcinogenesis: Emerging new paradigms. Biochim Biophys Acta Rev Cancer 2017; 1869:42-52. [PMID: 29154808 DOI: 10.1016/j.bbcan.2017.11.003] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Revised: 11/13/2017] [Accepted: 11/13/2017] [Indexed: 02/09/2023]
Abstract
Helicobacter Pylori is a gram negative rod shaped microaerophilic bacterium that colonizes the stomach of approximately half the world's population. Infection with c may cause chronic gastritis which via a quite well described process known as Correas cascade can progress through sequential development of atrophic gastritis, intestinal metaplasia and dysplasia to gastric cancer. H. pylori is currently the only bacterium that is classified as a class 1 carcinogen by the WHO, although the exact mechanisms by which this bacterium contributes to gastric carcinogenesis are still poorly understood. Only a minority of H. pylori-infected patients will eventually develop gastric cancer, suggesting that host factors may be important in determining the outcome of H. pylori infection. This is supported by a growing body of evidence suggesting that the host genetic background contributes to risk of H. pylori infection and gastric carcinogenesis. In particular single nucleotide polymorphisms in genes that influence bacterial handling via pattern recognition receptors appear to be involved, further strengthening the link between host risk factors, H. pylori incidence and cancer. Many of these genes influence cellular pathways leading to inflammatory signaling, inflammasome formation and autophagy. In this review we summarize known carcinogenic effects of H. pylori, and discuss recent findings that implicate host genetic pattern recognition pathways in the development of gastric cancer and their relation with H. pylori.
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Affiliation(s)
- Michiel C Mommersteeg
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical center Rotterdam, Office NA-619, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
| | - Jun Yu
- Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences and CUHK-Shenzhen Research Institute, Rm 707A, 7/F., Li Ka Shing Medical Science Building, The Chinese University of Hong Kong, Hong Kong.
| | - Maikel P Peppelenbosch
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical center Rotterdam, Office NA-619, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
| | - Gwenny M Fuhler
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical center Rotterdam, Office NA-619, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
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15
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Ding L, Jiang Q, Li G, Shen J, Du J, Lu X, Xiong X. Comprehensive assessment of association between TLR4 gene polymorphisms and cancer risk: a systematic meta-analysis. Oncotarget 2017; 8:100593-100602. [PMID: 29246004 PMCID: PMC5725046 DOI: 10.18632/oncotarget.21543] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Accepted: 09/25/2017] [Indexed: 12/20/2022] Open
Abstract
Previous studies have explored the association between toll-like receptor 4 (TLR4) polymorphisms and risk of various cancers, but the results remained controversial. To obtain an assessment of the effect of TLR4 polymorphisms (rs4986790, rs4986791 and rs11536889) on cancer risk, fifty-five articles (containing 20107 cases and 28244 controls) were recruited for meta-analysis. Our result indicated that two Single Nucleotide Polymorphisms (SNP) in TLR4 were associated with decreased cancer risk for rs4986791: OR = 0.764, 95% CI: 0.652-0.894, P = 0.001 in allele model; OR = 0.769, 95%CI: 0.650-0.909, P = 0.002 in recessive model; OR = 0.505, 95% CI: 0.352-0.726, P = 0.000 in dominant model; for 11536889: OR = 0.927, 95% CI: 0.872–0.984, P = 0.013 in allele model; OR = 0.926, 95% CI: 0.862–0.944,P = 0.034 in recessive model. In terms of subgroup analyses sorted by ethnicity, only polymorphism of rs4986791 had a significant influence on decrease of cancer risk among both Caucasian and Asian populations. The findings suggested that TLR4 polymorphisms may serve as a genetic risk factor for cancers.
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Affiliation(s)
- Lu Ding
- Department of Medical Informatics, Chongqing Medical University, Chongqing, 400016, China
| | - Qifeng Jiang
- Department of Medical Informatics, Chongqing Medical University, Chongqing, 400016, China
| | - Guang Li
- Department of Medical Informatics, Chongqing Medical University, Chongqing, 400016, China
| | - Jia Shen
- Department of Medical Informatics, Chongqing Medical University, Chongqing, 400016, China
| | - Jiayin Du
- Department of Medical Informatics, Chongqing Medical University, Chongqing, 400016, China
| | - Xiaochen Lu
- Department of Medical Informatics, Chongqing Medical University, Chongqing, 400016, China
| | - Xingliang Xiong
- Department of Medical Informatics, Chongqing Medical University, Chongqing, 400016, China
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16
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Spanou E, Kalisperati P, Pateras IS, Papalampros A, Barbouti A, Tzioufas AG, Kotsinas A, Sougioultzis S. Genetic Variability as a Regulator of TLR4 and NOD Signaling in Response to Bacterial Driven DNA Damage Response (DDR) and Inflammation: Focus on the Gastrointestinal (GI) Tract. Front Genet 2017; 8:65. [PMID: 28611823 PMCID: PMC5447025 DOI: 10.3389/fgene.2017.00065] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Accepted: 05/09/2017] [Indexed: 12/13/2022] Open
Abstract
The fundamental role of human Toll-like receptors (TLRs) and NOD-like receptors (NLRs), the two most studied pathogen recognition receptors (PRRs), is the protection against pathogens and excessive tissue injury. Recent evidence supports the association between TLR/NLR gene mutations and susceptibility to inflammatory, autoimmune, and malignant diseases. PRRs also interfere with several cellular processes, such as cell growth, apoptosis, cell proliferation, differentiation, autophagy, angiogenesis, cell motility and migration, and DNA repair mechanisms. We briefly review the impact of TLR4 and NOD1/NOD2 and their genetic variability in the process of inflammation, tumorigenesis and DNA repair, focusing in the gastrointestinal tract. We also review the available data on new therapeutic strategies utilizing TLR/NLR agonists and antagonists for cancer, allergic diseases, viral infections and vaccine development against both infectious diseases and cancer.
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Affiliation(s)
- Evagelia Spanou
- Gastroenterology Division, Department of Pathophysiology, “Laikon” General Hospital, University of AthensAthens, Greece
| | - Polyxeni Kalisperati
- Gastroenterology Division, Department of Pathophysiology, “Laikon” General Hospital, University of AthensAthens, Greece
| | - Ioannis S. Pateras
- Department of Histology and Embryology, University of AthensAthens, Greece
| | - Alexandros Papalampros
- 1st Department of Surgery, “Laikon” General Hospital, University of AthensAthens, Greece
| | - Alexandra Barbouti
- Department of Anatomy-Histology-Embryology, University of IoanninaIoannina, Greece
| | - Athanasios G. Tzioufas
- Department of Pathophysiology, “Laikon” General Hospital, University of AthensAthens, Greece
| | | | - Stavros Sougioultzis
- Gastroenterology Division, Department of Pathophysiology, “Laikon” General Hospital, University of AthensAthens, Greece
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17
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Chmiela M, Karwowska Z, Gonciarz W, Allushi B, Stączek P. Host pathogen interactions in Helicobacter pylori related gastric cancer. World J Gastroenterol 2017; 23:1521-1540. [PMID: 28321154 PMCID: PMC5340805 DOI: 10.3748/wjg.v23.i9.1521] [Citation(s) in RCA: 89] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Revised: 10/26/2016] [Accepted: 02/16/2017] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori (H. pylori), discovered in 1982, is a microaerophilic, spiral-shaped gram-negative bacterium that is able to colonize the human stomach. Nearly half of the world's population is infected by this pathogen. Its ability to induce gastritis, peptic ulcers, gastric cancer and mucosa-associated lymphoid tissue lymphoma has been confirmed. The susceptibility of an individual to these clinical outcomes is multifactorial and depends on H. pylori virulence, environmental factors, the genetic susceptibility of the host and the reactivity of the host immune system. Despite the host immune response, H. pylori infection can be difficult to eradicate. H. pylori is categorized as a group I carcinogen since this bacterium is responsible for the highest rate of cancer-related deaths worldwide. Early detection of cancer can be lifesaving. The 5-year survival rate for gastric cancer patients diagnosed in the early stages is nearly 90%. Gastric cancer is asymptomatic in the early stages but always progresses over time and begins to cause symptoms when untreated. In 97% of stomach cancer cases, cancer cells metastasize to other organs. H. pylori infection is responsible for nearly 60% of the intestinal-type gastric cancer cases but also influences the development of diffuse gastric cancer. The host genetic susceptibility depends on polymorphisms of genes involved in H. pylori-related inflammation and the cytokine response of gastric epithelial and immune cells. H. pylori strains differ in their ability to induce a deleterious inflammatory response. H. pylori-driven cytokines accelerate the inflammatory response and promote malignancy. Chronic H. pylori infection induces genetic instability in gastric epithelial cells and affects the DNA damage repair systems. Therefore, H. pylori infection should always be considered a pro-cancerous factor.
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18
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Expression profile of innate immune receptors, NLRs and AIM2, in human colorectal cancer: correlation with cancer stages and inflammasome components. Oncotarget 2016; 6:33456-69. [PMID: 26378020 PMCID: PMC4741778 DOI: 10.18632/oncotarget.5587] [Citation(s) in RCA: 101] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2015] [Accepted: 08/20/2015] [Indexed: 11/25/2022] Open
Abstract
NLRs (nucleotide-binding domain leucine-rich repeat proteins or NOD-like receptors) are regulators of inflammation and immunity. A subgroup of NLRs and the innate immune receptor, AIM2 (absent-in-melanoma 2), can induce the assembly of a large caspase-1 activating complex called the inflammasome. Other NLRs regulate key signaling pathways such as NF-kB and MAPK. Since inflammation is a central component of colorectal cancer (CRC), this work was undertaken to analyze NLR and AIM2 expression in human CRC by combining bioinformatics analysis and experimental verification using clinical tissue samples. Additional experiments analyzed the association of (i) gene expression and cancer staging, and (ii) gene expression among inflammasome components. Ten public CRC datasets from the Oncomine® Platform were analyzed. Genes analyzed include NLRP1, NLRP3, NLRP6, NLRP12, NLRC3, NLRC4, NLRC5, NOD1, NOD2 and AIM2. Additionally, forty case-matched cancer samples and adjacent healthy control tissues isolated from a cohort of Chinese CRC patients were profiled. Three patterns of gene expression in CRC are shown. The expression of NLRC3, a checkpoint of inflammation, and the inflammasome components NLRP1, NLRP3, NLRC4 and AIM2 were reduced in CRC. NOD1 and NOD2 expression was increased in CRC, while NLRC5, NLRP6 and NLRP12 showed little difference compared to controls. Reduced expression of NLRC3 in CRC was verified in all available databases analyzed and confirmed with our patient cohort. Furthermore, the extent of NLRC3 and AIM2 gene reduction was correlated with cancer progression. This report reveals the potential value of NLR and AIM2 genes as biomarkers of CRC and cancer progression.
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Tang W, Wang Y, Chen S, Lin J, Chen B, Yu S, Chen Y, Gu H, Kang M. Investigation of Cytotoxic T-lymphocyte antigen 4 Polymorphisms in Gastric Cardia Adenocarcinoma. Scand J Immunol 2016; 83:212-8. [PMID: 26709093 DOI: 10.1111/sji.12409] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Accepted: 12/17/2015] [Indexed: 11/28/2022]
Abstract
To assess the potential effects of Cytotoxic T-lymphocyte antigen 4 (CTLA4) gene polymorphisms on susceptibility to gastric cardia adenocarcinoma (GCA), we genotyped four polymorphisms (rs733618 A>G, rs16840252 C>T, rs231775 G>A and rs3087243 G>A) in CTLA4 and calculated odds ratios (ORs) with the corresponding 95% confidence intervals (95% CIs) for the genotype and allele distributions between GCA cases and controls. The CTLA4 genotypes were determined by the polymerase chain reaction-ligase detection reaction (PCR-LDR) analysis in 330 GCA patients and 608 unrelated cancer-free controls. In this case-control study, there was no significant difference in the genotype and allele distributions of four CTLA4 polymorphisms between GCA patients and controls. However, haplotype association analysis indicated that compared with CTLA4 Grs733618 Crs16840252 Grs231775 Crs3087243 , CTLA4 Grs733618 Crs16840252 Ars231775 Grs3087243 and Ars733618 Crs16840252 Grs231775 Ars3087243 haplotypes conferred increased risks of GCA (OR = 6.46, 95% CI = 1.33-31.28; P = 0.012; both); however, CTLA4 Ars733618 Crs16840252 Ars231775 Grs3087243 and Ars733618 Trs16840252 Grs231775 Grs3087243 haplotypes conferred decreased risks of GCA (P = 0.001 and P = 0.011, respectively). These results highlight that the rare CTLA4 haplotypes may affect the development of GCA in the Chinese population.
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Affiliation(s)
- W Tang
- Department of Thoracic Surgery, The Union Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China
| | - Y Wang
- Department of Cardiology, The People's Hospital of Xishuangbanna Dai Autonomous Prefecture, Jinghong, Yunnan, China
| | - S Chen
- Department of Thoracic Surgery, The Union Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China
| | - J Lin
- Department of Thoracic Surgery, The Union Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China
| | - B Chen
- Department of Thoracic Surgery, The Union Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China
| | - S Yu
- Department of Thoracic Surgery, The Union Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China
| | - Y Chen
- Department of Medical Oncology, Fujian Provincial Cancer Hospital, Fuzhou, Fujian, China
| | - H Gu
- Department of Cardiothoracic Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - M Kang
- Department of Thoracic Surgery, The Union Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China
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20
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Gong AM, Li XY, Xie YQ, Jia ZD, Li YX, Zou YY, Xu CQ, Wang ZY. Association between CD14 SNP -159 C/T and gastric cancer: an independent case-control study and an updated meta-analysis. Onco Targets Ther 2016; 9:4337-42. [PMID: 27486336 PMCID: PMC4958350 DOI: 10.2147/ott.s95807] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
PURPOSE The association between CD14 -159C/T polymorphism and the susceptibility to gastric cancer (GC) has been reported. However, the results were inconclusive. In the present study, a case-control study and a meta-analysis were performed to assess the possible association between -159C/T in the CD14 gene and GC risk. PATIENTS AND METHODS Relevant studies were searched in several databases including PubMed, Web of Science, EMBASE, Chinese National Knowledge Infrastructure database, and Wanfang database (last search was performed on December 30, 2015). In addition, a case-control study involving 164 GC cases and 169 controls was also performed in the analysis. Statistical analysis was performed by the software Revman5.3. RESULTS A total of ten published studies and the present case-control study involving 2,844 GC and 3,983 controls were included for the meta-analysis. The analysis result indicated that the T allele of CD14 -159C/T polymorphism did not confer risk for GC (in our study: [P=0.93]; in the meta-analysis: T vs 2N odds ratio =1.28 and 95% confidence interval (CI) =0.95-1.24, [P=0.24]). However, we found a significant association in the recessive model (in our study: TT vs TC+CC [P=0.04]; in the meta-analysis: TT vs TC+CC odds ratio =1.12 and 95% CI =1.01-1.26, [P=0.04]). Furthermore, a subgroup analysis by ethnicity showed that TT genotype was significantly associated with GC in Asian (odds ratio =1.17 and 95% CI =1.02-1.34, [P=0.02]) but not in Caucasian. CONCLUSION Our results highlight the TT genotype of CD14 -159C/T as a genetic susceptibility factor for gastric cancer, particularly, in Asians and population-based controls.
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Affiliation(s)
- Ai-Min Gong
- Department of Internal Medicine of Traditional Chinese Medicine, Hainan Medical University, Hainan; Department of Pathophysiology, Harbin Medical University, Harbin
| | - Xin-Yuan Li
- Department of Pathophysiology, Harbin Medical University, Harbin
| | - Yi-Qiang Xie
- Department of Internal Medicine of Traditional Chinese Medicine, Hainan Medical University, Hainan
| | - Zhan-Dong Jia
- Department of Nephrology, Ningbo Tradition Chinese Medicine Hospital affiliated to Zhejiang Chinese Medical University, Ningbo
| | | | - Yong-Yan Zou
- Department of Nephrology, Jining Tradition Chinese Medicine Hospital, Jining, People's Republic of China
| | - Chang-Qing Xu
- Department of Pathophysiology, Harbin Medical University, Harbin
| | - Zhen-Yu Wang
- Department of Pathophysiology, Harbin Medical University, Harbin
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21
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Yang H, Pan T, Duan G, Wang Y. A cumulative meta-analysis on the association of toll-like receptor 4 gene Asp299Gly polymorphism with cancer risk. Eur J Cancer 2016; 58:130-7. [PMID: 26922776 DOI: 10.1016/j.ejca.2015.12.032] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Accepted: 12/08/2015] [Indexed: 12/12/2022]
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22
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Finding gastric cancer related genes and clinical biomarkers for detection based on gene-gene interaction network. Math Biosci 2015; 276:1-7. [PMID: 26700107 DOI: 10.1016/j.mbs.2015.12.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Revised: 10/27/2015] [Accepted: 12/04/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND/OBJECTIVE Gastric cancer (GC) is the second leading cause of death resulted from cancer globally. The most common cause of GC is the infection of Helicobacter pylori, approximately 11% of cases are caused by genetic factors. The objective of this study was to develop an effective computational method to meaningfully interpret these GC-related genes and to predict potential prognostic genes for clinical detection. METHODS We employed the shortest path algorithm and permutation test to probe the genes that have relationship with known GC genes in gene-gene interaction network. We calculated the enrichment scores of gene ontology and pathways of gastric cancer related genes to characterize these genes in terms of molecular features. The optimal features that primly representing the gastric cancer related genes were selected using Random Forest classification and incremental feature selection. Random Forest classification was also used for the prediction of the novel gastric cancer related genes based on the selected features and the identification of novel prognostic genes based on the expression of genes. RESULTS Based on the shortest path analysis of 36 known GC genes, 39 genes occurring in shortest path were identified as GC-related genes. In subsequent classification, 4153 gene ontology terms and 157 pathway terms were identified as the optimal features to depict these gastric cancer related genes. Based on them, a total of 886 genes were predicted as related genes. These 886 genes could serve as expression biomarkers for clinical detection and they achieved a 100% accuracy for distinguishing gastric cancer from a case-control dataset, better than any of 886 random selected genes did. CONCLUSION By analyzing the features of known GC-related genes, we employed a systematic method to predict gastric cancer related genes and novel prognostic genes for accurate clinical detection.
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Xie Y, Zhi X, Su H, Wang K, Yan Z, He N, Zhang J, Chen D, Cui D. A Novel Electrochemical Microfluidic Chip Combined with Multiple Biomarkers for Early Diagnosis of Gastric Cancer. NANOSCALE RESEARCH LETTERS 2015; 10:477. [PMID: 26659608 PMCID: PMC4675772 DOI: 10.1186/s11671-015-1153-3] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Accepted: 11/06/2015] [Indexed: 05/26/2023]
Abstract
Early diagnosis is very important to improve the survival rate of patients with gastric cancer and to understand the biology of cancer. In order to meet the clinical demands for early diagnosis of gastric cancer, we developed a disposable easy-to-use electrochemical microfluidic chip combined with multiple antibodies against six kinds of biomarkers (carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), Helicobacter pylori CagA protein (H.P.), P53oncoprotein (P53), pepsinogen I (PG I), and PG-II). The six kinds of biomarkers related to gastric cancer can be detected sensitively and synchronously in a short time. The specially designed three electrodes system enables cross-contamination to be avoided effectively. The linear ranges of detection of the electrochemical microfluidic chip were as follows: 0.37-90 ng mL(-1) for CEA, 10.75-172 U mL(-1) for CA19-9, 10-160 U L(-1) for H.P., 35-560 ng mL(-1) for P53, 37.5-600 ng mL(-1) for PG I, and 2.5-80 ng mL(-1)for PG II. This method owns better sensitivity compared with enzyme-linked immunosorbent assay (ELISA) results of 394 specimens of gastric cancer sera. Furthermore, we established a multi-index prediction model based on the six kinds of biomarkers for predicting risk of gastric cancer. In conclusion, the electrochemical microfluidic chip for detecting multiple biomarkers has great potential in applications such as early screening of gastric cancer patients, and therapeutic evaluation, and real-time dynamic monitoring the progress of gastric cancer in near future.
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Affiliation(s)
- Yao Xie
- Department of Instrument Science and Engineering, Institute of Nano Biomedicine and Engineering, Key Lab. for Thin Film and Microfabrication Technology of Ministry of Education, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, Peoples' Republic of China
| | - Xiao Zhi
- Department of Instrument Science and Engineering, Institute of Nano Biomedicine and Engineering, Key Lab. for Thin Film and Microfabrication Technology of Ministry of Education, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, Peoples' Republic of China
- Institute of Translation Medicine, Tumor Personalized Therapy and Molecular Diagnosis Base of Ministry of Health and Family Planning Commission, Collaborative Innovational Center for System Biology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, Peoples' Republic of China
| | - Haichuan Su
- Department of Oncology, Tangdu Hospital, Fourth Military Medical University, 569 Xinsi Road, Xi'an, 710032, Peoples' Republic of China
| | - Kan Wang
- Department of Instrument Science and Engineering, Institute of Nano Biomedicine and Engineering, Key Lab. for Thin Film and Microfabrication Technology of Ministry of Education, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, Peoples' Republic of China
| | - Zhen Yan
- Department of Pharmaceutics, Fourth Military Medical University, 18 Changle West Road, Xi'an, 710032, Peoples' Republic of China
| | - Nongyue He
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, Peoples' Republic of China
| | - Jingpu Zhang
- Department of Instrument Science and Engineering, Institute of Nano Biomedicine and Engineering, Key Lab. for Thin Film and Microfabrication Technology of Ministry of Education, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, Peoples' Republic of China
| | - Di Chen
- Department of Instrument Science and Engineering, Institute of Nano Biomedicine and Engineering, Key Lab. for Thin Film and Microfabrication Technology of Ministry of Education, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, Peoples' Republic of China.
| | - Daxiang Cui
- Department of Instrument Science and Engineering, Institute of Nano Biomedicine and Engineering, Key Lab. for Thin Film and Microfabrication Technology of Ministry of Education, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, Peoples' Republic of China.
- Institute of Translation Medicine, Tumor Personalized Therapy and Molecular Diagnosis Base of Ministry of Health and Family Planning Commission, Collaborative Innovational Center for System Biology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, Peoples' Republic of China.
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Mocellin S, Verdi D, Pooley KA, Nitti D. Genetic variation and gastric cancer risk: a field synopsis and meta-analysis. Gut 2015; 64:1209-19. [PMID: 25731870 DOI: 10.1136/gutjnl-2015-309168] [Citation(s) in RCA: 135] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2015] [Accepted: 02/06/2015] [Indexed: 12/19/2022]
Abstract
BACKGROUND Data on genetic susceptibility to sporadic gastric carcinoma have been published at a growing pace, but to date no comprehensive overview and quantitative summary has been available. METHODS We conducted a systematic review and meta-analysis of the evidence on the association between DNA variation and risk of developing stomach cancer. To assess result credibility, summary evidence was graded according to the Venice criteria and false positive report probability (FPRP) was calculated to further validate result noteworthiness. Meta-analysis was also conducted for subgroups, which were defined by ethnicity (Asian vs Caucasian), tumour histology (intestinal vs diffuse), tumour site (cardia vs non-cardia) and Helicobacter pylori infection status (positive vs negative). RESULTS Literature search identified 824 eligible studies comprising 2 530 706 subjects (cases: 261 386 (10.3%)) and investigating 2841 polymorphisms involving 952 distinct genes. Overall, we performed 456 primary and subgroup meta-analyses on 156 variants involving 101 genes. We identified 11 variants significantly associated with disease risk and assessed to have a high level of summary evidence: MUC1 rs2070803 at 1q22 (diffuse carcinoma subgroup), MTX1 rs2075570 at 1q22 (diffuse), PSCA rs2294008 at 8q24.2 (non-cardia), PRKAA1 rs13361707 5p13 (non-cardia), PLCE1 rs2274223 10q23 (cardia), TGFBR2 rs3087465 3p22 (Asian), PKLR rs3762272 1q22 (diffuse), PSCA rs2976392 (intestinal), GSTP1 rs1695 11q13 (Asian), CASP8 rs3834129 2q33 (mixed) and TNF rs1799724 6p21.3 (mixed), with the first nine variants characterised by a low FPRP. We also identified polymorphisms with lower quality significant associations (n=110). CONCLUSIONS We have identified several high-quality biomarkers of gastric cancer susceptibility. These data will form the backbone of an annually updated online resource that will be integral to the study of gastric carcinoma genetics and may inform future screening programmes.
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Affiliation(s)
- Simone Mocellin
- Department of Surgery Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Daunia Verdi
- Department of Surgery Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Karen A Pooley
- Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK
| | - Donato Nitti
- Department of Surgery Oncology and Gastroenterology, University of Padova, Padova, Italy
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Wu Z, Jiang P, Zulqarnain H, Gao H, Zhang W. Relationship between single-nucleotide polymorphism of matrix metalloproteinase-2 gene and colorectal cancer and gastric cancer susceptibility: a meta-analysis. Onco Targets Ther 2015; 8:861-9. [PMID: 25945057 PMCID: PMC4406259 DOI: 10.2147/ott.s78031] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Background Recently, the published data on the association between matrix metalloproteinase-2 (MMP-2) (C-1306T) polymorphism and colorectal cancer (CRC) and gastric cancer (GC) (gastrointestinal cancer) risk remained controversial. The aim of this study is to investigate the relationship between the risk of CRC and GC and single-nucleotide polymorphism of MMP-2(C-1306T). Methods Medline, Embase, Science Citation Index, and PubMed were thoroughly searched to identify relevant studies. Odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of the association. Results We performed a meta-analysis of 14 studies including 642 cases and 692 controls for CRC and 1,936 cases and 3,490 controls for GC. The result indicates that there is significant relationship between MMP-2(C-1306T) polymorphism and CRC risk in recessive model and codominant model (TT vs CC/CT: OR: 2.39, 95% CI: 1.30–4.37, P=0.005; TT vs CC: OR: 2.36, 95% CI: 1.29–4.34, P=0.006). In subgroup analysis according to ethnicity, significant associations were found in Caucasians (TT vs CC/CT: OR: 2.87, 95% CI: 1.43–5.78, P=0.003; TT vs CC: OR: 2.86, 95% CI: 1.41–5.80, P=0.003), but we did not find significant evidence with GC in all genetic models, and in stratified analysis according to ethnicity, no significant risk was found in the subgroup too. Conclusion This meta-analysis considered that the MMP-2(C-1306T) polymorphism is a risk factor for CRC susceptibility, especially in Caucasians, but it does not support any relationship to GC, and further studies are needed to explore the association.
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Affiliation(s)
- Zesheng Wu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, People's Republic of China
| | - Peng Jiang
- Department of Oncology, Tumor Hospital of Xinjiang Medical University, Urumqi, People's Republic of China
| | - Haider Zulqarnain
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, People's Republic of China
| | - Hua Gao
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, People's Republic of China
| | - Wenbin Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, People's Republic of China
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Gene expression disorders of innate antibacterial signaling pathway in pancreatic cancer patients: implications for leukocyte dysfunction and tumor progression. Cent Eur J Immunol 2014; 39:498-507. [PMID: 26155170 PMCID: PMC4439963 DOI: 10.5114/ceji.2014.47736] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Accepted: 09/30/2014] [Indexed: 01/01/2023] Open
Abstract
The study was carried out to investigate changes in gene expression of innate antibacterial signaling pathways in patients with pancreatic cancer. Expression of the following genes was measured in peripheral blood leukocytes of 55 patients with pancreatic adenocarcinoma using real-time polymerase chain reaction (RT-PCR): TLR4, NOD1, MyD88, TRAF6 and HMGB1. The levels of expression of TLR4, NOD1 and TRAF6 genes were significantly elevated (p = 0.007; p = 0.001 and p = 0.01, respectively), while MyD88 expression was markedly reduced (p = 0.0002), as compared to controls. Expression of TLR4 and NOD1 exceeded the normal level more than 3.5-fold and there was a significant correlation found between the expression of these genes (r = 0.558, p < 0.001). TLR4, NOD1 and MyD88 genes were expressed at a similar level both before and after surgery. No significant changes in the expression of HMGB1 gene were observed. The results of the study clearly indicate abnormal expression of genes belonging to innate antibacterial signaling pathways in peripheral blood leukocytes of patients with pancreatic cancer, which may lead to leukocyte dysfunction. Overexpression of TLR4, NOD1 and TRAF6 genes, and decreased MyD88 gene expression may contribute to chronic inflammation and tumor progression by up-regulation of the innate antibacterial response. The parameters tested are useful for monitoring innate immunity gene disorders and pancreatic cancer progression.
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Abstract
Gastric cancer remains highly prevalent and accounts for a notable proportion of global cancer mortality. This cancer is also associated with poor survival rates. Understanding the genetic basis of gastric cancer will offer insights into its pathogenesis, help identify new biomarkers and novel treatment targets, aid prognostication and could be central to developing individualized treatment strategies in the future. An inherited component contributes to <3% of gastric cancers; the majority of genetic changes associated with gastric cancer are acquired. Over the past few decades, advances in technology and high-throughput analysis have improved understanding of the molecular aspects of the pathogenesis of gastric cancer. These aspects are multifaceted and heterogeneous and represent a wide spectrum of several key genetic influences, such as chromosomal instability, microsatellite instability, changes in microRNA profile, somatic gene mutations or functional single nucleotide polymorphisms. These genetic aspects of the pathogenesis of gastric cancer will be addressed in this Review.
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Affiliation(s)
- Mairi H McLean
- National Cancer Institute, Laboratory of Molecular Immunoregulation, Cancer &Inflammation Program, 1050 Boyles Street, Frederick, MD 21702-1201, USA
| | - Emad M El-Omar
- Division of Applied Medicine, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB51 5ER, UK
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Zhou Q, Wang C, Wang X, Wu X, Zhu Z, Liu B, Su L. Association between TLR4 (+896A/G and +1196C/T) polymorphisms and gastric cancer risk: an updated meta-analysis. PLoS One 2014; 9:e109605. [PMID: 25290654 PMCID: PMC4188729 DOI: 10.1371/journal.pone.0109605] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2014] [Accepted: 08/29/2014] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Toll-like receptor 4 (TLR4) is a receptor of lipopolysaccharide in the signaling transduction of gastric epithelial cell. It plays a pivotal role in activation of innate immunity and pathogen recognition and thus acts as a modulator in the development and progression of gastric cancer. Growing studies explored the association of polymorphisms in TLR4 with susceptibility to gastric cancer, but the results have remained controversial and conflicting. To investigate the effect of two selected TLR4 (+896A/G and +1196C/T) polymorphisms on gastric cancer, we performed a meta-analysis. METHODS A comprehensive search was conducted to identify all eligible case-control publications investigating the association between TLR4 polymorphisms and gastric cancer risk. Odds ratios (OR) and corresponding 95% confidence intervals (CI) were used to assess such association. RESULTS Up to March 26 2014, 10 published case-control studies from PubMed and EMBase were available, involving a total of 1888 gastric cancer patients and 3433 control subjects. In the overall meta-analyses, a significantly increased gastric cancer risk was detected in TLR4 +896A/G polymorphism (heterozygous model, AG vs. AA: OR = 1.67, 95% CI, 1.39-2.01; additive model, G vs. A: OR = 1.64, 95% CI, 1.37-1.95) and TLR4 +1196C/T polymorphism (heterozygous model, CT vs. CC: OR = 1.42, 95% CI, 1.11-1.81; additive model, T vs. C: OR = 1.36, 95% CI, 1.08-1.72), similar results were obtained in the subgroup analyses of Caucasian, whereas no associations were detected in any genetic models of non-Caucasian. CONCLUSIONS The overall results suggest that TLR4 polymorphisms (+896A/G and +1196C/T) may be associated with a significantly increased gastric cancer risk in Caucasian.
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Affiliation(s)
- Quan Zhou
- Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Chenchen Wang
- Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Xiaofeng Wang
- Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Xiongyan Wu
- Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Zhenggang Zhu
- Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Bingya Liu
- Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
- * E-mail: (LPS); (BYL)
| | - Liping Su
- Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
- * E-mail: (LPS); (BYL)
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Abstract
Helicobacter pylori colonizes mucosa, activates Toll-like and Nod-like receptors, and usually elicits a gastric T-helper 1/17 (Th1/Th17) type of immune response. Among several bacterial factors, the secreted peptidyl prolyl cis, trans-isomerase of H. pylori represents a key factor driving Th17 inflammation. A complex and fascinating balance between H. pylori and host factors takes part in the gastric niche and is responsible for the chronicity of the infection. Novel insights into the innate and adaptive responses against H. pylori, dealing with gastric epithelial cells, cytokines, and immune evasion have been elucidated over the past year and are discussed for the development of an effective vaccine.
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Affiliation(s)
- Mario M D'Elios
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
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Dalal RS, Moss SF. At the bedside: Helicobacter pylori, dysregulated host responses, DNA damage, and gastric cancer. J Leukoc Biol 2014; 96:213-24. [PMID: 24823809 PMCID: PMC4101088 DOI: 10.1189/jlb.4bt0214-100r] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2014] [Revised: 04/14/2014] [Accepted: 04/17/2014] [Indexed: 12/15/2022] Open
Abstract
Clinical trials performed in populations at high GC risk have demonstrated that eradication of Helicobacter pylori from the stomach with a course of combination antimicrobials helps prevent gastric carcinogenesis when they are administered before precancerous lesions have yet developed. In this review, we consider the insights into H. pylori-associated gastric carcinogenesis that have been gained from these and many other clinical studies in the field to highlight priority areas for basic research and clinical investigation. Among these are defining the magnitude of the risk reduction that may be achieved in clinical practice and at a population level by H. pylori eradication and investigating when, during the slow multistep progression to GC, intervention will be of the most benefit. Additional strategies to prevent GC induced by H. pylori, including chemoprevention, dietary modification, and close endoscopic surveillance, may also have value in augmenting the risk reduction. Why only a small subpopulation of those infected by H. pylori go on to develop GC may be partially explained by genetic susceptibility related to SNPs in several genes regulating the intensity of the gastric inflammatory response to H. pylori. Investigation of the basic mechanisms underlying the promotion of GC by H. pylori and the associated inflammatory response will likely continue to improve clinical strategies for the prevention of one of the most common causes of cancer death globally. See related review, At the Bench: H. pylori, dysregulated host responses, DNA damage, and gastric cancer.
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Affiliation(s)
- Rahul S Dalal
- Department of Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA
| | - Steven F Moss
- Department of Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA
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Castaño-Rodríguez N, Kaakoush NO, Mitchell HM. Pattern-recognition receptors and gastric cancer. Front Immunol 2014; 5:336. [PMID: 25101079 PMCID: PMC4105827 DOI: 10.3389/fimmu.2014.00336] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2014] [Accepted: 07/03/2014] [Indexed: 12/12/2022] Open
Abstract
Chronic inflammation has been associated with an increased risk of several human malignancies, a classic example being gastric adenocarcinoma (GC). Development of GC is known to result from infection of the gastric mucosa by Helicobacter pylori, which initially induces acute inflammation and, in a subset of patients, progresses over time to chronic inflammation, gastric atrophy, intestinal metaplasia, dysplasia, and finally intestinal-type GC. Germ-line encoded receptors known as pattern-recognition receptors (PRRs) are critical for generating mature pro-inflammatory cytokines that are crucial for both Th1 and Th2 responses. Given that H. pylori is initially targeted by PRRs, it is conceivable that dysfunction within genes of this arm of the immune system could modulate the host response against H. pylori infection, and subsequently influence the emergence of GC. Current evidence suggests that Toll-like receptors (TLRs) (TLR2, TLR3, TLR4, TLR5, and TLR9), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) (NOD1, NOD2, and NLRP3), a C-type lectin receptor (DC-SIGN), and retinoic acid-inducible gene (RIG)-I-like receptors (RIG-I and MDA-5), are involved in both the recognition of H. pylori and gastric carcinogenesis. In addition, polymorphisms in genes involved in the TLR (TLR1, TLR2, TLR4, TLR5, TLR9, and CD14) and NLR (NOD1, NOD2, NLRP3, NLRP12, NLRX1, CASP1, ASC, and CARD8) signaling pathways have been shown to modulate the risk of H. pylori infection, gastric precancerous lesions, and/or GC. Further, the modulation of PRRs has been suggested to suppress H. pylori-induced inflammation and enhance GC cell apoptosis, highlighting their potential relevance in GC therapeutics. In this review, we present current advances in our understanding of the role of the TLR and NLR signaling pathways in the pathogenesis of GC, address the involvement of other recently identified PRRs in GC, and discuss the potential implications of PRRs in GC immunotherapy.
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Affiliation(s)
- Natalia Castaño-Rodríguez
- School of Biotechnology and Biomolecular Sciences, The University of New South Wales , Sydney, NSW , Australia
| | - Nadeem O Kaakoush
- School of Biotechnology and Biomolecular Sciences, The University of New South Wales , Sydney, NSW , Australia
| | - Hazel M Mitchell
- School of Biotechnology and Biomolecular Sciences, The University of New South Wales , Sydney, NSW , Australia
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Association between CD14 gene polymorphisms and cancer risk: a meta-analysis. PLoS One 2014; 9:e100122. [PMID: 24978812 PMCID: PMC4076245 DOI: 10.1371/journal.pone.0100122] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2014] [Accepted: 05/21/2014] [Indexed: 12/12/2022] Open
Abstract
Background Two polymorphisms, -260C/T and -651C/T, in the CD14 gene have been implicated in susceptibility to cancer. However, the results remain inconclusive. This meta-analysis aimed to investigate the association between the two polymorphisms and risk of cancer. Methods All eligible case-control studies published up to March 2014 were identified by searching PubMed, Web of Science, CNKI and WanFang database. Pooled odds ratio (OR) with 95% confidence interval (CI) were used to access the strength of this association in fixed- or random-effects model. Results 17 case-control studies from fourteen articles were included. Of those, there were 17 studies (4198 cases and 4194 controls) for -260C/T polymorphism and three studies (832 cases and 1190 controls) for -651C/T polymorphism. Overall, no significant associations between the two polymorphisms of CD14 gene and cancer risk were found. When stratified by ethnicity, cancer type and source of control, similar results were observed among them. In addition, in further subgroups analysis by Helicobacter pylori (H. pylori) infection status and tumor location in gastric cancer subgroup, we found that the CD14 -260C/T polymorphism may increase the risk of gastric cancer in H. pylori-infected individuals. Conclusions This meta-analysis suggests that the CD14 -260C/T polymorphism may increase the risk of gastric cancer in H. pylori-infected individuals. However, large and well-designed studies are warranted to validate our findings.
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Abstract
Infection with Helicobacter pylori is established as the major risk factor for gastric cancer development. Damage of the mucosal barrier due to H. pylori-induced inflammation enhances the carcinogenic effect of other risk factors such as salt intake or tobacco smoking. The genetic disposition of both the bacterial strain and the host can increase the potential towards gastric cancer formation. Genetic variance of the bacterial proteins CagA and VacA is associated with a higher gastric cancer risk, as are polymorphisms and epigenetic changes in host gene coding for interleukins (IL1β, IL8), transcription factors (CDX2, RUNX3) and DNA repair enzymes. Application of high-throughput assays for genome-wide assessment of either genetic structural variance or gene expression patterns may lead to a better understanding of the pathobiological background of these processes, including the underlying signaling pathways. Understanding of the stepwise alterations that take place in the transition from chronic atrophic gastritis, via metaplastic changes, to invasive neoplasia is vital to define the 'point of no return' before which eradication of H. pylori has the potential to prevent gastric cancer. Currently, eradication as preventive strategy is only recommended for high-incidence regions in Asia; large population studies with an adequate follow-up are required to demonstrate the effectiveness of such an approach in Western populations.
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Affiliation(s)
- Jan Bornschein
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto von Guericke University of Magdeburg, Magdeburg, Germany
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Philpott DJ, Sorbara MT, Robertson SJ, Croitoru K, Girardin SE. NOD proteins: regulators of inflammation in health and disease. Nat Rev Immunol 2013; 14:9-23. [PMID: 24336102 DOI: 10.1038/nri3565] [Citation(s) in RCA: 482] [Impact Index Per Article: 40.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Entry of bacteria into host cells is an important virulence mechanism. Through peptidoglycan recognition, the nucleotide-binding oligomerization domain (NOD) proteins NOD1 and NOD2 enable detection of intracellular bacteria and promote their clearance through initiation of a pro-inflammatory transcriptional programme and other host defence pathways, including autophagy. Recent findings have expanded the scope of the cellular compartments monitored by NOD1 and NOD2 and have elucidated the signalling pathways that are triggered downstream of NOD activation. In vivo, NOD1 and NOD2 have complex roles, both during bacterial infection and at homeostasis. The association of alleles that encode constitutively active or constitutively inactive forms of NOD2 with different diseases highlights this complexity and indicates that a balanced level of NOD signalling is crucial for the maintenance of immune homeostasis.
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Affiliation(s)
- Dana J Philpott
- 1] Department of Immunology, University of Toronto, Toronto M5S 1A8, Canada. [2]
| | - Matthew T Sorbara
- 1] Department of Immunology, University of Toronto, Toronto M5S 1A8, Canada. [2]
| | | | - Kenneth Croitoru
- Institute of Medical Science, Department of Medicine, University of Toronto, Toronto M5S 1A8, Canada
| | - Stephen E Girardin
- 1] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto M5S 1A8, Canada. [2]
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