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Kos M, Bojarski K, Mertowska P, Mertowski S, Tomaka P, Dziki Ł, Grywalska E. New Horizons in the Diagnosis of Gastric Cancer: The Importance of Selected Toll-like Receptors in Immunopathogenesis Depending on the Stage, Clinical Subtype, and Gender of Newly Diagnosed Patients. Int J Mol Sci 2024; 25:9264. [PMID: 39273213 PMCID: PMC11394694 DOI: 10.3390/ijms25179264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 08/23/2024] [Accepted: 08/24/2024] [Indexed: 09/15/2024] Open
Abstract
INTRODUCTION Toll-like receptors (TLRs) play a vital role in the innate immune response, recognizing pathogens and initiating the inflammatory response. Research suggests that TLRs may also have a significant impact on the development and progression of cancers, including gastric cancer (GC). Understanding the role of individual TLRs in the immunopathogenesis of gastric cancer may provide new information necessary to develop more effective diagnostic and therapeutic methods. AIM OF THE STUDY This study aimed to determine the role of selected TLR-2, -3, -4, and -9 in the immunopathogenesis of patients with newly diagnosed and untreated gastric cancer. MATERIALS AND METHODS The study included 60 newly diagnosed, untreated GC patients and 25 healthy volunteers. The research included analyses assessing the percentage of the tested TLRs on T and B lymphocyte subpopulations using multicolor flow cytometry and assessing their concentration in the serum of the examined patients using ELISA tests. The statistical analyses performed included a comparison of patients in individual stages of gastric cancer, an analysis of the most common clinical subtypes of gastric cancer, and a comparative analysis of differences in the gender of recruited patients. RESULTS Our studies showed different expression levels of TLR-2, -3, -4, and -9 on T and B lymphocyte subpopulations, as well as their different concentrations in patients' serum. Significant differences in the expression of these receptors were observed depending on the stage of gastric cancer and its clinical subtypes. These differences were also visible in the context of patient gender. SUMMARY The results of our studies suggest that TLR-2, -3, -4, and -9 may play an important role in the immunopathogenesis of gastric cancer. The differential expression of these receptors depending on the stage of the disease, clinical subtype, and gender of patients may have potential diagnostic and therapeutic significance. Further research is necessary to understand better the mechanisms of action of TLRs in gastric cancer and to apply this knowledge in clinical practice.
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Affiliation(s)
- Marek Kos
- Department of Public Health, Medical University of Lublin, 1 Chodźki Street, 20-093 Lublin, Poland
| | - Krzysztof Bojarski
- General Surgery Department, SP ZOZ in Leczna, 52 Krasnystawska Street, 21-010 Leczna, Poland
| | - Paulina Mertowska
- Department of Experimental Immunology, Medical University of Lublin, 4a Chodźki Street, 20-093 Lublin, Poland
| | - Sebastian Mertowski
- Department of Experimental Immunology, Medical University of Lublin, 4a Chodźki Street, 20-093 Lublin, Poland
| | - Piotr Tomaka
- Department of Anesthesiology and Intensive Care, SP ZOZ in Leczna, 52 Krasnystawska Street, 21-010 Leczna, Poland
| | - Łukasz Dziki
- Department of General and Oncological Surgery, Faculty of Medicine, Medical University of Lodz, 251 Street, 92-213 Lodz, Poland
| | - Ewelina Grywalska
- Department of Experimental Immunology, Medical University of Lublin, 4a Chodźki Street, 20-093 Lublin, Poland
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Chong Y, Yu D, Lu Z, Nie F. Role and research progress of spasmolytic polypeptide‑expressing metaplasia in gastric cancer (Review). Int J Oncol 2024; 64:33. [PMID: 38299264 PMCID: PMC10836494 DOI: 10.3892/ijo.2024.5621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 12/20/2023] [Indexed: 02/02/2024] Open
Abstract
Gastric cancer ranks as one of the most prevalent cancers worldwide. While the incidence of gastric cancer in Western countries has notably diminished over the past century, it continues to be a leading cause of cancer‑related mortality on a global scale. The majority of gastric cancers in humans are attributed to chronic Helicobacter pylori infection and the progression of gastric cancer is often preceded by gastritis, atrophy, metaplasia and dysplasia. However, the precise mechanisms underlying the development of gastric cancer remain ambiguous, including the formation of gastric polyps and precancerous lesions. In humans, two types of precancerous metaplasia have been identified in relation to gastric malignancies: Intestinal metaplasia and spasmolytic polypeptide‑expressing metaplasia (SPEM). The role of SPEM in the induction of gastric cancer has gained recent attention and its link with early‑stage human gastric cancer is increasingly evident. To gain insight into SPEM, the present study reviewed the role and research progress of SPEM in gastric cancer.
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Affiliation(s)
- Yang Chong
- Department of Traditional Chinese Medicine, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu 225000, P.R. China
- Department of General Surgery, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu 225000, P.R. China
| | - Dong Yu
- Department of Traditional Chinese Medicine, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu 225000, P.R. China
- Department of General Surgery, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu 225000, P.R. China
| | - Zhaoyu Lu
- Department of Traditional Chinese Medicine, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu 225000, P.R. China
- Department of General Surgery, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu 225000, P.R. China
| | - Fengsong Nie
- Department of Traditional Chinese Medicine, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu 225000, P.R. China
- Department of General Surgery, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu 225000, P.R. China
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Qyi YZ, Aung HH, Aye SN, Tung WS, Naing C. Toll-like receptor 9 (-1237 T/C, -1486 T/C) and the risk of gastric cancer: a meta-analysis of genetic association studies. BMC Cancer 2023; 23:1027. [PMID: 37875868 PMCID: PMC10594725 DOI: 10.1186/s12885-023-11509-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 10/10/2023] [Indexed: 10/26/2023] Open
Abstract
BACKGROUND Gastric cancer has a complex aetiology including genetic factors. Individual case-control studies of toll like receptor (TLR) 9 (-1237 T/C, -1486 T/C) polymorphisms in the gastric cancer risk were available, and they showed variation in the findings. Therefore, we performed a meta-analysis to synthesize the evidence on the association between polymorphisms of TLR 9 (-1237 T/C, -1486 T/C) and the risk of gastric cancer using data from eligible studies. METHODS This study followed the PRISMA 2020 Checklist. Studies were searched in health-related databases. The methodological quality of studies was evaluated with the use of Newcastle-Ottawa Scale criteria. The summary odds ratio (OR) and its 95% confidence interval (CI) were used to determine the strength of association between each polymorphism and the risk of gastric cancer using five genetic models. Stratification was done by ethnic groups. For the robustness of the analysis, a leave-one-out meta-analysis was performed. RESULTS Eight case-control studies with 3,644 participants (1914 cases, 1730 controls) were conducted across six countries. Half of the studies were conducted in China. In the NOS methodological quality assessment, only three studies received a high-quality rating (i.e., a score of ≥ 7). TLR 9 (-1486 T/C) polymorphism and the risk of gastric cancer were assessed in six studies, four of Asian ethnicity and two of non-Asian. Under the dominant model, only in the Asian ethnic group showed a marginally and significantly increased risk of gastric cancer (overall: OR = 1.22, 95%CI = 0.90-1.67, I2 = 56%; Asian: OR = 1.24, 95%CI = 1.00-1.54, I2 = 0%, non-Asian: OR = 1.25, 95%CI = 0.38-4.09, I2 = 89%). Under the recessive model in the absence of heterogeneity, only the Asian group had a significantly higher risk of developing gastric cancer (overall: OR = 1.4, 95% CI = 0.74-2.64, I2 = 85%; Asian: OR: 1.41, 95% CI = 1.07-1.86, I2 = 0%, non-Asian: OR = 1.18, 95% CI = 0.12-11.76, I2 = 97%). Under the heterozygous model, there was no significant association with the risk of gastric cancer overall or among any ethnic subgroup. Under the homozygous model in the absence of heterogeneity, only the Asian group had a significantly higher risk of gastric cancer (overall, OR = 1.47, 95% CI = 0.76-2.86, I2 = 82%; Asian: OR = 1.54, 95% CI = 1.13-2.1, I2 = 0%; non-Asian: OR = 1.19, 95% CI = 0.1-14.33, I2 = 96%). Under the allele model, a significantly increased risk of gastric cancer was observed only in the Asian group (overall: OR = 1.23, 95% CI = 0.89-1.71, I2 = 84%; Asian: OR = 1.22, 95% CI = 1.05-1.41, I2 = 0%; non-Asian: OR = 1.24, 95% CI = 0.34-4.59, I2 = 97%). Four studies investigated the association between TLR 9 (-1237 T/C) polymorphism and the risk of developing gastric cancer. Under any of the five genetic models, there was no association between TLR 9 (-1237 T/C) and the development of gastric cancer in overall or in any ethnic subgroup. Sensitivity analysis revealed that the effect was unstable. With a small number of studies with a small number of participants, we addressed the issue of insufficient power for drawing conclusions. CONCLUSIONS The findings suggested that TLR9 (-1486 T/C) may play a role in the risk of gastric cancer specific to the Asian ethnic group. To substantiate the findings on the association between these two polymorphisms (TLR9 -1237 T/C, -1486 T/C) and the risk of gastric cancer, future well-designed case-control studies with a sufficient number of participants in multi-ethnic groups are recommended.
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Affiliation(s)
- Yap Zi Qyi
- School of Medicine, International Medical University, Kuala Lumpur, Malaysia
- School of Humanities, Social Sciences and Law, University of Dundee, Dundee, Scotland, UK
| | - Htar Htar Aung
- School of Medicine, International Medical University, Kuala Lumpur, Malaysia.
| | - Saint-Nway Aye
- School of Medicine, International Medical University, Kuala Lumpur, Malaysia
| | - Wong Siew Tung
- School of Medicine, International Medical University, Kuala Lumpur, Malaysia
| | - Cho Naing
- Faculty of Tropical Health and Medicine, James Cook University, Queensland, Australia
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Sultan AM, Shenouda R, Sultan AM, Shehta A, Nabiel Y. The Relation Between Host TLR9 -1486T/C, rs187084 Gene Polymorphisms and Helicobacter pylori cagA, sodB, hsp60, and vacA Virulence Genes among Gastric Cancer Patients. Pol J Microbiol 2022; 71:35-42. [PMID: 35635169 PMCID: PMC9152911 DOI: 10.33073/pjm-2022-003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 12/19/2021] [Indexed: 12/26/2022] Open
Abstract
To identify the associations between different genotypes of TLR9 -1486T/C (rs187084) with gastric cancer patients and reveal their relation to Helicobacter pylori virulence genes (cagA, sodB, hsp60 and vacA). Patients with gastric cancer were recruited to our study, diagnosed both endoscopically and histopathologically. H. pylori were isolated from gastric samples by culture and PCR amplification of the glmM gene. Virulence genes cagA, sodB, hsp60, and vacA were detected by multiplex PCR. Blood samples were used for genotyping of TLR9 -1486T/C (rs187084) by PCR-RFLP. Out of 132 patients with gastric cancer, 106 (80.3%) were positive for H. pylori. A similar number of healthy participants was recruited as controls. The prevalence of cagA, sodB, hsp60, and vacA genes among H. pylori was 90.6%, 70.8%, 83.0%, and 95.3%, respectively. The vacA gene alleles had a prevalence of 95.3% for vacAs1/s2, 52.8% for vacAm1, and 42.5% for vacAm2. The CC genotype of TLR9 -1486T/C had a significantly higher frequency in gastric cancer patients when compared to healthy participants (p = 0.045). Furthermore, the CC genotype demonstrated a significant association with H. pylori strains carrying sodB, hsp60, and vacAm1 virulence genes (p = 0.021, p = 0.049, and p = 0.048 respectively). Patients with CC genotype of TLR9 -1486T/C (rs187084) might be at higher risk for the development of gastric cancer, and its co-existence with H. pylori strains carrying sodB, hsp60, or vacAm1 virulence genes might have a synergistic effect in the development of gastric cancer. Further studies on a wider scale are recommended.
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Affiliation(s)
- Amira M. Sultan
- Medical Microbiology and Immunology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Ragy Shenouda
- Medical Microbiology and Immunology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Ahmad M. Sultan
- Gastroenterology Surgical Center, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Ahmed Shehta
- Gastroenterology Surgical Center, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Yasmin Nabiel
- Medical Microbiology and Immunology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
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Meliț LE, Mărginean CO, Săsăran MO, Mocan S, Ghiga DV, Bogliş A, Duicu C. Innate immunity - the hallmark of Helicobacter pylori infection in pediatric chronic gastritis. World J Clin Cases 2021; 9:6686-6697. [PMID: 34447815 PMCID: PMC8362532 DOI: 10.12998/wjcc.v9.i23.6686] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 06/14/2021] [Accepted: 07/05/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Innate immunity was found to be associated with both persistence of Helicobacter pylori (H. pylori) infection and increased risk of gastric cancer. AIM To identify the risk factors associated with H. pylori infection and to establish the role of TLR9 rs352140 in suppressing or promoting inflammation related to this infection in children. METHODS We performed a study of 155 children with digestive symptoms, who were divided into two groups according to the histopathological exam: Group 1 - 48 children with H. pylori-induced chronic gastritis, and Group 2 - control group. RESULTS Rural area and poor living conditions were significantly associated with H. pylori chronic gastritis (P = 0.0042/P < 0.0001). Both positive immunoglobulin A anti H. pylori and the rapid urease test were significantly associated with H. pylori infection (P < 0.0001). Significantly higher values of leukocytes and neutrophils within the peripheral blood were found in children with H. pylori chronic gastritis (P = 0.111/P = 0.284). We found a significant positive correlation between the variant TT genotype of TLR9 rs352140 polymorphism and both leucocytes and neutrophils (P = 0.0225/P = 0.0292). CONCLUSION Variant TT genotype carriers of the TLR9 rs352140 gene polymorphism might have a more severe degree of inflammation.
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Affiliation(s)
- Lorena Elena Meliț
- Department of Pediatrics I, “George Emil Palade” University of Medicine, Pharmacy, Sciences and Technology Târgu Mureș, Târgu Mureș 540136, Romania
| | - Cristina Oana Mărginean
- Department of Pediatrics I, “George Emil Palade” University of Medicine, Pharmacy, Sciences and Technology Târgu Mureș, Târgu Mureș 540136, Romania
| | - Maria Oana Săsăran
- Department of Pediatrics III, “George Emil Palade” University of Medicine, Pharmacy, Sciences and Technology Târgu Mureș, Târgu Mureș 540136, Romania
| | - Simona Mocan
- Department of Pathology, Emergency County Hospital Târgu Mureș, Târgu Mureș 540139, Romania
| | - Dana Valentina Ghiga
- Scientific Medical Research Methodology, “George Emil Palade” University of Medicine, Pharmacy, Sciences and Technology Târgu Mureș, Târgu Mureș 540136, Romania
| | - Alina Bogliş
- Department of Genetics, Center for Advanced Medical and Pharmaceutical Research, “George Emil Palade” University of Medicine, Pharmacy, Sciences and Technology Târgu Mureș, Târgu Mureș 540136, Romania
| | - Carmen Duicu
- Department of Pediatrics I, “George Emil Palade” University of Medicine, Pharmacy, Sciences and Technology Târgu Mureș, Târgu Mureș 540136, Romania
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Susi MD, Lourenço CDM, Rasmussen LT, Payão SLM, Rossi AFT, Silva AE, Oliveira-Cucolo JGD. Toll-like receptor 9 polymorphisms and Helicobacter pylori influence gene expression and risk of gastric carcinogenesis in the Brazilian population. World J Gastrointest Oncol 2019. [DOI: 10.4251/wjgo.v11.i11.0000] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
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Susi MD, Lourenço Caroline DM, Rasmussen LT, Payão SLM, Rossi AFT, Silva AE, Oliveira-Cucolo JGD. Toll-like receptor 9 polymorphisms and Helicobacter pylori influence gene expression and risk of gastric carcinogenesis in the Brazilian population. World J Gastrointest Oncol 2019; 11:998-1010. [PMID: 31798780 PMCID: PMC6883180 DOI: 10.4251/wjgo.v11.i11.998] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Revised: 07/26/2019] [Accepted: 08/28/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Toll-like receptors (TLRs) are the first line of host defense, and are involved in Helicobacter pylori (H. pylori) recognition and activation of both inflammatory and carcinogenic processes. The presence of single nucleotide polymorphisms (SNPs) in genes that activate the immune response may modulate the risk of precancerous lesions and gastric cancer (GC). Among them, Toll-like receptor 9 (TLR9) polymorphisms have emerged with a risk factor of infectious diseases and cancer, however the studies are still inconclusive.
AIM To evaluate whether TLR9 rs5743836 and rs187084 SNPs contribute to the risk of gastric carcinogenesis, and its influence on mRNA expression.
METHODS A case-control study was conducted to evaluate two TLR9 SNPs (TLR9-1237 TC-rs5743836 and TLR9-1486 CT-rs187084) in chronic gastritis (CG) and GC patients. A total of 609 DNA samples of peripheral blood [248 CG, 161 GC, and 200 samples from healthy individuals (C)] were genotyped by polymerase chain reaction-restriction fragment length polymorphism. All samples were tested for the H. pylori infection using Hpx1 and Hpx2 primers. Quantitative polymerase chain reaction by TaqMan® assay was used to quantify TLR9 mRNA from fresh gastric tissues (48 GC, 26 CG, and 14 C).
RESULTS For TLR9-1237, the TC + CC or CC genotypes were associated with a higher risk of GC than C [recessive model odds ratio (OR) = 5.01, 95% confidence interval (CI): 2.52-9.94, P < 0.0001], and the CG (recessive model OR =4.63; 95%CI: 2.44-8.79, P < 0.0001) groups. For TLR9-1486, an association between the CT + TT genotypes and increased risk of both GC (dominant model OR = 2.72, 95%CI: 1.57-4.72, P < 0.0001) and CG (dominant model OR = 1.79, 95%CI: 1.15-2.79, P = 0.0094) was observed when compared to the C group. Moreover, the presence of TLR9-1237 TC/CC + TLR9-1486 CC genotypes potentiate the risk for this neoplasm (OR = 18.57; 95%CI: 5.06-68.15, P < 0.0001). The TLR9 mRNA level was significantly higher in the GC group (RQ = 9.24, P < 0.0001) in relation to the CG group (RQ = 1.55, P = 0.0010) and normal mucosa (RQ = 1.0). When the samples were grouped according to the polymorphic genotypes and the presence of H. pylori infection, an influence of TLR9-1237 TC + CC polymorphic genotypes (P = 0.0083) and H. pylori infection (P < 0.0001) was observed on the upregulation of mRNA expression.
CONCLUSION Our findings show that TLR9 rs5743836 and rs187084 polymorphisms are associated with a higher risk of carcinogenesis gastric, and that TLR9 mRNA levels can be modulated by TLR9-1237 TC + CC variant genotypes and H. pylori infection.
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Affiliation(s)
- Manoela Dias Susi
- Department of Graduate-Level Research, USC-Sacred Heart University, Bauru 17011-970, SP, Brazil
| | | | - Lucas Trevizani Rasmussen
- Department of Genetics and Molecular Biology, FAMEMA-Marilia Medical School, Marília 17519-030, SP, Brazil
| | - Spencer Luis Marques Payão
- Department of Genetics and Molecular Biology, FAMEMA-Marilia Medical School, Marília 17519-030, SP, Brazil
| | - Ana Flávia Teixeira Rossi
- Department of Biology, São Paulo State University-UNESP, São José do Rio Preto 15054-000, SP, Brazil
| | - Ana Elizabete Silva
- Department of Biology, São Paulo State University-UNESP, São José do Rio Preto 15054-000, SP, Brazil
| | - Juliana Garcia de Oliveira-Cucolo
- Department of Molecular, Biological and Genetics and Molecular Biology Research Unit – UPGEM, Faculty of Medicine of São José do Rio Preto – FAMERP, São José do Rio Preto 15090-000, SP, Brazil
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Kasurinen A, Hagström J, Laitinen A, Kokkola A, Böckelman C, Haglund C. Evaluation of toll-like receptors as prognostic biomarkers in gastric cancer: high tissue TLR5 predicts a better outcome. Sci Rep 2019; 9:12553. [PMID: 31467388 PMCID: PMC6715705 DOI: 10.1038/s41598-019-49111-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2019] [Accepted: 08/12/2019] [Indexed: 12/24/2022] Open
Abstract
Toll-like receptors (TLRs), key proteins in innate immunity, appear to contribute to the inflammatory environment in carcinogenesis. Thus, we aimed to evaluate the tissue expressions of TLR1, TLR2, TLR4, TLR5, TLR7, and TLR9 as potential prognostic biomarkers in gastric cancer. We applied immunohistochemistry to study tissue samples from 313 patients operated on for gastric adenocarcinoma between 2000 and 2009 at the Department of Surgery, Helsinki University Hospital, Finland. A high expression of each TLR studied associated with the high expression of each other and with the intestinal-type histology (p < 0.001 for all). Five-year disease-specific survival among patients with a high TLR5 was 53.4% (95% confidence interval [CI] 43.4–63.4), whereas among patients with a low TLR5 it was 37.6% (95% CI 30.0–45.2; p = 0.014). A high TLR5 expression functioned as a marker of a better prognosis, particularly among those with a stage II disease (hazard ratio [HR] 0.33; 0.13–0.83; p = 0.019) or an intestinal-type cancer (HR 0.58; 95% CI 0.34–0.98; p = 0.043). In this study we show, for the first time, that a high TLR5 tissue expression may identify gastric cancer patients with a better prognosis, particularly among those with a stage II disease or an intestinal-type cancer.
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Affiliation(s)
- Aaro Kasurinen
- Translational Cancer Medicine Research Programme, University of Helsinki, Helsinki, Finland.
| | - Jaana Hagström
- Department of Pathology and Oral Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Alli Laitinen
- Translational Cancer Medicine Research Programme, University of Helsinki, Helsinki, Finland.,Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Arto Kokkola
- Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Camilla Böckelman
- Translational Cancer Medicine Research Programme, University of Helsinki, Helsinki, Finland.,Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Caj Haglund
- Translational Cancer Medicine Research Programme, University of Helsinki, Helsinki, Finland.,Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
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de la Fuente S, Citores MJ, Lucena JL, Muñoz P, Cuervas-Mons V. TLR9-1486C/T polymorphism is associated with hepatocellular carcinoma recurrence after liver transplantation. Biomark Med 2019; 13:995-1004. [PMID: 31317790 DOI: 10.2217/bmm-2019-0030] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Accepted: 06/10/2019] [Indexed: 02/07/2023] Open
Abstract
Aim: To determine whether TLR9 polymorphisms are associated with tumor recurrence after liver transplantation for hepatocellular carcinoma (HCC). Patients & methods: All patients who underwent liver transplantation, and had viable HCC in the explanted liver were included. TLR9-1237C/T and -1486C/T polymorphisms were analyzed by real-time PCR and melting curves analysis. Results: 20 of 159 patients (12.6%) developed post-transplant HCC recurrence. Tumors exceeding Milan criteria, moderately-to-poorly differentiated tumors and microvascular invasion on explants, and pretransplant α-fetoprotein level (all p < 0.01) were associated with an increased risk, while TLR9-1486TT genotype was associated with a decreased risk of HCC recurrence (p = 0.03). Conclusion: TLR9-1486C/T might help to preoperatively identify patients at low risk of post-transplant HCC recurrence.
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Affiliation(s)
- Sara de la Fuente
- Liver Transplantation Unit, Hospital Universitario Puerta de Hierro-Majadahonda, Manuel de Falla 1, 28022 Majadahonda, Madrid, Spain
- Department of Internal Medicine, Hospital Universitario Puerta de Hierro-Majadahonda, Manuel de Falla 1, 28022 Majadahonda, Madrid, Spain
| | - María-Jesús Citores
- Department of Internal Medicine, Instituto de Investigación Sanitaria Puerta de Hierro-Segovia de Arana, Joaquin Rodrigo 2, 28022 Majadahonda, Madrid, Spain
| | - José-Luis Lucena
- Liver Transplantation Unit, Hospital Universitario Puerta de Hierro-Majadahonda, Manuel de Falla 1, 28022 Majadahonda, Madrid, Spain
- Department of Surgery, Hospital Universitario Puerta de Hierrdo-Majadahonda, Manuel de Falla 1, 28022 Majadahonda, Madrid, Spain
| | - Pablo Muñoz
- Department of Internal Medicine, Instituto de Investigación Sanitaria Puerta de Hierro-Segovia de Arana, Joaquin Rodrigo 2, 28022 Majadahonda, Madrid, Spain
| | - Valentín Cuervas-Mons
- Liver Transplantation Unit, Hospital Universitario Puerta de Hierro-Majadahonda, Manuel de Falla 1, 28022 Majadahonda, Madrid, Spain
- Department of Internal Medicine, Hospital Universitario Puerta de Hierro-Majadahonda, Manuel de Falla 1, 28022 Majadahonda, Madrid, Spain
- Department of Medicine, Universidad Autónoma de Madrid, Arzobispo Morcillo, s/n, 28029 Madrid, Spain
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The Relationship between Toll-like Receptors and Helicobacter pylori-Related Gastropathies: Still a Controversial Topic. J Immunol Res 2019; 2019:8197048. [PMID: 30863783 PMCID: PMC6378784 DOI: 10.1155/2019/8197048] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Accepted: 01/02/2019] [Indexed: 12/13/2022] Open
Abstract
Innate immunity represents the first barrier against bacterial invasion. Toll-like receptors (TLRs) belong to the large family of pattern recognition receptors (PRRs), and their activation leads to the induction of inflammatory cytokines, chemokines, antigen-presenting molecules, and costimulatory molecules. Recent studies have focused on identifying the association between TLRs and Helicobacter pylori- (H. pylori-) related diseases. Therefore, this minireview focuses on assessing the role of these TLRs in the development of H. pylori-related gastropathies. Both TLR2 and TLR were found to be involved in H. pylori LPS recognition, with contradictory results most likely due to both the inability to obtain pure LPS in experimental studies and the heterogeneity of the bacterial LPS. In addition, TLR2 was found to be the most extensively expressed gene among all the TLRs in gastric tumors. High levels of TLR4 were also associated with a higher risk of gastric cancer. TLR5 was initially associated with the recognition of H. pylori flagellin, but it seems that this bacterium has developed mechanisms to escape this recognition representing an important factor involved in the persistence of this infection and subsequent carcinogenesis. TLR9, the only TLR with both anti- and proinflammatory roles, was involved in the recognition of H. pylori DNA. The dichotomous role of TLR9, promoting or suppressing the infection, depends on the gastric environment. Recently, TLR7 and TLR8 were shown to recognize purified H. pylori RNA, thereby inducing proinflammatory cytokines. TLR1 and TLR10 gene polymorphisms were associated with a higher risk for gastric cancer in H. pylori-infected individuals. Different gene polymorphisms of these TLRs were found to be associated with gastric cancer depending mostly on ethnicity. Further studies are required in order to develop preventive and therapeutic strategies against H. pylori infections based on the functions of TLRs.
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Joshi A, Punke EB, Mehmetoglu-Gurbuz T, Peralta DP, Garg H. TLR9 polymorphism correlates with immune activation, CD4 decline and plasma IP10 levels in HIV patients. BMC Infect Dis 2019; 19:56. [PMID: 30651082 PMCID: PMC6335820 DOI: 10.1186/s12879-019-3697-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Accepted: 01/09/2019] [Indexed: 12/31/2022] Open
Abstract
Background The mechanism behind HIV mediated immune activation remains debated, although the role of virus replication in this process is increasingly evident. Toll like Receptor 9 (TLR9) has been implicated in HIV mediated immune activation via sensing of viral CpG DNA. Polymorphisms in the TLR9 gene and promoter region including TLR9 1635A/G and 1486C/T have been found to be associated with multiple infectious diseases and cancers. Methods In the current study, we looked at the correlation of TLR9 polymorphisms 1635A/G and 1486C/T with key hallmarks of HIV disease in a cohort of 50 HIV infected patients. We analyzed CD4 counts, T cell immune activation characterized by upregulation of CD38 and HLA-DR and upregulation of plasma biomarkers of inflammation like LPS, sCD14, IL-6 and IP10 in the HIV patient cohort and compared it to healthy controls. Results We found that TLR9 1635AA genotype was associated with lower CD4 counts and significantly higher immune activation in both CD4+ and CD8+ T cells. Analysis of HIV associated plasma biomarkers including LPS, sCD14, IL-6 and IP10 revealed a strong correlation between IP10 and immune activation. Interestingly, IP10 levels were also found to be higher in HIV patients with the 1635AA genotype. Furthermore, the TLR9 1486C/T polymorphism that is in linkage disequilibrium with 1635A/G was weakly associated with lower CD4 counts, higher CD8 immune activation and higher IP10 levels. Conclusions As TLR9 stimulation is known to induce IP10 production by dendritic cells, our findings provide new insights into HIV mediated immune activation and CD4 loss. TLR9 stimulation by viral CpG DNA may be important to HIV immunopathogenesis and the TLR9 polymorphisms 1635A/G and 1486C/T may be associated with disease progression.
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Affiliation(s)
- Anjali Joshi
- Department of Biomedical Sciences, Center of Emphasis in Infectious Diseases, Texas Tech University Health Sciences Center, 5001 El Paso Dr, El Paso, TX, 79905, USA
| | - Erin B Punke
- Department of Biomedical Sciences, Center of Emphasis in Infectious Diseases, Texas Tech University Health Sciences Center, 5001 El Paso Dr, El Paso, TX, 79905, USA
| | - Tugba Mehmetoglu-Gurbuz
- Department of Biomedical Sciences, Center of Emphasis in Infectious Diseases, Texas Tech University Health Sciences Center, 5001 El Paso Dr, El Paso, TX, 79905, USA
| | - Diego P Peralta
- Division of Infectious Diseases, Department of Internal Medicine, Texas Tech University Health Sciences Center, El Paso, TX, 79905, USA
| | - Himanshu Garg
- Department of Biomedical Sciences, Center of Emphasis in Infectious Diseases, Texas Tech University Health Sciences Center, 5001 El Paso Dr, El Paso, TX, 79905, USA.
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12
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Fischer J, Weber ANR, Böhm S, Dickhöfer S, El Maadidi S, Deichsel D, Knop V, Klinker H, Möller B, Rasenack J, Wang L, Sharma M, Hinrichsen H, Spengler U, Buggisch P, Sarrazin C, Pawlita M, Waterboer T, Wiese M, Probst-Müller E, Malinverni R, Bochud PY, Gardiner C, O'Farrelly C, Berg T. Sex-specific effects of TLR9 promoter variants on spontaneous clearance of HCV infection. Gut 2017; 66:1829-1837. [PMID: 27196570 DOI: 10.1136/gutjnl-2015-310239] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Revised: 03/18/2016] [Accepted: 03/29/2016] [Indexed: 12/15/2022]
Abstract
OBJECTIVE As pathogen sensors, Toll-like receptors (TLR) play a role in the first defence line during HCV infection. However, the impact of the DNA sensor TLR9 on the natural course of HCV infection is unknown. To address this, TLR9 promoter polymorphisms (single nucleotide polymorphisms (SNPs)) rs187084 and rs5743836 were investigated for their effect on disease progression. DESIGN Therefore, the TLR9 SNPs and the interferon lambda 4 (IFNL4) rs12979860 were genotyped in chronically HCV type 1 infected (n=333), in patients who spontaneously cleared the infection (n=161), in the Swiss HCV cohort (n=1057) and the well-characterised German (n=305) and Irish (n=198) 'anti-D' cohorts. Functional analyses were done with promoter reporter constructs of human TLR9 in B cells and assessing TLR9 mRNA levels in whole blood of healthy volunteers. RESULTS The TLR9 rs187084 C allele was associated with spontaneous virus clearance in women of the study cohort (OR=2.15 (95% CI 1.18 to 3.90) p=0.012), of the Swiss HCV cohort (OR=2.06 (95% CI 1.02 to 4.18) p=0.044) and in both 'anti-D' cohorts (German: OR=2.01 (95% CI 1.14 to 3.55) p=0.016; Irish: OR=1.93 (95% CI 1.10 to 3.68) p=0.047). Multivariate analysis in the combined study and Swiss HCV cohorts supported the results (OR=1.99 (95% CI 1.30 to 3.05) p=0.002). Functional analyses revealed higher transcriptional activities for both TLR9 variants and an association of the C allele of rs5743836 with allele-specific TLR9 mRNA regulation by oestrogens in women. CONCLUSIONS TLR9 promoter SNPs are associated with the natural course of HCV infection and show higher transcriptional activities. Our results imply the DNA sensor TLR9 in natural immunity against the RNA virus, HCV.
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Affiliation(s)
- Janett Fischer
- Department of Gastroenterology and Rheumatology, Section of Hepatology, University Hospital, Leipzig, Germany
| | - Alexander N R Weber
- Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany
| | - Stephan Böhm
- Department of Gastroenterology and Rheumatology, Section of Hepatology, University Hospital, Leipzig, Germany
| | - Sabine Dickhöfer
- Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany
| | - Souhayla El Maadidi
- Department of Gastroenterology and Rheumatology, Section of Hepatology, University Hospital, Leipzig, Germany.,Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany
| | - Danilo Deichsel
- Department of Gastroenterology and Rheumatology, Section of Hepatology, University Hospital, Leipzig, Germany
| | - Viola Knop
- Medical Department 1, Goethe-University Hospital Frankfurt/Main, Frankfurt, Germany
| | - Hartwig Klinker
- Department of Internal Medicine II, University of Würzburg, Würzburg, Germany
| | - Bernd Möller
- Department of Medical Practice, Charlottenstraße 81, Berlin, Germany
| | - Jens Rasenack
- Medical Department, Albert-Ludwigs University Freiburg, Freiburg, Germany
| | - Lisa Wang
- Division of Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany
| | - Manu Sharma
- Division of Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany
| | - Holger Hinrichsen
- Department of Gastroenterology, Gastroenterologische Schwerpunkt-Praxis, Kiel, Germany
| | - Ulrich Spengler
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Peter Buggisch
- Liver Unit, IFI Institute for Interdisciplinary Medicine, Asklepios Klinik St. Georg Hamburg, Hamburg, Germany
| | - Christoph Sarrazin
- Medical Department 1, Goethe-University Hospital Frankfurt/Main, Frankfurt, Germany
| | - Michael Pawlita
- Department of Genome Modifications and Carcinogenesis (F020), Research Program Infection and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Tim Waterboer
- Department of Genome Modifications and Carcinogenesis (F020), Research Program Infection and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Manfred Wiese
- Department of Gastroenterology and Rheumatology, Section of Hepatology, University Hospital, Leipzig, Germany
| | | | | | - Pierre-Yves Bochud
- Infectious Diseases Service, University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Clair Gardiner
- School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
| | - Cliona O'Farrelly
- School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
| | - Thomas Berg
- Department of Gastroenterology and Rheumatology, Section of Hepatology, University Hospital, Leipzig, Germany
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Abstract
Helicobacter pylori is the most common bacterial infection worldwide, and virtually all infected persons develop co-existing gastritis. H. pylori is able to send and receive signals from the gastric mucosa, which enables both host and microbe to engage in a dynamic equilibrium. In order to persist within the human host, H. pylori has adopted dichotomous strategies to both induce inflammation as a means of liberating nutrients while simultaneously tempering the immune response to augment its survival. Toll-like receptors (TLRs) and Nod proteins are innate immune receptors that are present in epithelial cells and represent the first line of defense against pathogens. To ensure persistence, H. pylori manipulates TLR-mediated defenses using strategies that include rendering its LPS and flagellin to be non-stimulatory to TLR4 and TLR5, respectively; translocating peptidoglycan into host cells to induce NOD1-mediated anti-inflammatory responses; and translocating DNA into host cells to induce TLR9 activation.
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Merchant JL, Ding L. Hedgehog Signaling Links Chronic Inflammation to Gastric Cancer Precursor Lesions. Cell Mol Gastroenterol Hepatol 2017; 3:201-210. [PMID: 28275687 PMCID: PMC5331830 DOI: 10.1016/j.jcmgh.2017.01.004] [Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2016] [Accepted: 01/11/2017] [Indexed: 12/24/2022]
Abstract
Since its initial discovery in Drosophila, Hedgehog (HH) signaling has long been associated with foregut development. The mammalian genome expresses 3 HH ligands, with sonic hedgehog (SHH) levels highest in the mucosa of the embryonic foregut. More recently, interest in the pathway has shifted to improving our understanding of its role in gastrointestinal cancers. The use of reporter mice proved instrumental in our ability to probe the expression pattern of SHH ligand and the cell types responding to canonical HH signaling during homeostasis, inflammation, and neoplastic transformation. SHH is highly expressed in parietal cells and is required for these cells to produce gastric acid. Furthermore, myofibroblasts are the predominant cell type responding to HH ligand in the uninfected stomach. Chronic infection caused by Helicobacter pylori and associated inflammation induces parietal cell atrophy and the expansion of metaplastic cell types, a precursor to gastric cancer in human subjects. During Helicobacter infection in mice, canonical HH signaling is required for inflammatory cells to be recruited from the bone marrow to the stomach and for metaplastic development. Specifically, polarization of the invading myeloid cells to myeloid-derived suppressor cells requires the HH-regulated transcription factor GLI1, thereby creating a microenvironment favoring wound healing and neoplastic transformation. In mice, GLI1 mediates the phenotypic shift to gastric myeloid-derived suppressor cells by directly inducing Schlafen 4 (slfn4). However, the human homologs of SLFN4, designated SLFN5 and SLFN12L, also correlate with intestinal metaplasia and could be used as biomarkers to predict the subset of individuals who might progress to gastric cancer and benefit from treatment with HH antagonists.
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Key Words
- ATPase, adenosine triphosphatase
- DAMP, damage-associated molecular pattern
- DAMPs
- GLI, glioma-associated protein
- GLI1
- Gr-MDSC, granulocytic myeloid-derived suppressor cell
- HH, hedgehog
- HHIP, hedgehog-interacting protein
- IFN, interferon
- IL, interleukin
- MDSC, myeloid-derived suppressor cell
- MDSCs
- Metaplasia
- Mo-MDSC, monocytic myeloid-derived suppressor cell
- PTCH, Patched
- SHH
- SHH, sonic hedgehog
- SLFN4, Schlafen 4
- SMO, Smoothened
- SP, spasmolytic polypeptide
- SPEM
- SPEM, spasmolytic polypeptide–expressing mucosa
- SST, somatostatin
- TLR, Toll-like receptor
- mRNA, messenger RNA
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Affiliation(s)
- Juanita L. Merchant
- Department of Internal Medicine-Gastroenterology, University of Michigan, Ann Arbor, Michigan,Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan,Correspondence Address correspondence to: Juanita L. Merchant, MD, PhD, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, Michigan 48109-2200. fax: (734) 763-4686.University of Michigan109 Zina Pitcher PlaceAnn ArborMichigan 48109-2200
| | - Lin Ding
- Department of Internal Medicine-Gastroenterology, University of Michigan, Ann Arbor, Michigan
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15
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Lin L, Zhang J. Role of intestinal microbiota and metabolites on gut homeostasis and human diseases. BMC Immunol 2017; 18:2. [PMID: 28061847 PMCID: PMC5219689 DOI: 10.1186/s12865-016-0187-3] [Citation(s) in RCA: 464] [Impact Index Per Article: 58.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Accepted: 12/20/2016] [Indexed: 12/12/2022] Open
Abstract
Background A vast diversity of microbes colonizes in the human gastrointestinal tract, referred to intestinal microbiota. Microbiota and products thereof are indispensable for shaping the development and function of host innate immune system, thereby exerting multifaceted impacts in gut health. Methods This paper reviews the effects on immunity of gut microbe-derived nucleic acids, and gut microbial metabolites, as well as the involvement of commensals in the gut homeostasis. We focus on the recent findings with an intention to illuminate the mechanisms by which the microbiota and products thereof are interacting with host immunity, as well as to scrutinize imbalanced gut microbiota (dysbiosis) which lead to autoimmune disorders including inflammatory bowel disease (IBD), Type 1 diabetes (T1D) and systemic immune syndromes such as rheumatoid arthritis (RA). Results In addition to their well-recognized benefits in the gut such as occupation of ecological niches and competition with pathogens, commensal bacteria have been shown to strengthen the gut barrier and to exert immunomodulatory actions within the gut and beyond. It has been realized that impaired intestinal microbiota not only contribute to gut diseases but also are inextricably linked to metabolic disorders and even brain dysfunction. Conclusions A better understanding of the mutual interactions of the microbiota and host immune system, would shed light on our endeavors of disease prevention and broaden the path to our discovery of immune intervention targets for disease treatment.
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Affiliation(s)
- Lan Lin
- Department of Bioengineering, Medical School, Southeast University, Nanjing, 210009, People's Republic of China.
| | - Jianqiong Zhang
- Key Laboratory of Developmental Genes and Human Disease, Ministry of Education, Department of Microbiology and Immunology, Medical School, Southeast University, Nanjing, 210009, People's Republic of China.
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Paradowska E, Jabłońska A, Studzińska M, Skowrońska K, Suski P, Wiśniewska-Ligier M, Woźniakowska-Gęsicka T, Nowakowska D, Gaj Z, Wilczyński J, Leśnikowski ZJ. TLR9 -1486T/C and 2848C/T SNPs Are Associated with Human Cytomegalovirus Infection in Infants. PLoS One 2016; 11:e0154100. [PMID: 27105145 PMCID: PMC4841553 DOI: 10.1371/journal.pone.0154100] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Accepted: 04/08/2016] [Indexed: 12/19/2022] Open
Abstract
Toll-like receptor 9 (TLR9) recognizes non-methylated viral CpG-containing DNA and serves as a pattern recognition receptor that signals the presence of human cytomegalovirus (HCMV). Here, we present the genotype distribution of single-nucleotide polymorphisms (SNPs) of the TLR9 gene in infants and the relationship between TLR9 polymorphisms and HCMV infection. Four polymorphisms (-1237T/C, rs5743836; -1486T/C, rs187084; 1174G/A, rs352139; and 2848C/T, rs352140) in the TLR9 gene were genotyped in 72 infants with symptomatic HCMV infection and 70 healthy individuals. SNP genotyping was performed by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Digested fragments were separated and identified by capillary electrophoresis. The HCMV DNA copy number was measured by a quantitative real-time PCR assay. We found an increased frequency of heterozygous genotypes TLR9 -1486T/C and 2848C/T in infants with HCMV infection compared with uninfected cases. Heterozygous variants of these two SNPs increased the risk of HCMV disease in children (P = 0.044 and P = 0.029, respectively). In infants with a mutation present in at least one allele of -1486T/C and 2848C/T SNPs, a trend towards increased risk of cytomegaly was confirmed after Bonferroni's correction for multiple testing (Pc = 0.063). The rs352139 GG genotype showed a significantly reduced relative risk for HCMV infection (Pc = 0.006). In contrast, the -1237T/C SNP was not related to viral infection. We found no evidence for linkage disequilibrium with the four examined TLR9 SNPs. The findings suggest that the TLR9 -1486T/C and 2848C/T polymorphisms could be a genetic risk factor for the development of HCMV disease.
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Affiliation(s)
- Edyta Paradowska
- Laboratory of Molecular Virology and Biological Chemistry, Institute of Medical Biology, Polish Academy of Sciences, Lodz, Poland
- * E-mail:
| | - Agnieszka Jabłońska
- Laboratory of Molecular Virology and Biological Chemistry, Institute of Medical Biology, Polish Academy of Sciences, Lodz, Poland
| | - Mirosława Studzińska
- Laboratory of Molecular Virology and Biological Chemistry, Institute of Medical Biology, Polish Academy of Sciences, Lodz, Poland
| | - Katarzyna Skowrońska
- Laboratory of Molecular Virology and Biological Chemistry, Institute of Medical Biology, Polish Academy of Sciences, Lodz, Poland
| | - Patrycja Suski
- Laboratory of Molecular Virology and Biological Chemistry, Institute of Medical Biology, Polish Academy of Sciences, Lodz, Poland
| | - Małgorzata Wiśniewska-Ligier
- Department of Pediatrics, Immunology, and Nephrology, Polish Mother's Memorial Hospital Research Institute, Lodz, Poland
| | | | - Dorota Nowakowska
- Department of Perinatology and Gynecology, Polish Mother’s Memorial Hospital Research Institute, Lodz, Poland
| | - Zuzanna Gaj
- Department of Perinatology and Gynecology, Polish Mother’s Memorial Hospital Research Institute, Lodz, Poland
- Scientific Laboratory of the Center of Medical Laboratory Diagnostics, Polish Mother's Memorial Hospital Research Institute, Lodz, Poland
| | - Jan Wilczyński
- 2nd Department of Obstetrics and Gynecology, Warsaw Medical University, Warsaw, Poland
| | - Zbigniew J. Leśnikowski
- Laboratory of Molecular Virology and Biological Chemistry, Institute of Medical Biology, Polish Academy of Sciences, Lodz, Poland
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Wan GX, Cao YW, Li WQ, Li YC, Zhang WJ, Li F. Associations between TLR9 polymorphisms and cancer risk: evidence from an updated meta-analysis of 25,685 subjects. Asian Pac J Cancer Prev 2015; 15:8279-85. [PMID: 25339018 DOI: 10.7314/apjcp.2014.15.19.8279] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
A meta-analysis incorporating 34 case-control studies from 19 articles involving 12,197 cases and 13,488 controls was conducted to assess the effects of three genetic variants of Toll-like receptor 9 (TLR9): rs187084, rs352140, and rs5743836. Studies on associations between TLR9 polymorphisms and cancer risk were systematically searched in electronic databases. The reported odds ratios (OR) and 95% confidence intervals (CI) were pooled to assess the strength of any associations. The results showed that the rs187084 polymorphism was significantly associated with an increased risk of cancer (CC vs TC+TT: OR=1.14, 95% CI=1.02-1.28), specifically cervical cancer (C vs T: OR=1.19, 95% CI=1.05-1.34; TC vs TT: OR=1.32, 95% CI=1.10-1.58; CC vs TT: OR=1.31, 95% CI= 1.03-1.68; CC+TC vs TT: OR=1.32, 95% CI=1.11-1.56), and that this association was significantly positive in Caucasians (CC vs. TC+TT: OR=1.18, 95% CI=1.01-1.38). The rs352140 polymorphism had a protective effect on breast cancer (GA vs GG: OR=0.77, 95% CI=0.66-0.89), whereas the rs5743836 polymorphism was likely protective for digestive system cancers (CC+TC vs TT: OR=0.81, 95% CI=0.66-0.98). In conclusion, our results suggest that the rs187084 polymorphism may be associated with an elevated cancer risk, whereas polymorphisms of rs352140 and rs5743836 may play protective roles in the development of breast and digestive system cancers, respectively. From the results of this meta-analysis further large-scale case-control studies are warranted to verify associations between TLR9 polymorphisms and cancer.
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Affiliation(s)
- Guo-Xing Wan
- Department of Pathology and the Key Laboratories for Xinjiang Endemic and Ethnic Diseases (a joint venture with the Chinese Ministry of Education), Shihezi University School of Medicine, Shihezi, Xinjiang, China E-mail :
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Yu CY, Chen HY. Genetic Variations and Gastric Cancer. Gastrointest Tumors 2015. [DOI: 10.1159/000431265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
<b><i>Background:</i></b> Gastric cancer (GC) has an apparent hereditary component. However, in a large fraction of gastric cases, no known genetic syndrome or family history can be identified, suggesting the presence of ‘missing heritability' in GC etiology. Genome-wide association studies (GWAS) and traditional candidate gene studies have both led to the identification of multiple replicable common genetic variants associated with GC risk. <b><i>Summary:</i></b> We summarize the genetic variants associated with GC risk identified up to date. Achievements derived from translational cancer research including the following aspects: (a) contribution to the our understanding of gastric tumorigenesis, (b) guidance to individualized treatment and (c) prediction of patient prognosis. We also prospect future research direction such as post-GWAS analyses and rare variants studies. <b><i>Key Message:</i></b> Many genetic variants were found through GWAS or candidate gene studies, and interpreting their underlying mechanisms will help us translate risk profiles generated from these variations into use in the clinical setting for targeted screening and treatment. <b><i>Practical Implications:</i></b> Investigation of the potential use of genetic variations as prognostic and predictive markers is a developing field. Many people could benefit from a better understanding of genetic polymorphisms to potentially identify a priori individuals who might have the best chance of survival and therefore derive most clinical benefit from treatment. Outcomes of particular scientific interest for molecular epidemiologic studies should include overall survival, recurrence- and progression-free survival, response to treatment, and early and late toxicities stemming from chemotherapy and radiation.
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Liu S, Wang X, Shi Y, Han L, Zhao Z, Zhao C, Luo B. Toll-like receptor gene polymorphisms and susceptibility to Epstein-Barr virus-associated and -negative gastric carcinoma in Northern China. Saudi J Gastroenterol 2015; 21:95-103. [PMID: 25843196 PMCID: PMC4392582 DOI: 10.4103/1319-3767.153832] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND/AIMS Various polymorphisms in toll-like receptor (TLR) genes have been identified and associated with susceptibility to various malignancies, such as gastric carcinoma (GC), breast cancer, and prostate cancer. However, little is known about the polymorphisms of TLR genes and the susceptibility to GC in Northern China, especially to Epstein-Barr virus-associated GC (EBVaGC). We focused on the association with susceptibility to GC, especially to EBVaGC. PATIENTS AND METHODS Polymorphisms of the TLR2, 3, 4, and 9 genes were measured in 52 cases of EBVaGC and 157 cases of EBV-negative GC (EBVnGC). Ninety-four peripheral blood samples from healthy individuals were also examined. RESULTS For the TLR2 gene (196 to 174 del), there was no significant difference between the GC group and control group in genotype, but there was a significant difference in the del allele. As for the TLR3 gene (c. 1377C/T), there were significant differences between the GC group and the control group in both genotype and allelic frequency. No SNPs single nucleotide polymorphisms (SNPs) were found in the TLR4 gene at the sites Asp299Gly and Thr399Ile. As for TLR9 1486T/C (rs187084) and C2848T (rs352140), there was also no association between the GC group and control. In all of the indicators, there were no significant differences between EBVaGCs and EBVnGCs. CONCLUSIONS The TLR3 gene (c. 1377C/T) polymorphisms and the del allele of the TLR2 gene ( 196 to 174) were both associated with susceptibility to GC in Shangdong Province of Northern China. There was no interaction between EBV and TLR gene polymorphisms in EBVaGC.
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Affiliation(s)
- Shuzhen Liu
- Department of Blood Transfusion, Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266003, China,Department of Medical Microbiology, Qingdao University Medical College, 38 Dengzhou Road, Qingdao, 266021, China
| | - Xiaofeng Wang
- Department of Medical Microbiology, Qingdao University Medical College, 38 Dengzhou Road, Qingdao, 266021, China
| | - Yuanyuan Shi
- Department of Medical Microbiology, Qingdao University Medical College, 38 Dengzhou Road, Qingdao, 266021, China
| | - Lu Han
- Department of Medical Microbiology, Qingdao University Medical College, 38 Dengzhou Road, Qingdao, 266021, China
| | - Zhenzhen Zhao
- Department of Medical Microbiology, Qingdao University Medical College, 38 Dengzhou Road, Qingdao, 266021, China
| | - Chengquan Zhao
- Department of Pathology, University of Pittsburgh Medical Center, 300 Halket Street, Pittsburgh, PA 15213, USA
| | - Bing Luo
- Department of Medical Microbiology, Qingdao University Medical College, 38 Dengzhou Road, Qingdao, 266021, China,Address for correspondence: Dr. Bing Luo, Department of Medical Microbiology, Qingdao University Medical College, 38 Dengzhou Road, Qingdao, 266021, China. E-mail:
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Zhang Y, Li Y, Li Y, Li R, Ma Y, Wang H, Wang Y. Chloroquine inhibits MGC803 gastric cancer cell migration via the Toll-like receptor 9/nuclear factor kappa B signaling pathway. Mol Med Rep 2014; 11:1366-71. [PMID: 25369757 DOI: 10.3892/mmr.2014.2839] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2014] [Accepted: 09/29/2014] [Indexed: 11/06/2022] Open
Abstract
Stimulation of Toll‑like receptor 9 (TLR9) has been associated with invasion in various types of cancer cell in vitro. The present study aimed to evaluate the expression of TLR9 in MGC803 gastric cancer cells and investigate the effect of a non‑specific TLR9 inhibitor, chloroquine (CQ), on MGC803 cell migration via the TLR9/nuclear factor kappa B (NFκB) signaling pathway. The expression of TLR9 was investigated using reverse transcription polymerase chain reaction (RT‑PCR), flow cytometry and western blot analysis. The effects of CQ on MGC803 cell proliferation were measured by MTT colorimetric assay. The mRNA expression levels of cyclooxygenase‑2 (COX‑2), matrix metalloproteinase (MMP)‑2, MMP‑7 and NFκB p65 were evaluated by RT‑PCR in MGC803 cells stimulated by various concentrations of CQ. The migration of gastric cancer cells treated with CQ at 12, 24 and 36 h was measured by wound healing assay. The results indicated that MGC803 cells expressed TLR9 and that CQ had anti‑proliferative effects on MGC803 cells and inhibited mRNA expression of COX‑2, MMP‑2, MMP‑7 and NFκB p65 (P<0.05). Furthermore, CQ inhibited the bioactivity of NFκB p65 and prevented the migration of MGC803 cells in a dose‑dependent manner (P<0.05). In conclusion, the results indicated that the TLR9/NFκB signaling pathway was involved in gastric cancer cell migration and that CQ had anti‑tumor activity.
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Affiliation(s)
- Yanli Zhang
- Department of Microbiology, College of Basic Medicine, Ningixia Medical University, Yinchuan, Ningxia 750004, P.R. China
| | - Yunhong Li
- Ningxia Key Laboratory of Cerebrocranial Diseases, Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China
| | - Yalan Li
- Department of Microbiology, College of Basic Medicine, Ningixia Medical University, Yinchuan, Ningxia 750004, P.R. China
| | - Rui Li
- Department of Microbiology, College of Basic Medicine, Ningixia Medical University, Yinchuan, Ningxia 750004, P.R. China
| | - Yajun Ma
- Department of Microbiology, College of Basic Medicine, Ningixia Medical University, Yinchuan, Ningxia 750004, P.R. China
| | - Hao Wang
- Department of Microbiology, College of Basic Medicine, Ningixia Medical University, Yinchuan, Ningxia 750004, P.R. China
| | - Yin Wang
- Ningxia Key Laboratory of Cerebrocranial Diseases, Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China
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21
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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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22
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Sandholm J, Selander KS. Toll-like receptor 9 in breast cancer. Front Immunol 2014; 5:330. [PMID: 25101078 PMCID: PMC4105583 DOI: 10.3389/fimmu.2014.00330] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2014] [Accepted: 06/30/2014] [Indexed: 12/13/2022] Open
Abstract
Toll-like receptor 9 (TLR9) is a cellular DNA receptor of the innate immune system. DNA recognition via TLR9 results in an inflammatory reaction, which eventually also activates a Th1-biased adaptive immune attack. In addition to cells of the immune system, TLR9 mRNA and protein are also widely expressed in breast cancer cell lines and in clinical breast cancer specimens. Although synthetic TLR9-ligands induce cancer cell invasion in vitro, the role of TLR9 in cancer pathophysiology has remained unclear. In the studies conducted so far, tumor TLR9 expression has been shown to have prognostic significance only in patients that have triple-negative breast cancer (TNBC). Specifically, high tumor TLR9 expression predicts good prognosis among TNBC patients. Pre-clinical studies suggest that TLR9 expression may affect tumor immunophenotype and contribute to the immunogenic benefit of chemotherapy. In this review, we discuss the possible contribution of tumor TLR9 to the pathogenesis and treatment responses in breast cancer.
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Affiliation(s)
- Jouko Sandholm
- Turku Centre for Biotechnology, University of Turku and Åbo Akademi University , Turku , Finland
| | - Katri S Selander
- Department of Pathology, Lapland Central Hospital , Rovaniemi , Finland ; Division of Hematology-Oncology, Department of Medicine, University of Alabama at Birmingham , Birmingham, AL , USA ; Comprehensive Cancer Center, University of Alabama at Birmingham , Birmingham, AL , USA
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23
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Castaño-Rodríguez N, Kaakoush NO, Pardo AL, Goh KL, Fock KM, Mitchell HM. Genetic polymorphisms in the Toll-like receptor signalling pathway in Helicobacter pylori infection and related gastric cancer. Hum Immunol 2014; 75:808-15. [PMID: 24929142 DOI: 10.1016/j.humimm.2014.06.001] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2014] [Revised: 06/03/2014] [Accepted: 06/03/2014] [Indexed: 12/28/2022]
Abstract
BACKGROUND Gastric cancer (GC) is a progressive process initiated by Helicobacter pylori-induced inflammation. Initial recognition of H. pylori involves Toll-like receptors (TLRs), central molecules in the host inflammatory response. Here, we investigated the association between novel polymorphisms in genes involved in the TLR signalling pathway, including TLR2, TLR4, LBP, MD-2, CD14 and TIRAP, and risk of H. pylori infection and related GC. METHODS A case-control study comprising 310 ethnic Chinese individuals (87 non-cardia GC cases and 223 controls with functional dyspepsia) was conducted. Twenty-five polymorphisms were detected by MALDI-TOF mass spectrometry, PCR, PCR-RFLP and real-time PCR. RESULTS Seven polymorphisms showed significant associations with GC (TLR4 rs11536889, TLR4 rs10759931, TLR4 rs1927911, TLR4 rs10116253, TLR4 rs10759932, TLR4 rs2149356 and CD14 -260 C/T). In multivariate analyses, TLR4 rs11536889 remained a risk factor for GC (OR: 3.58, 95% CI: 1.20-10.65). TLR4 rs10759932 decreased the risk of H. pylori infection (OR: 0.59, 95% CI: 0.41-0.86). Statistical analyses assessing the joint effect of H. pylori infection and the selected polymorphisms revealed strong associations with GC (TLR2, TLR4, MD-2, LBP and TIRAP polymorphisms). CONCLUSIONS Novel polymorphisms in TLR2, TLR4, MD-2, LBP, CD14 and TIRAP, genes encoding important molecules of the TLR signalling pathway, showed clear associations with H. pylori-related GC in Chinese.
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Affiliation(s)
- Natalia Castaño-Rodríguez
- School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW 2052, Australia
| | - Nadeem O Kaakoush
- School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW 2052, Australia
| | - Aryce L Pardo
- School of Statistics, National University of Colombia, Medellin, Colombia
| | - Khean-Lee Goh
- Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Kwong Ming Fock
- Division of Gastroenterology, Department of Medicine, Changi General Hospital, Singapore, Singapore
| | - Hazel M Mitchell
- School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW 2052, Australia.
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24
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Uno K, Kato K, Shimosegawa T. Novel role of toll-like receptors in Helicobacter pylori - induced gastric malignancy. World J Gastroenterol 2014; 20:5244-51. [PMID: 24833854 PMCID: PMC4017039 DOI: 10.3748/wjg.v20.i18.5244] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2013] [Revised: 12/13/2013] [Accepted: 01/06/2014] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori (H. pylori) infects the human stomach during infancy and develops into chronic active inflammation. The majority of H. pylori tend to colonize within the mucous gel layer of the stomach. The stomach lacks its own immune function, thus innate immunity as the first line of defense is vital for specific immunity against H. pylori. We review recent discoveries in the pathophysiologic roles of toll-like receptors (TLRs), mainly TLR2 and TLR4, in H. pylori-induced inflammation. In addition, the TLR pathways activated by H. pylori-induced inflammation have been shown to be closely associated not only with gastric carcinogenesis, but also with formation of the tumor microenvironment through the production of pro-inflammatory cytokines, chemokines, and reactive oxygen species. Although the correlation between single nucleotide polymorphisms of TLRs and gastric cancer risk remains unclear, a recent study demonstrated that STAT3-driven up-regulation of TLR2 might promote gastric tumorigenesis independent of inflammation. Further research on the regulation of TLRs in H. pylori-associated gastric carcinogenesis will uncover diagnostic/predictive biomarkers and therapeutic targets for gastric cancer.
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25
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Chang WJ, Du Y, Zhao X, Ma LY, Cao GW. Inflammation-related factors predicting prognosis of gastric cancer. World J Gastroenterol 2014; 20:4586-4596. [PMID: 24782611 PMCID: PMC4000495 DOI: 10.3748/wjg.v20.i16.4586] [Citation(s) in RCA: 150] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 12/24/2013] [Accepted: 01/20/2014] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC), which is mainly induced by Helicobacter pylori (H. pylori) infection, is one of the leading causes of cancer-related death in the developing world. Active inflammation initiated by H. pylori infection and maintained by inherent immune disorders promotes carcinogenesis and postoperative recurrence. However, the presence with H. pylori in tumors has been linked to a better prognosis, possibly due to the induction of antitumor immunity. Tumor infiltrations of tumor-associated macrophages, myeloid-derived suppressor cells, neutrophils, Foxp3+ regulatory T cells are correlated with poor prognosis. Tumor infiltrating CD8+ cytotoxic T lymphocytes, dendritic cells, and CD45RO T cells are generally associated with good prognosis of GC, although some subsets of these immune cells have inverse prognosis prediction values. High ratios of Foxp3+/CD4+ and Foxp3+/CD8+ in tumors are associated with a poor prognosis; whereas high Th1/Th2 ratio in tumors predicts a good prognosis. High levels of interleukin (IL)-6, IL-10, IL-32, and chemokine C-C motif ligands (CCL)7 and CCL21 in circulation, high expression of CXC chemokine receptor 4, chemokine C-C motif receptor (CCR)3, CCR4, CCR5, CCR7, hypoxia-inducible factor-1α, signal transducer activator of transcription-3, cyclooxygenase-2, and orphan nuclear receptor 4A2 in tumors are associated with an unfavorable prognosis. Increased serum levels of matrix metalloproteinases (MMP)-3, MMP-7, and MMP-11 and increased levels of MMP-9, MMP-12, and MMP-21 in tumors are consistently associated with poor survival of GC. Further emphasis should be put on the integration of these biomarkers and validation in large cohorts for personalized prediction of GC postoperative prognosis.
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26
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Marusawa H, Jenkins BJ. Inflammation and gastrointestinal cancer: an overview. Cancer Lett 2013; 345:153-6. [PMID: 23981579 DOI: 10.1016/j.canlet.2013.08.025] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2013] [Revised: 08/14/2013] [Accepted: 08/14/2013] [Indexed: 12/13/2022]
Abstract
Gastrointestinal cancers collectively rank as the most lethal cancers worldwide, and are strongly linked with chronic inflammation. Despite advances over the last decade into our understanding of the etiology of these malignancies, both from a host perspective and with respect to environmental factors, current treatment strategies comprising surgery, chemotherapy and/or radiotherapy are still associated with unacceptably poor patient survival rates. Accordingly, there is a pressing need to identify new molecular targets which can underpin the development of next-generation treatment strategies to improve patient outcomes, and serve as biomarkers for early disease detection. In this review we provide an updated discussion on the identity of such candidate molecules, with a focus on innate immune system regulators within the gastrointestinal mucosal epithelium which promote inflammation and tumorigenesis.
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Affiliation(s)
- Hiroyuki Marusawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Brendan John Jenkins
- Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia.
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