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1
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Fang Y, Fan C, Li Y, Xie H. The influence of Helicobacter pylori infection on acute coronary syndrome and lipid metabolism in the Chinese ethnicity. Front Cell Infect Microbiol 2024; 14:1437425. [PMID: 39290976 PMCID: PMC11405380 DOI: 10.3389/fcimb.2024.1437425] [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: 05/27/2024] [Accepted: 08/16/2024] [Indexed: 09/19/2024] Open
Abstract
Background Acute coronary syndrome (ACS) patients frequently present a relatively high prevalence of Helicobacter pylori (H. pylori) infection. H. pylori was previously hypothesized to induce ACS through the regulation of lipid levels. However, the risk of H. pylori-induced ACS varies significantly among different ethnic groups, and the associations between H. pylori and lipid parameters remain unclear. This study aimed to systematically assess the risk of ACS in Chinese populations with H. pylori infection while also evaluating the effects of H. pylori on lipid parameters. Materials and methods A hospital-based case-control study involving 280 participants was conducted. Immunoblotting was used for the detection and genotyping of H. pylori. The associations between H. pylori and ACS, as well as lipid parameters, were analyzed via the chi-square test and a multiple logistic regression model. Results H. pylori infection significantly increased the risk of ACS among all participants (adjusted odds ratio (OR) = 4.04, 95% confidence interval (CI): 1.76-9.25, P < 0.05), with no associations with virulence factors (cytotoxin-associated gene A (CagA) or vacuole toxin geneA (VacA)). Subgroup analysis revealed a significant increase in the risk of ACS among the elderly population aged 56-64 years with H. pylori infection. Additionally, a substantial association was observed between H. pylori and acute myocardial infarction (AMI). No significant differences were found in lipid parameters, including low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and the LDL/HDL ratio, between individuals positive and negative for H. pylori infection. Similar results were observed between the ACS group and the control group. Conclusions Our study has demonstrated for the first time that H. pylori does not significantly impact lipid metabolism but increases the risk of ACS fourfold in the Chinese population (OR = 4.04, 95% CI: 1.76-9.25). Furthermore, the virulence factors of H. pylori (CagA and VacA) may not be involved in the mechanisms by which they promote the development of ACS. This finding provides additional evidence for the association between H. pylori and ACS among different ethnic groups and refutes the biological mechanism by which H. pylori affects ACS through lipid metabolism regulation. Regular screening for H. pylori and eradication treatment in elderly individuals and those at high risk for ACS may be effective measures for reducing the incidence of ACS. Future research should include multicenter randomized controlled trials and explore host genetics and the effects of H. pylori on the gut microbiota as potential biological pathways linking H. pylori and ACS.
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Affiliation(s)
- Yizhen Fang
- Department of Clinical Laboratory, Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Department of Clinical Laboratory, Xiamen Key Laboratory of Precision Medicine for Cardiovascular Disease, Xiamen, China
| | - Chunming Fan
- Department of Clinical Laboratory, Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Department of Clinical Laboratory, Xiamen Key Laboratory of Precision Medicine for Cardiovascular Disease, Xiamen, China
| | - Yun Li
- Blood Transfusion Department, Affiliated Fuzhou First Hospital of Fujian Medical University, Fuzhou, China
| | - Huabin Xie
- Department of Clinical Laboratory, Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Department of Clinical Laboratory, Xiamen Key Laboratory of Precision Medicine for Cardiovascular Disease, Xiamen, China
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2
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Trautmann D, Suazo F, Torres K, Simón L. Antitumor Effects of Resveratrol Opposing Mechanisms of Helicobacter pylori in Gastric Cancer. Nutrients 2024; 16:2141. [PMID: 38999888 PMCID: PMC11243391 DOI: 10.3390/nu16132141] [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: 06/18/2024] [Revised: 07/02/2024] [Accepted: 07/02/2024] [Indexed: 07/14/2024] Open
Abstract
Gastric cancer is an aggressive and multifactorial disease. Helicobacter pylori (H. pylori) is identified as a significant etiological factor in gastric cancer. Although only a fraction of patients infected with H. pylori progresses to gastric cancer, bacterial infection is critical in the pathology and development of this malignancy. The pathogenic mechanisms of this bacterium involve the disruption of the gastric epithelial barrier and the induction of chronic inflammation, oxidative stress, angiogenesis and metastasis. Adherence molecules, virulence (CagA and VacA) and colonization (urease) factors are important in its pathogenicity. On the other hand, resveratrol is a natural polyphenol with anti-inflammatory and antioxidant properties. Resveratrol also inhibits cancer cell proliferation and angiogenesis, suggesting a role as a potential therapeutic agent against cancer. This review explores resveratrol as an alternative cancer treatment, particularly against H. pylori-induced gastric cancer, due to its ability to mitigate the pathogenic effects induced by bacterial infection. Resveratrol has shown efficacy in reducing the proliferation of gastric cancer cells in vitro and in vivo. Moreover, the synergistic effects of resveratrol with chemotherapy and radiotherapy underline its therapeutic potential. However, further research is needed to fully describe its efficacy and safety in treating gastric cancer.
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Affiliation(s)
- Daniela Trautmann
- Nutrition and Dietetic School, Universidad Finis Terrae, Santiago 7501015, Chile
| | - Francesca Suazo
- Nutrition and Dietetic School, Universidad Finis Terrae, Santiago 7501015, Chile
| | - Keila Torres
- Nutrition and Dietetic School, Universidad Finis Terrae, Santiago 7501015, Chile
- Department of Hematology and Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile
| | - Layla Simón
- Nutrition and Dietetic School, Universidad Finis Terrae, Santiago 7501015, Chile
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3
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Wen W, Ertas YN, Erdem A, Zhang Y. Dysregulation of autophagy in gastric carcinoma: Pathways to tumor progression and resistance to therapy. Cancer Lett 2024; 591:216857. [PMID: 38583648 DOI: 10.1016/j.canlet.2024.216857] [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: 02/06/2024] [Revised: 03/22/2024] [Accepted: 04/02/2024] [Indexed: 04/09/2024]
Abstract
The considerable death rates and lack of symptoms in early stages of gastric cancer (GC) make it a major health problem worldwide. One of the most prominent risk factors is infection with Helicobacter pylori. Many biological processes, including those linked with cell death, are disrupted in GC. The cellular "self-digestion" mechanism necessary for regular balance maintenance, autophagy, is at the center of this disturbance. Misregulation of autophagy, however, plays a role in the development of GC. In this review, we will examine how autophagy interacts with other cell death processes, such as apoptosis and ferroptosis, and how it affects the progression of GC. In addition to wonderful its role in the epithelial-mesenchymal transition, it is engaged in GC metastasis. The role of autophagy in GC in promoting drug resistance stands out. There is growing interest in modulating autophagy for GC treatment, with research focusing on natural compounds, small-molecule inhibitors, and nanoparticles. These approaches could lead to breakthroughs in GC therapy, offering new hope in the fight against this challenging disease.
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Affiliation(s)
- Wen Wen
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Liaoning Clinical Research Center for Laboratory Medicine, Shenyang, China
| | - Yavuz Nuri Ertas
- Department of Biomedical Engineering, Erciyes University, Kayseri, Turkey; ERNAM-Nanotechnology Research and Application Center, Erciyes University, Kayseri, Turkey.
| | - Ahmet Erdem
- Institute for Quantitative Health Science and Engineering (IQ), Department of Biomedical Engineering, College of Engineering and Human Medicine, Michigan State University, East Lansing, MI, 48824, USA; Department of Biomedical Engineering, Kocaeli University, Umuttepe Campus, Kocaeli, 41001 Turkey.
| | - Yao Zhang
- Department of Gynaecology, Shengjing Hospital of China Medical University, Shenyang, China.
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Guzmán J, Castillo D, González-Siccha AD, Bussalleu A, Trespalacios-Rangel AA, Lescano AG, Sauvain M. Helicobacter pylori cagA, vacA, iceA and babA Genotypes from Peruvian Patients with Gastric Intestinal Metaplasia. Cancers (Basel) 2024; 16:1476. [PMID: 38672558 PMCID: PMC11047899 DOI: 10.3390/cancers16081476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Revised: 03/10/2024] [Accepted: 03/13/2024] [Indexed: 04/28/2024] Open
Abstract
We explored the clinical-stage association of gastric intestinal metaplasia (IM) compared to cases of chronic non-atrophic gastritis (CNAG) and its relationship with virulence genotypes of Helicobacter pylori (H. pylori) clinical isolates from patients with dyspepsia in Peru. This study was cross-sectional and included 158 H. pylori clinical isolates; each isolate corresponded to a different Peruvian patient, genotyped by polymerase chain reaction to detect cagA gene and EPIYA motifs, the vacA gene (alleles s1, s2, i1, i2, d1, d2, m1, m2 and subtypes s1a, s1b and s1c), the iceA gene (alleles 1 and 2), and the babA gene (allele 2). We observed that 38.6% presented with IM and that all clinical isolates were CagA positive. The EPIYA-ABC motif was predominant (68.4%), and we observed a high frequency for the vacA gene alleles s1 (94.9%), m1 (81.7%), i1 (63.9%), and d1 (70.9%). Strains with both iceA alleles were also detected (69.6%) and 52.2% were babA2 positive. In addition, it was observed that the cagA+/vacAs1m1 (PR: 2.42, 1.14 to 5.13, p < 0.05) and cagA+/vacAs1am1 (PR: 1.67, 1.13 to 2.45, p < 0.01) genotypes were associated with IM. Our findings revealed the cagA and vacA risk genotypes predominance, and we provided clinically relevant associations between Peruvian patients with H. pylori infection and IM clinical stage.
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Affiliation(s)
- Jesús Guzmán
- Laboratorio Centinela de Helicobacter pylori, Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima 15024, Peru; (D.C.); (A.B.); (M.S.)
- Facultad de Salud Pública y Administración, Universidad Peruana Cayetano Heredia, Lima 15102, Peru;
| | - Denis Castillo
- Laboratorio Centinela de Helicobacter pylori, Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima 15024, Peru; (D.C.); (A.B.); (M.S.)
| | - Anabel D. González-Siccha
- Departamento de Bioquímica, Facultad de Farmacia y Bioquímica, Universidad Nacional de Trujillo, Trujillo 13011, Peru;
| | - Alejandro Bussalleu
- Laboratorio Centinela de Helicobacter pylori, Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima 15024, Peru; (D.C.); (A.B.); (M.S.)
| | - Alba A. Trespalacios-Rangel
- Grupo de Investigación en Enfermedades Infecciosas, Departamento de Microbiología, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá 110231, Colombia;
| | - Andres G. Lescano
- Facultad de Salud Pública y Administración, Universidad Peruana Cayetano Heredia, Lima 15102, Peru;
| | - Michel Sauvain
- Laboratorio Centinela de Helicobacter pylori, Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima 15024, Peru; (D.C.); (A.B.); (M.S.)
- UMR 152 Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Institut de Recherche pour le Développement (IRD), Université de Toulouse, CEDEX 9, 31062 Toulouse, France
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Yang XT, Niu PQ, Li XF, Sun MM, Wei W, Chen YQ, Zheng JY. Differential cytokine expression in gastric tissues highlights helicobacter pylori's role in gastritis. Sci Rep 2024; 14:7683. [PMID: 38561502 PMCID: PMC10984929 DOI: 10.1038/s41598-024-58407-x] [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: 03/27/2023] [Accepted: 03/28/2024] [Indexed: 04/04/2024] Open
Abstract
Helicobacter pylori (H. pylori), known for causing gastric inflammation, gastritis and gastric cancer, prompted our study to investigate the differential expression of cytokines in gastric tissues, which is crucial for understanding H. pylori infection and its potential progression to gastric cancer. Focusing on Il-1β, IL-6, IL-8, IL-12, IL-18, and TNF-α, we analysed gene and protein levels to differentiate between H. pylori-infected and non-infected gastritis. We utilised real-time quantitative polymerase chain reaction (RT-qPCR) for gene quantification, immunohistochemical staining, and ELISA for protein measurement. Gastric samples from patients with gastritis were divided into three groups: (1) non-gastritis (N-group) group, (2) gastritis without H. pylori infection (G-group), and (3) gastritis with H. pylori infection (GH-group), each consisting of 8 samples. Our findings revealed a statistically significant variation in cytokine expression. Generally, cytokine levels were higher in gastritis, but in H. pylori-infected gastritis, IL-1β, IL-6, and IL-8 levels were lower compared to H. pylori-independent gastritis, while IL-12, IL-18, and TNF-α levels were higher. This distinct cytokine expression pattern in H. pylori-infected gastritis underscores a unique inflammatory response, providing deeper insights into its pathogenesis.
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Affiliation(s)
- Xing-Tang Yang
- Department of Gastroenterology, Chongming Branch, Shanghai Tenth People's Hospital, Tongji University School of Medicine, No. 66 Xiangyangdong Road, Bao Town, Chongming District, Shanghai, 202157, People's Republic of China.
- Department of Emergency, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, People's Republic of China.
| | - Pei-Qin Niu
- Department of Gastroenterology, Chongming Branch, Shanghai Tenth People's Hospital, Tongji University School of Medicine, No. 66 Xiangyangdong Road, Bao Town, Chongming District, Shanghai, 202157, People's Republic of China.
| | - Xiao-Feng Li
- Department of Emergency, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, People's Republic of China
| | - Ming-Ming Sun
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, People's Republic of China
| | - Wei Wei
- Department of Emergency, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, People's Republic of China
| | - Yan-Qing Chen
- Department of Emergency, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, People's Republic of China
| | - Jia-Yi Zheng
- Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, People's Republic of China
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Xu JY, Fan JX, Hu M, Zeng J. Microorganism-regulated autophagy in gastrointestinal cancer. PeerJ 2023; 11:e16130. [PMID: 37786582 PMCID: PMC10541808 DOI: 10.7717/peerj.16130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Accepted: 08/28/2023] [Indexed: 10/04/2023] Open
Abstract
Gastrointestinal cancer has always been one of the most urgent problems to be solved, and it has become a major global health issue. Microorganisms in the gastrointestinal tract regulate normal physiological and pathological processes. Accumulating evidence reveals the role of the imbalance in the microbial community during tumorigenesis. Autophagy is an important intracellular homeostatic process, where defective proteins and organelles are degraded and recycled under stress. Autophagy plays a dual role in tumors as both tumor suppressor and tumor promoter. Many studies have shown that autophagy plays an important role in response to microbial infection. Here, we provide an overview on the regulation of the autophagy signaling pathway by microorganisms in gastrointestinal cancer.
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Affiliation(s)
- Jun-Yu Xu
- Chongqing Normal University, Chongqing, China
| | | | - Min Hu
- Chongqing Normal University, Chongqing, China
| | - Jun Zeng
- Chongqing Normal University, Chongqing, China
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Jamal Eddin TM, Nasr SM, Gupta I, Zayed H, Al Moustafa AE. Helicobacter pylori and epithelial mesenchymal transition in human gastric cancers: An update of the literature. Heliyon 2023; 9:e18945. [PMID: 37609398 PMCID: PMC10440535 DOI: 10.1016/j.heliyon.2023.e18945] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 07/25/2023] [Accepted: 08/03/2023] [Indexed: 08/24/2023] Open
Abstract
Gastric cancer, a multifactorial disease, is considered one of the most common malignancies worldwide. In addition to genetic and environmental risk factors, infectious agents, such as Epstein-Barr virus (EBV) and Helicobacter pylori (H.pylori) contribute to the onset and development of gastric cancer. H. pylori is a type I carcinogen that colonizes the gastric epithelium of approximately 50% of the world's population, thus increasing the risk of gastric cancer development. On the other hand, epithelial mesenchymal transition (EMT) is a fundamental process crucial to embryogenic growth, wound healing, organ fibrosis and cancer progression. Several studies associate gastric pathogen infection of the epithelium with EMT initiation, provoking cancer metastasis in the gastric mucosa through various molecular signaling pathways. Additionally, EMT is implicated in the progression and development of H. pylori-associated gastric cancer. In this review, we recapitulate recent findings elucidating the association between H. pylori infection in EMT promotion leading to gastric cancer progression and metastasis.
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Affiliation(s)
- Tala M. Jamal Eddin
- College of Health Sciences, QU Health, Qatar University, PO Box 2713, Doha, Qatar
| | - Shahd M.O. Nasr
- College of Health Sciences, QU Health, Qatar University, PO Box 2713, Doha, Qatar
| | - Ishita Gupta
- College of Medicine, QU Health, Qatar University, PO Box 2713, Doha, Qatar
| | - Hatem Zayed
- College of Health Sciences, QU Health, Qatar University, PO Box 2713, Doha, Qatar
| | - Ala-Eddin Al Moustafa
- College of Medicine, QU Health, Qatar University, PO Box 2713, Doha, Qatar
- Biomedical Research Center, Qatar University, PO Box 2713, Doha, Qatar
- Oncology Department, Faculty of Medicine, McGill University, Montreal, QC, H3G 2M1, Canada
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Liu W, Kong W, Hui W, Wang C, Jiang Q, Shi H, Gao F. Characteristics of different types of Helicobacter pylori: New evidence from non-amplified white light endoscopy. Front Microbiol 2023; 13:999564. [PMID: 36713187 PMCID: PMC9881747 DOI: 10.3389/fmicb.2022.999564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 12/21/2022] [Indexed: 01/15/2023] Open
Abstract
Background Different types of Helicobacter pylori (H. pylori) were analyzed to determine their infection characteristics using serology, pathology, and non-magnification white light endoscopy combined with the Kimura-Takemoto classification, and the regular arrangement of collecting venules (RAC) as well. Materials and methods A retrospective analysis of 685 inpatients who have completed the 14C-urea breath test, the H. pylori antibody typing classification, the serum gastric function tests (PGI/PGII/G-17), the endoscope detection, and the pathological examinations. Results The levels of PGI, PGII, and G-17 were in descending order from the type I H. pylori infection group to the type II H. pylori infection group than the control group (F = 14.31; 26.23; 9.12, P < 0.01). Using the Kimura-Takemoto classification, there were significant differences among the three groups of different degrees of atrophy ( χ 2 =29.81; 482.78; 292.5, P< 0.01). Based on the characteristics of RAC, the H. pylori infection rates were in descending order from the type I H. pylori infection group to the type II H. pylori infection group than the control group ( χ 2 = 200.39; 174.72; 143.51, P < 0.01). The type I H. pylori infection group had higher grades than those of the type II H. pylori infection group in the OLGA and OLGIM staging systems, while the differences are statistically significant only in the OLGA staging system ( χ 2 =10.63, P < 0.05). Conclusion With the aid of non-amplified white light endoscopy, we found new evidence of type I H. pylori infection accelerating the progression of gastric mucosal atrophy through the degree of atrophy and the range of infection, whereas type II H. pylori infection has a low ability of migration and atrophy progression. Individual virulence factor-based eradication therapy may be a better choice in future.
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Affiliation(s)
- Weidong Liu
- College of Life Science and Technology, Xinjiang University, Urumqi, China
| | - Wenjie Kong
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China,Xinjiang Clinical Research Center for Digestive Diseases, Urumqi, China
| | - Wenjia Hui
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China,Xinjiang Clinical Research Center for Digestive Diseases, Urumqi, China
| | - Chun Wang
- Department of Pathology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Qi Jiang
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China,Xinjiang Clinical Research Center for Digestive Diseases, Urumqi, China
| | - Hong Shi
- Department of Gastroenterology, ZhongShan Hospital, Fudan University, Shanghai, China
| | - Feng Gao
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China,Xinjiang Clinical Research Center for Digestive Diseases, Urumqi, China,*Correspondence: Feng Gao,
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Inflammation and Gastric Cancer. Diseases 2022; 10:diseases10030035. [PMID: 35892729 PMCID: PMC9326573 DOI: 10.3390/diseases10030035] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 06/16/2022] [Accepted: 06/19/2022] [Indexed: 11/17/2022] Open
Abstract
Gastric cancer remains a major killer globally, although its incidence has declined over the past century. It is the fifth most common cancer and the third most common reason for cancer-related deaths worldwide. Gastric cancer is the outcome of a complex interaction between environmental, host genetic, and microbial factors. There is significant evidence supporting the association between chronic inflammation and the onset of cancer. This association is particularly robust for gastrointestinal cancers in which microbial pathogens are responsible for the chronic inflammation that can be a triggering factor for the onset of those cancers. Helicobacter pylori is the most prominent example since it is the most widespread infection, affecting nearly half of the world’s population. It is well-known to be responsible for inducing chronic gastric inflammation progressing to atrophy, metaplasia, dysplasia, and eventually, gastric cancer. This review provides an overview of the association of the factors playing a role in chronic inflammation; the bacterial characteristics which are responsible for the colonization, persistence in the stomach, and triggering of inflammation; the microbiome involved in the chronic inflammation process; and the host factors that have a role in determining whether gastritis progresses to gastric cancer. Understanding these interconnections may improve our ability to prevent gastric cancer development and enhance our understanding of existing cases.
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10
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Biswas P, Pal S, Das M, Dam S. Microbe-Induced Oxidative Stress in Cancer Development and Efficacy of Probiotics as Therapeutics in Preventing Its Onset and Progression. HANDBOOK OF OXIDATIVE STRESS IN CANCER: THERAPEUTIC ASPECTS 2022:3513-3542. [DOI: 10.1007/978-981-16-5422-0_159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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11
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Koustas E, Trifylli EM, Sarantis P, Kontolatis NI, Damaskos C, Garmpis N, Vallilas C, Garmpi A, Papavassiliou AG, Karamouzis MV. The Implication of Autophagy in Gastric Cancer Progression. Life (Basel) 2021; 11:life11121304. [PMID: 34947835 PMCID: PMC8705750 DOI: 10.3390/life11121304] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 11/23/2021] [Accepted: 11/25/2021] [Indexed: 02/05/2023] Open
Abstract
Gastric cancer is the fifth most common malignancy and the third leading cause of cancer-related death worldwide. The three entirely variable entities have distinct epidemiology, molecular characteristics, prognosis, and strategies for clinical management. However, many gastric tumors appear to be resistant to current chemotherapeutic agents. Moreover, a significant number of gastric cancer patients, with a lack of optimal treatment strategies, have reduced survival. In recent years, multiple research data have highlighted the importance of autophagy, an essential catabolic process of cytoplasmic component digestion, in cancer. The role of autophagy as a tumor suppressor or tumor promoter mechanism remains controversial. The multistep nature of the autophagy process offers a wide array of targetable points for designing novel chemotherapeutic strategies. The purpose of this review is to summarize the current knowledge regarding the interplay between gastric cancer development and the autophagy process and decipher the role of autophagy in this kind of cancer. A plethora of different agents that direct or indirect target autophagy may be a novel therapeutic approach for gastric cancer patients.
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Affiliation(s)
- Evangelos Koustas
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (E.-M.T.); (P.S.); (N.I.K.); (C.V.); (A.G.P.); (M.V.K.)
- Correspondence:
| | - Eleni-Myrto Trifylli
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (E.-M.T.); (P.S.); (N.I.K.); (C.V.); (A.G.P.); (M.V.K.)
| | - Panagiotis Sarantis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (E.-M.T.); (P.S.); (N.I.K.); (C.V.); (A.G.P.); (M.V.K.)
| | - Nikolaos I. Kontolatis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (E.-M.T.); (P.S.); (N.I.K.); (C.V.); (A.G.P.); (M.V.K.)
| | - Christos Damaskos
- Renal Transplantation Unit, ‘Laiko’ General Hospital, 11527 Athens, Greece;
- ‘N.S. Christeas’ Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Nikolaos Garmpis
- ‘N.S. Christeas’ Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
- Second Department of Propedeutic Surgery, ‘Laiko’ General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Christos Vallilas
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (E.-M.T.); (P.S.); (N.I.K.); (C.V.); (A.G.P.); (M.V.K.)
| | - Anna Garmpi
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Athanasios G. Papavassiliou
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (E.-M.T.); (P.S.); (N.I.K.); (C.V.); (A.G.P.); (M.V.K.)
| | - Michalis V. Karamouzis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (E.-M.T.); (P.S.); (N.I.K.); (C.V.); (A.G.P.); (M.V.K.)
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de Brito BB, Lemos FFB, Carneiro CDM, Viana AS, Barreto NMPV, Assis GADS, Braga BDC, Santos MLC, Silva FAFD, Marques HS, Silva NOE, de Melo FF. Immune response to Helicobacter pylori infection and gastric cancer development. World J Meta-Anal 2021; 9:257-276. [DOI: 10.13105/wjma.v9.i3.257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 04/24/2021] [Accepted: 06/15/2021] [Indexed: 02/06/2023] Open
Abstract
Gastric adenocarcinoma is a global health concern, and Helicobacter pylori (H. pylori) infection is the main risk factor for its occurrence. Of note, the immune response against the pathogen seems to be a determining factor for gastric oncogenesis, and increasing evidence have emphasized several host and bacterium factors that probably influence in this setting. The development of an inflammatory process against H. pylori involves a wide range of mechanisms such as the activation of pattern recognition receptors and intracellular pathways resulting in the production of proinflammatory cytokines by gastric epithelial cells. This process culminates in the establishment of distinct immune response profiles that result from the cytokine-induced differentiation of T naïve cells into specific T helper cells. Cytokines released from each type of T helper cell orchestrate the immune system and interfere in the development of gastric cancer in idiosyncratic ways. Moreover, variants in genes such as single nucleotide polymorphisms have been associated with variable predispositions for the occurrence of gastric malignancy because they influence both the intensity of gene expression and the affinity of the resultant molecule with its receptor. In addition, various repercussions related to some H. pylori virulence factors seem to substantially influence the host immune response against the infection, and many of them have been associated with gastric tumorigenesis.
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Affiliation(s)
- Breno Bittencourt de Brito
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabian Fellipe Bueno Lemos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Caroline da Mota Carneiro
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Andressa Santos Viana
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | | | - Barbara Dicarlo Costa Braga
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Maria Luísa Cordeiro Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | - Hanna Santos Marques
- Campus Vitória da Conquista, Universidade Estadual do Sudoeste da Bahia, Vitória da Conquista 45031900, Bahia, Brazil
| | - Natália Oliveira e Silva
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
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Clauditz TS, Wallace MB, Lauwers GY. Inflammatory Disorders of the Stomach. GASTROINTESTINAL PATHOLOGY 2021:73-98. [DOI: 10.1002/9781119073048.ch4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Pereira-Marques J, Ferreira RM, Machado JC, Figueiredo C. The influence of the gastric microbiota in gastric cancer development. Best Pract Res Clin Gastroenterol 2021; 50-51:101734. [PMID: 33975676 DOI: 10.1016/j.bpg.2021.101734] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 02/12/2021] [Accepted: 02/15/2021] [Indexed: 01/31/2023]
Abstract
Colonization of the stomach by Helicobacter pylori is the trigger for a series of gastric mucosal changes that culminate in gastric cancer. Infection with this bacterium is considered the major risk factor for this malignancy. The introduction of high-throughput sequencing technologies coupled to advanced computational pipelines offered an improved understanding of the microbiome, and it is now currently accepted that, besides H. pylori, the stomach harbours a complex microbial community. While it is well established that H. pylori plays a central role in gastric carcinogenesis, the significance of the non-H. pylori microbiota is yet to be clarified. This review will address the state of the art on the relationship between the gastric microbiota and gastric cancer development, and identify areas where additional research is needed before translating microbiome research into preventive and therapeutic strategies to reduce gastric cancer burden.
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Affiliation(s)
- Joana Pereira-Marques
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal; Ipatimup - Institute of Molecular Pathology and Immunology of the University of Porto, Rua Júlio Amaral de Carvalho 45, 4200-135, Porto, Portugal.
| | - Rui M Ferreira
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal; Ipatimup - Institute of Molecular Pathology and Immunology of the University of Porto, Rua Júlio Amaral de Carvalho 45, 4200-135, Porto, Portugal.
| | - Jose C Machado
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal; Ipatimup - Institute of Molecular Pathology and Immunology of the University of Porto, Rua Júlio Amaral de Carvalho 45, 4200-135, Porto, Portugal; Department of Pathology, Faculty of Medicine of the University of Porto, Alameda Prof. Hernâni Monteiro, 4200 - 319, Porto, Portugal.
| | - Ceu Figueiredo
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal; Ipatimup - Institute of Molecular Pathology and Immunology of the University of Porto, Rua Júlio Amaral de Carvalho 45, 4200-135, Porto, Portugal; Department of Pathology, Faculty of Medicine of the University of Porto, Alameda Prof. Hernâni Monteiro, 4200 - 319, Porto, Portugal.
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Soyfoo DM, Doomah YH, Xu D, Zhang C, Sang HM, Liu YY, Zhang GX, Jiang JX, Xu SF. New genotypes of Helicobacter Pylori VacA d-region identified from global strains. BMC Mol Cell Biol 2021; 22:4. [PMID: 33413074 PMCID: PMC7791883 DOI: 10.1186/s12860-020-00338-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Accepted: 12/16/2020] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Pathogenesis of Helicobacter Pylori (HP) vacuolating toxin A (vacA) depends on polymorphic diversity within the signal (s), middle (m), intermediate (i), deletion (d) and c-regions. These regions show distinct allelic diversity. The s-region, m-region and the c-region (a 15 bp deletion at the 3'-end region of the p55 domain of the vacA gene) exist as 2 types (s1, s2, m1, m2, c1 and c2), while the i-region has 3 allelic types (i1, i2 and i3). The locus of d-region of the vacA gene has also been classified into 2 genotypes, namely d1 and d2. We investigated the "d-region"/"loop region" through bioinformatics, to predict its properties and relation to disease. One thousand two hundred fifty-nine strains from the NCBI nucleotide database and the dryad database with complete vacA sequences were included in the study. The sequences were aligned using BioEdit and analyzed using Lasergene and BLAST. The secondary structure and physicochemical properties of the region were predicted using PredictProtein. RESULTS We identified 31 highly polymorphic genotypes in the "d-region", with a mean length of 34 amino acids (9 ~ 55 amino acids). We further classified the 31 genotypes into 3 main types, namely K-type (strains starting with the KDKP motif in the "d-region"), Q-type (strains starting with the KNQT motif), and E-type (strains starting with the ESKT motif) respectively. The most common type, K-type, is more prevalent in cancer patients (80.87%) and is associated with the s1i1m1c1 genotypes (P < .01). Incidentally, a new region expressing sequence diversity (2 aa deletion) at the C-terminus of the p55 domain of vacA was identified during bioinformatics analysis. CONCLUSIONS Prediction of secondary structures shows that the "d-region" adopts a loop conformation and is a disordered region.
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Affiliation(s)
- Djaleel Muhammad Soyfoo
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yussriya Hanaa Doomah
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Dong Xu
- Department of Electrical Engineering and Computer Science, Bond Life Sciences Center, University of Missouri, Columbia, MO, USA
| | - Chao Zhang
- Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, 10021, USA.,Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY, 10021, USA
| | - Huai-Ming Sang
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yan-Yan Liu
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Guo-Xin Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jian-Xia Jiang
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
| | - Shun-Fu Xu
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
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Baj J, Forma A, Sitarz M, Portincasa P, Garruti G, Krasowska D, Maciejewski R. Helicobacter pylori Virulence Factors-Mechanisms of Bacterial Pathogenicity in the Gastric Microenvironment. Cells 2020; 10:E27. [PMID: 33375694 PMCID: PMC7824444 DOI: 10.3390/cells10010027] [Citation(s) in RCA: 183] [Impact Index Per Article: 36.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 12/18/2020] [Accepted: 12/22/2020] [Indexed: 12/11/2022] Open
Abstract
Gastric cancer constitutes one of the most prevalent malignancies in both sexes; it is currently the fourth major cause of cancer-related deaths worldwide. The pathogenesis of gastric cancer is associated with the interaction between genetic and environmental factors, among which infection by Helicobacter pylori (H. pylori) is of major importance. The invasion, survival, colonization, and stimulation of further inflammation within the gastric mucosa are possible due to several evasive mechanisms induced by the virulence factors that are expressed by the bacterium. The knowledge concerning the mechanisms of H. pylori pathogenicity is crucial to ameliorate eradication strategies preventing the possible induction of carcinogenesis. This review highlights the current state of knowledge and the most recent findings regarding H. pylori virulence factors and their relationship with gastric premalignant lesions and further carcinogenesis.
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Affiliation(s)
- Jacek Baj
- Department of Anatomy, Medical University of Lublin, 20-400 Lublin, Poland;
| | - Alicja Forma
- Chair and Department of Forensic Medicine, Medical University of Lublin, 20-090 Lublin, Poland;
| | - Monika Sitarz
- Department of Conservative Dentistry with Endodontics, Medical University of Lublin, 20-090 Lublin, Poland;
| | - Piero Portincasa
- Clinica Medica “Augusto Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro”, 70124 Bari, Italy;
| | - Gabriella Garruti
- Section of Endocrinology, Department of Emergency and Organ Transplantations, University of Bari “Aldo Moro” Medical School, Piazza G. Cesare 11, 70124 Bari, Italy;
| | - Danuta Krasowska
- Department of Dermatology, Venerology and Paediatric Dermatology of Medical University of Lublin, 20-081 Lublin, Poland;
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Gullo I, Grillo F, Mastracci L, Vanoli A, Carneiro F, Saragoni L, Limarzi F, Ferro J, Parente P, Fassan M. Precancerous lesions of the stomach, gastric cancer and hereditary gastric cancer syndromes. Pathologica 2020; 112:166-185. [PMID: 33179620 PMCID: PMC7931572 DOI: 10.32074/1591-951x-166] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 06/30/2020] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer accounts for about 6% of cancers worldwide, being the fifth most frequently diagnosed malignancy and the third leading cause of cancer related death. Gastric carcinogenesis is a multistep and multifactorial process and is the result of the complex interplay between genetic susceptibility and environmental factors. The identification of predisposing conditions and of precancerous lesions is the basis for screening programs and early stage treatment. Furthermore, although most gastric cancers are sporadic, familial clustering is observed in up to 10% of patients. Among them, hereditary cases, related to known cancer susceptibility syndromes and/or genetic causes are thought to account for 1-3% of all gastric cancers. The pathology report of gastric resections specimens therefore requires a standardized approach as well as in depth knowledge of prognostic and treatment associated factors.
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Affiliation(s)
- Irene Gullo
- Department of Pathology, Centro Hospitalar Universitário de São João (CHUSJ) & Department of Pathology, Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal and Instituto de Investigação e Inovação em Saúde (i3S) & Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Portugal
| | - Federica Grillo
- Correspondence Federica Grillo Anatomic Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics (DICS), University of Genova and Ospedale Policlinico San Martino, IRCCS for Oncology and Neuroscience, Genova, Italy, largo Rosanna Benzi 10, 16132 Genova, Italy Tel. +39 010 5555957 Fax: +39 010 5556392 E-mail:
| | | | - Alessandro Vanoli
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Fatima Carneiro
- Department of Pathology, Centro Hospitalar Universitário de São João (CHUSJ) & Department of Pathology, Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal and Instituto de Investigação e Inovação em Saúde (i3S) & Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Portugal
| | - Luca Saragoni
- UO Anatomia Patologica, Ospedale G.B. Morgagni-L. Pierantoni, Forlì, Italy
| | - Francesco Limarzi
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST/IRCCS), Meldola (FC), Italy
| | - Jacopo Ferro
- Anatomic Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics (DICS), University of Genova, Italy
| | - Paola Parente
- Pathology Unit, Fondazione IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG) Italy
| | - Matteo Fassan
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, Italy
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18
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Functional Properties of Helicobacter pylori VacA Toxin m1 and m2 Variants. Infect Immun 2020; 88:IAI.00032-20. [PMID: 32284370 DOI: 10.1128/iai.00032-20] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 04/05/2020] [Indexed: 12/14/2022] Open
Abstract
Helicobacter pylori colonizes the gastric mucosa and secretes a pore-forming toxin (VacA). Two main types of VacA, m1 and m2, can be distinguished by phylogenetic analysis. Type m1 forms of VacA have been extensively studied, but there has been relatively little study of m2 forms. In this study, we generated H. pylori strains producing chimeric proteins in which VacA m1 segments of a parental strain were replaced by corresponding m2 sequences. In comparison to the parental m1 VacA protein, a chimeric protein (designated m2/m1) containing m2 sequences in the N-terminal portion of the m region was less potent in causing vacuolation of HeLa cells, AGS gastric cells, and AZ-521 duodenal cells and had reduced capacity to cause membrane depolarization or death of AZ-521 cells. Consistent with the observed differences in activity, the chimeric m2/m1 VacA protein bound to cells at reduced levels compared to the binding levels of the parental m1 protein. The presence of two strain-specific insertions or deletions within or adjacent to the m region did not influence toxin activity. Experiments with human gastric organoids grown as monolayers indicated that m1 and m2/m1 forms of VacA had similar cell-vacuolating activities. Interestingly, both forms of VacA bound preferentially to the basolateral surface of organoid monolayers and caused increased cell vacuolation when interacting with the basolateral surface compared to the apical surface. These data provide insights into functional correlates of sequence variation in the VacA midregion (m region).
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19
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Mechanisms of the Epithelial-Mesenchymal Transition and Tumor Microenvironment in Helicobacter pylori-Induced Gastric Cancer. Cells 2020; 9:cells9041055. [PMID: 32340207 PMCID: PMC7225971 DOI: 10.3390/cells9041055] [Citation(s) in RCA: 105] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 04/16/2020] [Accepted: 04/17/2020] [Indexed: 12/11/2022] Open
Abstract
Helicobacter pylori (H. pylori) is one of the most common human pathogens, affecting half of the world’s population. Approximately 20% of the infected patients develop gastric ulcers or neoplastic changes in the gastric stroma. An infection also leads to the progression of epithelial–mesenchymal transition within gastric tissue, increasing the probability of gastric cancer development. This paper aims to review the role of H. pylori and its virulence factors in epithelial–mesenchymal transition associated with malignant transformation within the gastric stroma. The reviewed factors included: CagA (cytotoxin-associated gene A) along with induction of cancer stem-cell properties and interaction with YAP (Yes-associated protein pathway), tumor necrosis factor α-inducing protein, Lpp20 lipoprotein, Afadin protein, penicillin-binding protein 1A, microRNA-29a-3p, programmed cell death protein 4, lysosomal-associated protein transmembrane 4β, cancer-associated fibroblasts, heparin-binding epidermal growth factor (HB-EGF), matrix metalloproteinase-7 (MMP-7), and cancer stem cells (CSCs). The review summarizes the most recent findings, providing insight into potential molecular targets and new treatment strategies for gastric cancer.
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20
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Marques V, Cunha B, Couto A, Sampaio P, Fonseca LP, Aleixo S, Calado CRC. Characterization of gastric cells infection by diverse Helicobacter pylori strains through Fourier-transform infrared spectroscopy. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2019; 210:193-202. [PMID: 30453195 DOI: 10.1016/j.saa.2018.11.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 10/29/2018] [Accepted: 11/02/2018] [Indexed: 06/09/2023]
Abstract
The infection of Helicobacter pylori, covering 50% of the world-population, leads to diverse gastric diseases as ulcers and cancer along the life-time of the human host. To promote the discovery of biomarkers of bacterial infection, in the present work, Fourier-transform infrared spectra were acquired from adenocarcinoma gastric cells, incubated with H. pylori strains presenting different genotypes concerning the virulent factors cytotoxin associated gene A and vacuolating cytotoxin A. Defined absorbance ratios were evaluated by diverse methods of statistical inference, according to the fulfillment of the tests assumptions. It was possible to define from the gastric cells, diverse absorbance ratios enabling to discriminate: i) The infection; ii) the bacteria genotype; and iii) the gastric disease of the patients from which the bacteria were isolated. These biomarkers could fasten the knowledge of the complex infection process while promoting a platform for a new diagnostic method, rapid but also specific and sensitive towards the diagnosis of both infection and bacterial virulence.
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Affiliation(s)
- Vanda Marques
- ISEL-Instituto Superior de Engenharia de Lisboa, Instituto Politécnico de Lisboa, Rua Conselheiro Emídio Navarro 1, 1959-007 Lisboa, Portugal
| | - Bernardo Cunha
- ISEL-Instituto Superior de Engenharia de Lisboa, Instituto Politécnico de Lisboa, Rua Conselheiro Emídio Navarro 1, 1959-007 Lisboa, Portugal; IBB-Institute for Biotechnology and Bioengineering, Centre for Biological and Chemical Engineering, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
| | - Andreia Couto
- ISEL-Instituto Superior de Engenharia de Lisboa, Instituto Politécnico de Lisboa, Rua Conselheiro Emídio Navarro 1, 1959-007 Lisboa, Portugal
| | - Pedro Sampaio
- Faculty of Engineering, Lusophone University of Humanities and Technology, Campo Grande, 376, 1749-019 Lisbon, Portugal
| | - Luís P Fonseca
- IBB-Institute for Biotechnology and Bioengineering, Centre for Biological and Chemical Engineering, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
| | - Sandra Aleixo
- ISEL-Instituto Superior de Engenharia de Lisboa, Instituto Politécnico de Lisboa, Rua Conselheiro Emídio Navarro 1, 1959-007 Lisboa, Portugal; Centro de Estatística e Aplicações, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal
| | - Cecília R C Calado
- ISEL-Instituto Superior de Engenharia de Lisboa, Instituto Politécnico de Lisboa, Rua Conselheiro Emídio Navarro 1, 1959-007 Lisboa, Portugal.
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21
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Pereira-Marques J, Ferreira RM, Pinto-Ribeiro I, Figueiredo C. Helicobacter pylori Infection, the Gastric Microbiome and Gastric Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1149:195-210. [PMID: 31016631 DOI: 10.1007/5584_2019_366] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
After a long period during which the stomach was considered as an organ where microorganisms could not thrive, Helicobacter pylori was isolated in vitro from gastric biopsies, revolutionising the fields of Microbiology and Gastroenterology. Since then, and with the introduction of high-throughput sequencing technologies that allowed deep characterization of microbial communities, a growing body of knowledge has shown that the stomach contains a diverse microbial community, which is different from that of the oral cavity and of the intestine. Gastric cancer is a heterogeneous disease that is the end result of a cascade of events arising in a small fraction of patients colonized with H. pylori. In addition to H. pylori infection and to multiple host and environmental factors that influence disease development, alterations to the composition and function of the normal gastric microbiome, also known as dysbiosis, may also contribute to malignancy. Chronic inflammation of the mucosa in response to H. pylori may alter the gastric environment, paving the way to the growth of a dysbiotic gastric bacterial community. This dysbiotic microbiome may promote the development of gastric cancer by sustaining inflammation and/or inducing genotoxicity. This chapter summarizes what is known about the gastric microbiome in the context of H. pylori-associated gastric cancer, introducing the emerging dimension of the microbiome into the pathogenesis of this highly incident and deadly disease.
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Affiliation(s)
- Joana Pereira-Marques
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- Ipatimup - Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
- ICBAS - Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal
| | - Rui M Ferreira
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- Ipatimup - Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
| | - Ines Pinto-Ribeiro
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- Ipatimup - Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
- Faculty of Medicine, University of Porto, Porto, Portugal
| | - Ceu Figueiredo
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
- Ipatimup - Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal.
- Faculty of Medicine, University of Porto, Porto, Portugal.
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Butt J, Varga MG, Blot WJ, Teras L, Visvanathan K, Le Marchand L, Haiman C, Chen Y, Bao Y, Sesso HD, Wassertheil-Smoller S, Ho GY, Tinker LE, Peek RM, Potter JD, Cover TL, Hendrix LH, Huang LC, Hyslop T, Um C, Grodstein F, Song M, Zeleniuch-Jacquotte A, Berndt S, Hildesheim A, Waterboer T, Pawlita M, Epplein M. Serologic Response to Helicobacter pylori Proteins Associated With Risk of Colorectal Cancer Among Diverse Populations in the United States. Gastroenterology 2019; 156:175-186.e2. [PMID: 30296434 PMCID: PMC6309494 DOI: 10.1053/j.gastro.2018.09.054] [Citation(s) in RCA: 85] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Revised: 09/12/2018] [Accepted: 09/27/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Previous studies reported an association of the bacteria Helicobacter pylori, the primary cause of gastric cancer, and risk of colorectal cancer (CRC). However, these findings have been inconsistent, appear to vary with population characteristics, and may be specific for virulence factor VacA. To more thoroughly evaluate the potential association of H pylori antibodies with CRC risk, we assembled a large consortium of cohorts representing diverse populations in the United States. METHODS We used H pylori multiplex serologic assays to analyze serum samples from 4063 incident cases of CRC, collected before diagnosis, and 4063 matched individuals without CRC (controls) from 10 prospective cohorts for antibody responses to 13 H pylori proteins, including virulence factors VacA and CagA. The association of seropositivity to H pylori proteins, as well as protein-specific antibody level, with odds of CRC was determined by conditional logistic regression. RESULTS Overall, 40% of controls and 41% of cases were H pylori-seropositive (odds ratio [OR], 1.09; 95% CI, 0.99-1.20). H pylori VacA-specific seropositivity was associated with an 11% increased odds of CRC (OR, 1.11; 95% CI, 1.01-1.22), and this association was particularly strong among African Americans (OR, 1.45; 95% CI, 1.08-1.95). Additionally, odds of CRC increased with level of VacA antibody in the overall cohort (P = .008) and specifically among African Americans (P = .007). CONCLUSIONS In an analysis of a large consortium of cohorts representing diverse populations, we found serologic responses to H pylori VacA to associate with increased risk of CRC risk, particularly for African Americans. Future studies should seek to understand whether this marker is related to virulent H pylori strains carried in these populations.
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Affiliation(s)
- Julia Butt
- Infection and Cancer Epidemiology, Division of Molecular Diagnostics of Oncogenic Infections, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany (; ; )
- Cancer Control and Population Sciences Program, Duke Cancer Institute, and Department of Population Health Sciences, Duke University, 2424 Erwin Road, Suite 602, Durham, NC 27705, USA ()
| | - Matthew G. Varga
- University of North Carolina at Chapel Hill, Department of Epidemiology, Gillings School for Global Public Health and Lineberger Comprehensive Cancer Center, 2102E McGavran Greenberg Hall, Chapel Hill, NC 27599, USA ()
| | - William J. Blot
- Division of Epidemiology, Vanderbilt University Medical Center, 2525 West End Avenue Nashville, TN 37203, USA ()
| | - Lauren Teras
- Behavioral and Epidemiology Research Group, American Cancer Society, 250 Williams St, Atlanta, GA 30303, USA (; )
| | - Kala Visvanathan
- Department of Epidemiology, Johns Hopkins School of Public Health, 615 N. Wolfe Street, Baltimore, MD 21205 USA ()
| | - Loïc Le Marchand
- Epidemiology Program, University of Hawai’i Cancer Center, 701 Ilalo Street, Honolulu, HI 96813 USA ()
| | - Christopher Haiman
- University of Southern California and USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA ()
| | - Yu Chen
- Department of Population Health, New York University School of Medicine, 650 First Avenue, New York, NY 10016 USA (; )
| | - Ying Bao
- Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115 USA (; )
| | - Howard D. Sesso
- Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115 USA (; )
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, 667 Huntington Avenue, Boston, MA 02115 USA (; )
| | - Sylvia Wassertheil-Smoller
- Department of Epidemiology & Population Health, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461 USA ()
| | - Gloria Y.F. Ho
- Department of Occupational Medicine, Epidemiology and Prevention, Feinstein Institute for Medical Research, Northwell Health; Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Great Neck, NY 11021 USA ()
| | - Lesley E. Tinker
- Cancer Prevention Program, Division of Public Health Sciences at Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue, Seattle, WA 98109 USA ()
| | - Richard M. Peek
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, 2215 Garland Avenue, 1030C MRB IV (1025C), Nashville, TN 37232 USA, ()
| | - John D. Potter
- Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue, Seattle WA 98109 USA ()
| | - Timothy L. Cover
- Department of Medicine and Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232 USA; Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN USA ()
| | - Laura H. Hendrix
- Department of Biostatistics and Bioinformatics, Duke University, 2424 Erwin Road, Durham, NC 27705 USA (; )
| | - Li-Ching Huang
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN 37203 USA ()
| | - Terry Hyslop
- Cancer Control and Population Sciences Program, Duke Cancer Institute, and Department of Population Health Sciences, Duke University, 2424 Erwin Road, Suite 602, Durham, NC 27705, USA ()
- Department of Biostatistics and Bioinformatics, Duke University, 2424 Erwin Road, Durham, NC 27705 USA (; )
| | - Caroline Um
- Behavioral and Epidemiology Research Group, American Cancer Society, 250 Williams St, Atlanta, GA 30303, USA (; )
| | - Francine Grodstein
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, 667 Huntington Avenue, Boston, MA 02115 USA (; )
| | - Mingyang Song
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, 667 Huntington Avenue, Boston, MA 02115 USA (; )
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA 02115 USA ()
- Clinical and Translational Epidemiology Unit and Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02115 USA, ()
| | - Anne Zeleniuch-Jacquotte
- Department of Population Health, New York University School of Medicine, 650 First Avenue, New York, NY 10016 USA (; )
| | - Sonja Berndt
- Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Room SG/6E102, Rockville, MD 20850 USA (; )
| | - Allan Hildesheim
- Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Room SG/6E102, Rockville, MD 20850 USA (; )
| | - Tim Waterboer
- Infection and Cancer Epidemiology, Division of Molecular Diagnostics of Oncogenic Infections, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany (; ; )
| | - Michael Pawlita
- Infection and Cancer Epidemiology, Division of Molecular Diagnostics of Oncogenic Infections, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany (; ; )
| | - Meira Epplein
- Cancer Control and Population Sciences Program, Duke Cancer Institute, and Department of Population Health Sciences, Duke University, 2424 Erwin Road, Suite 602, Durham, NC 27705, USA ()
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Cao Y, Luo Y, Zou J, Ouyang J, Cai Z, Zeng X, Ling H, Zeng T. Autophagy and its role in gastric cancer. Clin Chim Acta 2018; 489:10-20. [PMID: 30472237 DOI: 10.1016/j.cca.2018.11.028] [Citation(s) in RCA: 103] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 11/17/2018] [Accepted: 11/20/2018] [Indexed: 02/08/2023]
Abstract
Autophagy, which is tightly regulated by a series of autophagy-related genes (ATGs), is a vital intracellular homeostatic process through which defective proteins and organelles are degraded and recycled under starvation, hypoxia or other specific cellular stress conditions. For both normal cells and tumour cells, autophagy not only sustains cell survival but can also promote cell death. Autophagy-related signalling pathways include mTOR-dependent pathways, such as the AMPK/mTOR and PI3K/Akt/mTOR pathways, and non-mTOR dependent pathways, such as the P53 pathway. Additionally, autophagy plays a dual role in gastric carcinoma (GC), including a tumour-suppressor role and a tumour-promoter role. Long-term Helicobacter pylori infection can impair autophagy, which may eventually promote tumourigenesis of the gastric mucosa. Moreover, Beclin1, LC3 and P62/SQSTM1 are regarded as autophagy-related markers with GC prognostic value. Autophagy inhibitors and autophagy inducers show promise for GC treatment. This review describes research progress regarding autophagy and its significant role in gastric cancer.
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Affiliation(s)
- Yijing Cao
- Key Laboratory of Tumor Cellular & Molecular Pathology (University of South China), College of Hunan Province, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, PR China; Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study [Hunan Provincial Education Department document (Approval number: 2014-405)], Hengyang, Hunan 421001, PR China
| | - Yichen Luo
- Key Laboratory of Tumor Cellular & Molecular Pathology (University of South China), College of Hunan Province, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, PR China; Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study [Hunan Provincial Education Department document (Approval number: 2014-405)], Hengyang, Hunan 421001, PR China
| | - Juan Zou
- Key Laboratory of Tumor Cellular & Molecular Pathology (University of South China), College of Hunan Province, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, PR China; Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study [Hunan Provincial Education Department document (Approval number: 2014-405)], Hengyang, Hunan 421001, PR China
| | - Jun Ouyang
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, PR China
| | - Zhihong Cai
- Key Laboratory of Tumor Cellular & Molecular Pathology (University of South China), College of Hunan Province, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, PR China; Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study [Hunan Provincial Education Department document (Approval number: 2014-405)], Hengyang, Hunan 421001, PR China
| | - Xi Zeng
- Key Laboratory of Tumor Cellular & Molecular Pathology (University of South China), College of Hunan Province, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, PR China; Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study [Hunan Provincial Education Department document (Approval number: 2014-405)], Hengyang, Hunan 421001, PR China
| | - Hui Ling
- Key Laboratory of Tumor Cellular & Molecular Pathology (University of South China), College of Hunan Province, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, PR China; Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study [Hunan Provincial Education Department document (Approval number: 2014-405)], Hengyang, Hunan 421001, PR China.
| | - Tiebing Zeng
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study [Hunan Provincial Education Department document (Approval number: 2014-405)], Hengyang, Hunan 421001, PR China; Institute of Pathogenic Biology, Key Laboratory of Special Pathogen Prevention and Control of Hunan Province, University of South China, Hengyang, Hunan 421001, PR China.
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Structural Analysis of Variability and Interaction of the N-terminal of the Oncogenic Effector CagA of Helicobacter pylori with Phosphatidylserine. Int J Mol Sci 2018; 19:ijms19103273. [PMID: 30360352 PMCID: PMC6214045 DOI: 10.3390/ijms19103273] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Revised: 09/13/2018] [Accepted: 09/14/2018] [Indexed: 01/01/2023] Open
Abstract
Helicobacter pylori cytotoxin-associated gene A protein (CagA) has been associated with the increase in virulence and risk of cancer. It has been demonstrated that CagA’s translocation is dependent on its interaction with phosphatidylserine. We evaluated the variability of the N-terminal CagA in 127 sequences reported in NCBI, by referring to molecular interaction forces with the phosphatidylserine and the docking of three mutations chosen from variations in specific positions. The major sites of conservation of the residues involved in CagA–Phosphatidylserine interaction were 617, 621 and 626 which had no amino acid variation. Position 636 had the lowest conservation score; mutations in this position were evaluated to observe the differences in intermolecular forces for the CagA–Phosphatidylserine complex. We evaluated the docking of three mutations: K636A, K636R and K636N. The crystal and mutation models presented a ΔG of −8.919907, −8.665261, −8.701923, −8.515097 Kcal/mol, respectively, while mutations K636A, K636R, K636N and the crystal structure presented 0, 3, 4 and 1 H-bonds, respectively. Likewise, the bulk effect of the ΔG and amount of H-bonds was estimated in all of the docking models. The type of mutation affected both the ΔG (χ2(1)=93.82, p-value <2.2×10−16) and the H-bonds (χ2(1)=91.93, p-value <2.2×10−16). Overall, 76.9% of the strains that exhibit the K636N mutation produced a severe pathology. The average H-bond count diminished when comparing the mutations with the crystal structure of all the docking models, which means that other molecular forces are involved in the CagA–Phosphatidylserine complex interaction.
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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] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Revised: 07/03/2018] [Accepted: 07/11/2018] [Indexed: 01/05/2023]
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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Inhibition of the CCL5/CCR5 Axis against the Progression of Gastric Cancer. Int J Mol Sci 2018; 19:ijms19051477. [PMID: 29772686 PMCID: PMC5983686 DOI: 10.3390/ijms19051477] [Citation(s) in RCA: 106] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Revised: 05/11/2018] [Accepted: 05/14/2018] [Indexed: 12/14/2022] Open
Abstract
Despite the progress made in molecular and clinical research, patients with advanced-stage gastric cancer (GC) have a bad prognosis and very low survival rates. Furthermore, it is challenging to find the complex molecular mechanisms that are involved in the development of GC, its progression, and its resistance to therapy. The interactions of chemokines, also known as chemotactic cytokines, with their receptors regulate immune and inflammatory responses. However, updated research demonstrates that cancer cells subvert the normal chemokine role, transforming them into fundamental constituents of the tumor microenvironment (TME) with tumor-promoting effects. C-C chemokine ligand 5 (CCL5) is a chemotactic cytokine, and its expression and secretion are regulated in T cells. C-C chemokine receptor type 5 (CCR5) is expressed in T cells, macrophages, other leukocytes, and certain types of cancer cells. The interaction between CCL5 and CCR5 plays an active role in recruiting leukocytes into target sites. This review summarizes recent information on the role of the CCL5 chemokine and its receptor CCR5 in GC cell proliferation, metastasis formation, and in the building of an immunosuppressive TME. Moreover, it highlights the development of new therapeutic strategies to inhibit the CCL5/CCR5 axis in different ways and their possible clinical relevance in the treatment of GC.
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27
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Raju GSR, Pavitra E, Merchant N, Lee H, Prasad GLV, Nagaraju GP, Huh YS, Han YK. Targeting autophagy in gastrointestinal malignancy by using nanomaterials as drug delivery systems. Cancer Lett 2018; 419:222-232. [DOI: 10.1016/j.canlet.2018.01.044] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Revised: 01/12/2018] [Accepted: 01/12/2018] [Indexed: 02/06/2023]
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Ruíz-García E, Guadarrama-Orozco J, Vidal-Millán S, Lino-Silva LS, López-Camarillo C, Astudillo-de la Vega H. Gastric cancer in Latin America. Scand J Gastroenterol 2018; 53:124-129. [PMID: 29275643 DOI: 10.1080/00365521.2017.1417473] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Every year, cancer affects more than one million Latin Americans. The increasing incidence of cancer could be secondary to an aging population, westernization of life style, and urbanization. LA has among the highest incidence rates of gastric cancer, compared to other countries. In this review, different studies on gastric cancer and its relation with risks factors, such as infections, diet and life styles typical of LA, besides the different molecular alterations of that specific population (mainly at a genetic polymorphism level) are analyzed. An exhaustive research was made in PubMed, MEDLINE and Embase of the most relevant studies conducted in the last 27 years (1990-2017) in LA.
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Affiliation(s)
- Erika Ruíz-García
- a Laboratorio de Medicina Traslacional , Instituto Nacional de Cancerología , Ciudad de México , México.,b Departamento de Tumores Gastro-Intestinales , Instituto Nacional de Cancerología , Ciudad de México , México
| | - Jorge Guadarrama-Orozco
- a Laboratorio de Medicina Traslacional , Instituto Nacional de Cancerología , Ciudad de México , México
| | - Silvia Vidal-Millán
- c Laboratorio de Diagnóstico Molecular , Instituto Nacional de Cancerología , Ciudad de México , México
| | - Leonardo S Lino-Silva
- d Departamento de Patología , Instituto Nacional de Cancerología , Ciudad de México , México
| | - César López-Camarillo
- e Posgrado en Ciencias Genómicas , Universidad Autónoma de la Ciudad de México , Ciudad de México , México
| | - Horacio Astudillo-de la Vega
- f Laboratorio de Investigación Traslacional en Cáncer y Terapia Celular , Centro Médico Siglo XXI, IMSS , Ciudad de México , México
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30
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Rugge M, Genta RM, Di Mario F, El-Omar EM, El-Serag HB, Fassan M, Hunt RH, Kuipers EJ, Malfertheiner P, Sugano K, Graham DY. Gastric Cancer as Preventable Disease. Clin Gastroenterol Hepatol 2017; 15:1833-1843. [PMID: 28532700 DOI: 10.1016/j.cgh.2017.05.023] [Citation(s) in RCA: 135] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Revised: 04/26/2017] [Accepted: 05/16/2017] [Indexed: 02/07/2023]
Abstract
Gastric cancer, 1 of the 5 most common causes of cancer death, is associated with a 5-year overall survival rate less than 30%. A minority of cancers occurs as part of syndromic diseases; more than 90% of adenocarcinomas are considered as the ultimate consequence of a longstanding mucosal inflammation. Helicobacter pylori infection is the leading etiology of non-self-limiting gastritis, which may result in atrophy of the gastric mucosa and impaired acid secretion. Gastric atrophy establishes a field of cancerization prone to further molecular and phenotypic changes, possibly resulting in cancer growth. This well-understood natural history provides the clinicopathologic rationale for primary and secondary cancer prevention strategies. A large body of evidence demonstrates that combined primary (H pylori eradication) and secondary (mainly endoscopy) prevention efforts may prevent or limit the progression of gastric oncogenesis. This approach, which is tailored to different country-specific gastric cancer incidence, socioeconomic, and cultural factors, requires that the complementary competences of gastroenterologists, oncologists, and pathologists be amalgamated into a common strategy of health policy.
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Affiliation(s)
- Massimo Rugge
- Department of Medicine (DIMED), University of Padua, Padua, Italy; Veneto Tumor Registry, Veneto Region, Padua, Italy.
| | - Robert M Genta
- Miraca Life Sciences Research Institute, Irving, and Departments of Pathology and Medicine, Baylor College of Medicine, Houston, Texas
| | - Francesco Di Mario
- Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy
| | - Emad M El-Omar
- St George and Sutherland Clinical School, University of New South Wales, Sydney, Australia
| | - Hashem B El-Serag
- Department of Medicine, Michael E. DeBakey VA Medical Center, Baylor College of Medicine, Houston, Texas
| | - Matteo Fassan
- Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Richard H Hunt
- Division of Gastroenterology, Department of Medicine and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Canada
| | - Ernst J Kuipers
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | | | - Kentaro Sugano
- Department of Medicine, Jichi Medical University, Tochigi, Japan
| | - David Y Graham
- Department of Medicine, Michael E. DeBakey VA Medical Center, Baylor College of Medicine, Houston, Texas
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31
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McClain MS, Beckett AC, Cover TL. Helicobacter pylori Vacuolating Toxin and Gastric Cancer. Toxins (Basel) 2017; 9:toxins9100316. [PMID: 29023421 PMCID: PMC5666363 DOI: 10.3390/toxins9100316] [Citation(s) in RCA: 97] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Revised: 10/03/2017] [Accepted: 10/05/2017] [Indexed: 12/13/2022] Open
Abstract
Helicobacter pylori VacA is a channel-forming toxin unrelated to other known bacterial toxins. Most H. pylori strains contain a vacA gene, but there is marked variation among strains in VacA toxin activity. This variation is attributable to strain-specific variations in VacA amino acid sequences, as well as variations in the levels of VacA transcription and secretion. In this review, we discuss epidemiologic studies showing an association between specific vacA allelic types and gastric cancer, as well as studies that have used animal models to investigate VacA activities relevant to gastric cancer. We also discuss the mechanisms by which VacA-induced cellular alterations may contribute to the pathogenesis of gastric cancer.
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Affiliation(s)
- Mark S McClain
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
| | - Amber C Beckett
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
| | - Timothy L Cover
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
- Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN 37212, USA.
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32
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Detection of Helicobacter pylori vacA , cagA and iceA1 virulence genes associated with gastric diseases in Egyptian patients. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2017. [DOI: 10.1016/j.ejmhg.2017.04.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
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33
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Silva-Fernandes IJDL, Oliveira ESD, Santos JC, Ribeiro ML, Ferrasi AC, Pardini MIDMC, Burbano RMR, Rabenhorst SHB. The intricate interplay between MSI and polymorphisms of DNA repair enzymes in gastric cancer H.pylori associated. Mutagenesis 2017; 32:471-478. [DOI: 10.1093/mutage/gex013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2016] [Accepted: 04/24/2017] [Indexed: 12/15/2022] Open
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34
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Choi HI, Choi JP, Seo J, Kim BJ, Rho M, Han JK, Kim JG. Helicobacter pylori-derived extracellular vesicles increased in the gastric juices of gastric adenocarcinoma patients and induced inflammation mainly via specific targeting of gastric epithelial cells. Exp Mol Med 2017; 49:e330. [PMID: 28496197 PMCID: PMC5454444 DOI: 10.1038/emm.2017.47] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Revised: 11/23/2016] [Accepted: 11/29/2016] [Indexed: 02/07/2023] Open
Abstract
Evidence indicates that Helicobacter pylori is the causative agent of chronic gastritis and perhaps gastric malignancy. Extracellular vesicles (EVs) play an important role in the evolutional process of malignancy due to their genetic material cargo. We aimed to evaluate the clinical significance and biological mechanism of H. pylori EVs on the pathogenesis of gastric malignancy. We performed 16S rDNA-based metagenomic analysis of gastric juices either from endoscopic or surgical patients. From each sample of gastric juices, the bacteria and EVs were isolated. We evaluated the role of H. pylori EVs on the development of gastric inflammation in vitro and in vivo. IVIS spectrum and confocal microscopy were used to examine the distribution of EVs. The metagenomic analyses of the bacteria and EVs showed that Helicobacter and Streptococcus are the two major bacterial genera, and they were significantly increased in abundance in gastric cancer (GC) patients. H. pylori EVs are spherical and contain CagA and VacA. They can induce the production of tumor necrosis factor-α, interleukin (IL)-6 and IL-1β by macrophages, and IL-8 by gastric epithelial cells. Also, EVs induce the expression of interferon gamma, IL-17 and EV-specific immunoglobulin Gs in vivo in mice. EVs were shown to infiltrate and remain in the mouse stomach for an extended time. H. pylori EVs, which are abundant in the gastric juices of GC patients, can induce inflammation and possibly cancer in the stomach, mainly via the production of inflammatory mediators from gastric epithelial cells after selective uptake by the cells.
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Affiliation(s)
- Hyun-Il Choi
- Division of Molecular and Life Sciences, Department of Life Science, Pohang University of Science and Technology (POSTECH), Pohang City, Gyeongsangbuk-do, Republic of Korea
| | - Jun-Pyo Choi
- Asan Institute for Life Sciences Asan Medical Center, Seoul, Republic of Korea
| | - Jiwon Seo
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Republic of Korea
| | - Beom Jin Kim
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Republic of Korea
| | - Mina Rho
- Department of Computer Science and Engineering, Hanyang University, Seoul, Republic of Korea
| | - Jin Kwan Han
- Division of Molecular and Life Sciences, Department of Life Science, Pohang University of Science and Technology (POSTECH), Pohang City, Gyeongsangbuk-do, Republic of Korea
| | - Jae Gyu Kim
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Republic of Korea
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Qian HR, Yang Y. Functional role of autophagy in gastric cancer. Oncotarget 2017; 7:17641-51. [PMID: 26910278 PMCID: PMC4951239 DOI: 10.18632/oncotarget.7508] [Citation(s) in RCA: 80] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Accepted: 02/06/2016] [Indexed: 12/11/2022] Open
Abstract
Autophagy is a highly regulated catabolic pathway responsible for the degradation of long-lived proteins and damaged intracellular organelles. Perturbations in autophagy are found in gastric cancer. In host gastric cells, autophagy can be induced by Helicobacter pylori (or H. pylori) infection, which is associated with the oncogenesis of gastric cancer. In gastric cancer cells, autophagy has both pro-survival and pro-death functions in determining cell fate. Besides, autophagy modulates gastric cancer metastasis by affecting a wide range of pathological events, including extracellular matrix (ECM) degradation, epithelial-to-mesenchymal transition (EMT), tumor angiogenesis, and tumor microenvironment. In addition, some of the autophagy-related proteins, such as Beclin 1, microtubule-associated protein 1 light chain 3 (MAP1-LC3), and p62/sequestosome 1 (SQSTM1) have certain prognostic values for gastric cancer. In this article, we review the recent studies regarding the functional role of autophagy in gastric cancer.
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Affiliation(s)
- Hao-ran Qian
- Department of General Surgery, Institute of Micro-Invasive Surgery of Zhejiang University, Sir Run Run Shaw Hospital, Medical College of Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Yi Yang
- Department of Pharmacology, Hangzhou Key Laboratory of Medical Neurobiology, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, PR China
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Wang YK, Kuo FC, Liu CJ, Wu MC, Shih HY, Wang SSW, Wu JY, Kuo CH, Huang YK, Wu DC. Diagnosis of Helicobacter pylori infection: Current options and developments. World J Gastroenterol 2016. [PMID: 26523098 DOI: 10.3748/wjg.v21.i40.11221.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/11/2022] Open
Abstract
Accurate diagnosis of Helicobacter pylori (H. pylori) infection is a crucial part in the effective management of many gastroduodenal diseases. Several invasive and non-invasive diagnostic tests are available for the detection of H. pylori and each test has its usefulness and limitations in different clinical situations. Although none can be considered as a single gold standard in clinical practice, several techniques have been developed to give the more reliable results. Invasive tests are performed via endoscopic biopsy specimens and these tests include histology, culture, rapid urease test as well as molecular methods. Developments of endoscopic equipment also contribute to the real-time diagnosis of H. pylori during endoscopy. Urea breathing test and stool antigen test are most widely used non-invasive tests, whereas serology is useful in screening and epidemiological studies. Molecular methods have been used in variable specimens other than gastric mucosa. More than detection of H. pylori infection, several tests are introduced into the evaluation of virulence factors and antibiotic sensitivity of H. pylori, as well as screening precancerous lesions and gastric cancer. The aim of this article is to review the current options and novel developments of diagnostic tests and their applications in different clinical conditions or for specific purposes.
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Affiliation(s)
- Yao-Kuang Wang
- Yao-Kuang Wang, Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung 812, Taiwan
| | - Fu-Chen Kuo
- Yao-Kuang Wang, Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung 812, Taiwan
| | - Chung-Jung Liu
- Yao-Kuang Wang, Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung 812, Taiwan
| | - Meng-Chieh Wu
- Yao-Kuang Wang, Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung 812, Taiwan
| | - Hsiang-Yao Shih
- Yao-Kuang Wang, Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung 812, Taiwan
| | - Sophie S W Wang
- Yao-Kuang Wang, Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung 812, Taiwan
| | - Jeng-Yih Wu
- Yao-Kuang Wang, Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung 812, Taiwan
| | - Chao-Hung Kuo
- Yao-Kuang Wang, Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung 812, Taiwan
| | - Yao-Kang Huang
- Yao-Kuang Wang, Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung 812, Taiwan
| | - Deng-Chyang Wu
- Yao-Kuang Wang, Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung 812, Taiwan
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Javadi MB, Katzenmeier G. The Forgotten Virulence Factor: The 'non-conventional' Hemolysin TlyA And Its Role in Helicobacter pylori Infection. Curr Microbiol 2016; 73:930-937. [PMID: 27686341 DOI: 10.1007/s00284-016-1141-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Accepted: 09/19/2016] [Indexed: 12/15/2022]
Abstract
Helicobacter pylori is a human-specific Gram-negative pathogenic bacterium which colonizes the gastric mucosal layer in the stomach causing diseases such as peptic ulcer, adenocarcinoma, and gastric lymphoma. It is estimated that approximately half of the world's population is infected with H. pylori making it the most intensively characterized microbial pathogen up to now. Hemolysis has been suggested to significantly contribute to colonization of the stomach and disease progression by H. pylori. In a number of earlier studies, TlyA was characterized as a putative pore-forming cytolysin. Although a few observations in the literature suggest a role for TlyA as significant virulence factor of H. pylori, the molecular and structural characterization of this protein is much curtailed at present. Given the intensive characterization of numerous H. pylori virulence factors over the past decade, surprisingly little information exists for the TlyA toxin and its significance for pathogenesis. This review provides a brief overview on microbial hemolysis and its role for pathogenesis and discusses recent research efforts aimed at an improved understanding of the role of the 'non-conventional' hemolysin and its associated RNA methyltransferase TlyA from H. pylori.
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Affiliation(s)
- Mohammad Bagher Javadi
- Bacterial Toxin Research Cluster, Institute of Molecular Biosciences, Mahidol University, Nakornpathom, 73170, Thailand
| | - Gerd Katzenmeier
- Bacterial Toxin Research Cluster, Institute of Molecular Biosciences, Mahidol University, Nakornpathom, 73170, Thailand.
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Zhang Y, Wang H, Bi C, Xiao Y, Liu Z. Expression of CDX2 in gastric cardia adenocarcinoma and its correlation with H. pylori and cell proliferation. Oncotarget 2016; 7:54973-54982. [PMID: 27384681 PMCID: PMC5342395 DOI: 10.18632/oncotarget.10362] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2015] [Accepted: 06/12/2016] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Gastric cardia cancer (GCC) is located in the distal stomach, and strongly correlates with atrophic gastritis and Helicobacter pylori (H.pylori) infection. Caudal-related homeobox transcription factor 2 (CDX2) is homeobox gene encoding an intestine-specific transcription factor usually expressed in the intestinal epithelium cells. However, in several recent published papers, CDX2 was found to be aberrantly expressed in gastric, thyroid and ovarian cancer. RESULTS Higher expression of CDX2 was found in GCC tissues in comparison with non-malignant cardia mucosa (p<0.05). Moreover, immunohistochemical analysis demonstrated that CDX2 expression correlated with lymphatic metastasis. In addition, we found that CDX2 expression progressively increased with the level of H. pylori infection (p<0.05), and also correlated with cell proliferation, based on Ki67 staining. METHODS To investigate the relationship between CDX2, cell proliferation and H. pylori infection, we detected CDX2, Ki62 and H.pylori expression in 83 non-malignant gastric cardia mucosacases and 60 GCC specimens in the Chaoshan area, a high-risk region for esophageal and gastric cardia cancer. CONCLUSION These findings provide pathological evidence that H. pylori infectionis a driving force of gastric cardia carcinogenesis by upregulating CDX2 and inducing inflammation. These results provide new pathological evidence that H. pylori infection induces GCC tumorigenesis.
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Affiliation(s)
- Ying Zhang
- Department of Pathology, Shantou University Medical College, Shantou, Guangdong Province, China
| | - Hu Wang
- Department of Orthopaedics, First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Chao Bi
- Department of Pathology, Shantou University Medical College, Shantou, Guangdong Province, China
| | - Yinping Xiao
- Department of Pathology, Shantou University Medical College, Shantou, Guangdong Province, China
| | - Zhaoyong Liu
- Department of Orthopaedics, First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
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Thi Huyen Trang T, Thanh Binh T, Yamaoka Y. Relationship between vacA Types and Development of Gastroduodenal Diseases. Toxins (Basel) 2016; 8:toxins8060182. [PMID: 27294955 PMCID: PMC4926148 DOI: 10.3390/toxins8060182] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Revised: 05/29/2016] [Accepted: 05/31/2016] [Indexed: 02/07/2023] Open
Abstract
The Helicobacter pylori vacuolating cytotoxin (VacA) is a secreted pore-forming toxin and a major virulence factor in the pathogenesis of H. pylori infection. While VacA is present in almost all strains, only some forms are toxigenic and pathogenic. While vacA and its genotypes are considered as markers of H. pylori-related diseases or disorders, the pathophysiological mechanisms of VacA and its genotypes remain controversial. This review outlines key findings of publications regarding vacA with emphasis on the relationship between vacA genotypes and the development of human disease.
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Affiliation(s)
- Tran Thi Huyen Trang
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-Machi, Yufu-City, Oita 879-5593, Japan.
- Department of Molecular Biology, 108 Hospital, Hanoi, Vietnam.
| | - Tran Thanh Binh
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-Machi, Yufu-City, Oita 879-5593, Japan.
- Department of Endoscopy, Cho Ray Hospital, Ho Chi Minh, Vietnam.
| | - Yoshio Yamaoka
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-Machi, Yufu-City, Oita 879-5593, Japan.
- Department of Medicine-Gastroenterology, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, TX 77030, USA.
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Helicobacter pylori vacA Genotypes in Chronic Gastritis and Gastric Carcinoma Patients from Macau, China. Toxins (Basel) 2016; 8:toxins8050142. [PMID: 27164143 PMCID: PMC4885057 DOI: 10.3390/toxins8050142] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2016] [Revised: 04/11/2016] [Accepted: 04/29/2016] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori is the major triggering factor for gastric carcinoma, but only a small proportion of infected patients develop this disease. Differences in virulence observed among H. pylori strains, namely in the vacuolating cytotoxin vacA gene, may contribute to this discrepancy. Infection with vacA s1, i1 and m1 strains increases the risk for progression of gastric premalignant lesions and for gastric carcinoma. However, in East Asian countries most of the H. pylori strains are vacA s1, regardless of the patients’ clinical status, and the significance of the vacA i1 and m1 genotypes for gastric carcinoma in this geographic area remains to be fully elucidated. The aim of the present study was to investigate this relationship in 290 patients from Macau, China. Using very sensitive and accurate genotyping methods, we detected infection with vacA i1 and with vacA m1 strains in, respectively, 85.2% and 52.6% of the patients that were infected with single genotypes. The prevalence of cagA-positive strains was 87.5%. No significant associations were observed between vacA genotypes or cagA and gastric carcinoma. It is worth noting that 37.5% of the infected patients had coexistence of H. pylori strains with different vacA genotypes. Additional studies directed to other H. pylori virulence factors should be performed to identify high risk patients in East Asia.
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Junaid M, Linn AK, Javadi MB, Al-Gubare S, Ali N, Katzenmeier G. Vacuolating cytotoxin A (VacA) - A multi-talented pore-forming toxin from Helicobacter pylori. Toxicon 2016; 118:27-35. [PMID: 27105670 DOI: 10.1016/j.toxicon.2016.04.037] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2015] [Revised: 03/12/2016] [Accepted: 04/18/2016] [Indexed: 12/18/2022]
Abstract
Helicobacter pylori is associated with severe and chronic diseases of the stomach and duodenum such as peptic ulcer, non-cardial adenocarcinoma and gastric lymphoma, making Helicobacter pylori the only bacterial pathogen which is known to cause cancer. The worldwide rate of incidence for these diseases is extremely high and it is estimated that about half of the world's population is infected with H. pylori. Among the bacterial virulence factors is the vacuolating cytotoxin A (VacA), which represents an important determinant of pathogenicity. Intensive characterization of VacA over the past years has provided insight into an ample variety of mechanisms contributing to host-pathogen interactions. The toxin is considered as an important target for ongoing research for several reasons: i) VacA displays unique features and structural properties and its mechanism of action is unrelated to any other known bacterial toxin; ii) the toxin is involved in disease progress and colonization by H. pylori of the stomach; iii) VacA is a potential and promising candidate for the inclusion as antigen in a vaccine directed against H. pylori and iv) the vacA gene is characterized by a high allelic diversity, and allelic variants contribute differently to the pathogenicity of H. pylori. Despite the accumulation of substantial data related to VacA over the past years, several aspects of VacA-related activity have been characterized only to a limited extent. The biologically most significant effect of VacA activity on host cells is the formation of membrane pores and the induction of vacuole formation. This review discusses recent findings and advances on structure-function relations of the H. pylori VacA toxin, in particular with a view to membrane channel formation, oligomerization, receptor binding and apoptosis.
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Affiliation(s)
- Muhammad Junaid
- Department of Pharmacy, Division of Pharmacology, University of Malakand, Khyber Pakhtunkhwa 18550, Pakistan; Bacterial Toxin Research Cluster, Institute of Molecular Biosciences, Mahidol University, Nakornpathom 73170, Thailand.
| | - Aung Khine Linn
- Bacterial Toxin Research Cluster, Institute of Molecular Biosciences, Mahidol University, Nakornpathom 73170, Thailand.
| | - Mohammad Bagher Javadi
- Bacterial Toxin Research Cluster, Institute of Molecular Biosciences, Mahidol University, Nakornpathom 73170, Thailand.
| | - Sarbast Al-Gubare
- Bacterial Toxin Research Cluster, Institute of Molecular Biosciences, Mahidol University, Nakornpathom 73170, Thailand.
| | - Niaz Ali
- Department of Basic Medical Sciences, Khyber Medical University, Peshawar 25000, Pakistan.
| | - Gerd Katzenmeier
- Bacterial Toxin Research Cluster, Institute of Molecular Biosciences, Mahidol University, Nakornpathom 73170, Thailand.
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Sun LM, Wu JN, Lin CL, Day JD, Liang JA, Liou LR, Kao CH. Infective Endocarditis and Cancer Risk: A Population-Based Cohort Study. Medicine (Baltimore) 2016; 95:e3198. [PMID: 27015220 PMCID: PMC4998415 DOI: 10.1097/md.0000000000003198] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
This study investigated the possible relationship between endocarditis and overall and individual cancer risk among study participants in Taiwan.We used data from the National Health Insurance program of Taiwan to conduct a population-based, observational, and retrospective cohort study. The case group consisted of 14,534 patients who were diagnosed with endocarditis between January 1, 2000 and December 31, 2010. For the control group, 4 patients without endocarditis were frequency matched to each endocarditis patient according to age, sex, and index year. Competing risks regression analysis was conducted to determine the effect of endocarditis on cancer risk.A large difference was noted in Charlson comorbidity index between endocarditis and nonendocarditis patients. In patients with endocarditis, the risk for developing overall cancer was significant and 119% higher than in patients without endocarditis (adjusted subhazard ratio = 2.19, 95% confidence interval = 1.98-2.42). Regarding individual cancers, in addition to head and neck, uterus, female breast and hematological malignancies, the risks of developing colorectal cancer, and some digestive tract cancers were significantly higher. Additional analyses determined that the association of cancer with endocarditis is stronger within the 1st 5 years after endocarditis diagnosis.This population-based cohort study found that patients with endocarditis are at a higher risk for colorectal cancer and other cancers in Taiwan. The risk was even higher within the 1st 5 years after endocarditis diagnosis. It suggested that endocarditis is an early marker of colorectal cancer and other cancers. The underlying mechanisms must still be explored and may account for a shared risk factor of infection in both endocarditis and malignancy.
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Affiliation(s)
- Li-Min Sun
- From the Department of Radiation Oncology, Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung (L-MS); General Affairs Office, China Medical University Hospital, Taichung (J-NW); Department of Industrial Engineering and Management, National Kaohsiung University of Applied Sciences, Kaohsiung (J-NW, J-DD); Management Office for Health Data, China Medical University Hospital (C-LL); College of Medicine (C-LL); Graduate Institute of Clinical Medical Science, School of Medicine, College of Medicine, China Medical University, Taichung (J-AL, C-HK); Department of Surgery, Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung (L-RL); Department of Radiation Oncology (J-AL); and Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan (C-HK)
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Dixon BREA, Radin JN, Piazuelo MB, Contreras DC, Algood HMS. IL-17a and IL-22 Induce Expression of Antimicrobials in Gastrointestinal Epithelial Cells and May Contribute to Epithelial Cell Defense against Helicobacter pylori. PLoS One 2016; 11:e0148514. [PMID: 26867135 PMCID: PMC4750979 DOI: 10.1371/journal.pone.0148514] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Accepted: 01/19/2016] [Indexed: 12/11/2022] Open
Abstract
Helicobacter pylori colonization of the human stomach can lead to adverse clinical outcomes including gastritis, peptic ulcers, or gastric cancer. Current data suggest that in addition to bacterial virulence factors, the magnitude and types of immune responses influence the outcome of colonization. Specifically, CD4+ T cell responses impact the pathology elicited in response to H. pylori. Because gastritis is believed to be the initiating host response to more detrimental pathological outcomes, there has been a significant interest in pro-inflammatory T cell cytokines, including the cytokines produced by T helper 17 cells. Th17 cells produce IL-17A, IL-17F, IL-21 and IL-22. While these cytokines have been linked to inflammation, IL-17A and IL-22 are also associated with anti-microbial responses and control of bacterial colonization. The goal of this research was to determine the role of IL-22 in activation of antimicrobial responses in models of H. pylori infection using human gastric epithelial cell lines and the mouse model of H. pylori infection. Our data indicate that IL-17A and IL-22 work synergistically to induce antimicrobials and chemokines such as IL-8, components of calprotectin (CP), lipocalin (LCN) and some β-defensins in both human and primary mouse gastric epithelial cells (GEC) and gastroids. Moreover, IL-22 and IL-17A-activated GECs were capable of inhibiting growth of H. pylori in vitro. While antimicrobials were activated by IL-17A and IL-22 in vitro, using a mouse model of H. pylori infection, the data herein indicate that IL-22 deficiency alone does not render mice more susceptible to infection, change their antimicrobial gene transcription, or significantly change their inflammatory response.
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Affiliation(s)
- Beverly R. E. A. Dixon
- Department of Medicine, Vanderbilt University, Nashville, Tennessee, United States of America
| | - Jana N. Radin
- Department of Medicine, Vanderbilt University, Nashville, Tennessee, United States of America
| | - M. Blanca Piazuelo
- Department of Medicine, Vanderbilt University, Nashville, Tennessee, United States of America
| | - Diana C. Contreras
- Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee, United States of America
| | - Holly M. Scott Algood
- Veterans Affairs Tennessee Valley Healthcare Services, Nashville, Tennessee, United States of America
- Department of Medicine, Vanderbilt University, Nashville, Tennessee, United States of America
- Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee, United States of America
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Wang L, Tan RZ, Chen Y, Wang HL, Liu YH, Wen D, Fan JM. CagA promotes proliferation and secretion of extracellular matrix by inhibiting signaling pathway of apoptosis in rat glomerular mesangial cells. Ren Fail 2016; 38:458-64. [PMID: 26837331 DOI: 10.3109/0886022x.2016.1138831] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Cytotoxin-associated antigen A (CagA), a major virulence factor of Helicobacter pylori (Hp), is associated with the pathogenesis of peptic ulcer and gastric cancer. Recent researches demonstrated that Hp exists in palatine tonsil in all studied IgA nephropathy (IgAN) patients, most of which were CagA-positive, suggesting that CagA may be a causative pathogenic factor of IgAN. However, the underlying molecular mechanisms and signaling pathway are still largely unclear. In the present study, CCK8 assay, enzyme-linked immunosorbent assay, and immunohistochemistry were performed to investigate the effect of CagA on cell proliferation and extracellular matrix secretion in rat glomerular mesangial cells. RT-PCR and western blotting were used to reveal the potential signaling pathway. Rat glomerular mesangial cells were treated with recombinant CagA protein for 72 h, in a dose- and time-dependent manner. We found that CagA promoted cell proliferation and extracellular matrix secretion by inhibiting signaling pathway of apoptosis. Taken together, these findings suggested that CagA induced cellular injury in glomerular mesangium by proliferation and secretion of extracellular matrix, and may play an important role in pathogenesis of IgAN.
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Affiliation(s)
- Li Wang
- a Research Center of Combine Traditional Chinese and Western Medicine, Affiliated Traditional Medicine Hospital , Sichuan Medical University , Luzhou , Sichuan , China
| | - Rui-Zhi Tan
- a Research Center of Combine Traditional Chinese and Western Medicine, Affiliated Traditional Medicine Hospital , Sichuan Medical University , Luzhou , Sichuan , China
| | - Yue Chen
- b Department of Nephrology , The First People's Hospital of Zigong , Zigong , Sichuan , China
| | - Hong-Lian Wang
- a Research Center of Combine Traditional Chinese and Western Medicine, Affiliated Traditional Medicine Hospital , Sichuan Medical University , Luzhou , Sichuan , China
| | - Yu-Hang Liu
- a Research Center of Combine Traditional Chinese and Western Medicine, Affiliated Traditional Medicine Hospital , Sichuan Medical University , Luzhou , Sichuan , China
| | - Dan Wen
- c College of Clinical Medical , Sichuan Medical University , Luzhou , Sichuan , China
| | - Jun-Ming Fan
- d Department of Nephrology , The Affiliated Hospital of Sichuan Medical University , Luzhou , Sichuan , China ;,e State Key Laboratory of Biotherapy of Human Disease, West China Hospital , Sichuan University , Chengdu , Sichuan , China
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Di Ciaula A. Increased deaths from gastric cancer in communities living close to waste landfills. INTERNATIONAL JOURNAL OF ENVIRONMENTAL HEALTH RESEARCH 2016; 26:281-90. [PMID: 26540187 DOI: 10.1080/09603123.2015.1109069] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Municipal waste landfills (MWLs) have been linked with some malignancies, but data about gastric cancer (GC) are still uncertain. METHODS Number of deaths from GC, death rates, and odds ratios (ORs) were calculated considering all residents in the 258 towns in the Apulia Region (4,099,547 subjects, years 2006-2009), living within 3 km from each of the 16 regional MWLs (n = 716,404) or in control areas (n = 3,383,143). RESULTS Males living close to MWLs showed a higher death rate for GC, a twofold higher mean number of GC deaths and higher adjusted ORs of GC, compared with controls areas. CONCLUSIONS In a large population and over a wide time period, an increased risk of death from GC has been shown in males living in communities close to MWLs. Primary prevention policies acting through more sustainable waste management might probably partially reduce deaths from GC in areas with MWLs.
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Affiliation(s)
- Agostino Di Ciaula
- a Division of Internal Medicine, Hospital of Bisceglie (BAT) Italy ; International Society of Doctors for Environment (ISDE) , Arezzo , Italy
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46
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Rosadi F, Fiorentini C, Fabbri A. Bacterial protein toxins in human cancers. Pathog Dis 2015; 74:ftv105. [DOI: 10.1093/femspd/ftv105] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/29/2015] [Indexed: 12/16/2022] Open
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Wang YK, Kuo FC, Liu CJ, Wu MC, Shih HY, Wang SSW, Wu JY, Kuo CH, Huang YK, Wu DC. Diagnosis of Helicobacter pylori infection: Current options and developments. World J Gastroenterol 2015; 21:11221-11235. [PMID: 26523098 PMCID: PMC4616200 DOI: 10.3748/wjg.v21.i40.11221] [Citation(s) in RCA: 232] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Revised: 08/06/2015] [Accepted: 09/28/2015] [Indexed: 02/06/2023] Open
Abstract
Accurate diagnosis of Helicobacter pylori (H. pylori) infection is a crucial part in the effective management of many gastroduodenal diseases. Several invasive and non-invasive diagnostic tests are available for the detection of H. pylori and each test has its usefulness and limitations in different clinical situations. Although none can be considered as a single gold standard in clinical practice, several techniques have been developed to give the more reliable results. Invasive tests are performed via endoscopic biopsy specimens and these tests include histology, culture, rapid urease test as well as molecular methods. Developments of endoscopic equipment also contribute to the real-time diagnosis of H. pylori during endoscopy. Urea breathing test and stool antigen test are most widely used non-invasive tests, whereas serology is useful in screening and epidemiological studies. Molecular methods have been used in variable specimens other than gastric mucosa. More than detection of H. pylori infection, several tests are introduced into the evaluation of virulence factors and antibiotic sensitivity of H. pylori, as well as screening precancerous lesions and gastric cancer. The aim of this article is to review the current options and novel developments of diagnostic tests and their applications in different clinical conditions or for specific purposes.
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48
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Gastric cancer and gene copy number variation: emerging cancer drivers for targeted therapy. Oncogene 2015; 35:1475-82. [PMID: 26073079 DOI: 10.1038/onc.2015.209] [Citation(s) in RCA: 109] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2015] [Revised: 05/12/2015] [Accepted: 05/13/2015] [Indexed: 12/15/2022]
Abstract
Gastric cancer (GC) is among the most common malignancy in the world with poor prognosis and limited treatment options. It has been established that gastric carcinogenesis is caused by a complex interaction between host and environmental factors. Copy number variation (CNV) refers to a form of genomic structural variation that results in abnormal gene copy numbers, including gene amplification, gain, loss and deletion. DNA CNV is an important influential factor for the expression of both protein-coding and non-coding genes, affecting the activity of various signaling pathways. CNV arises as a result of preferential selection that favors cancer development, and thus, targeting the amplified 'driver genes' in GC may provide novel opportunities for personalized therapy. The detection of CNVs in chromosomal or mitochondrial DNA from tissue or blood samples may assist the diagnosis, prognosis and targeted therapy of GC. In this review, we discuss the recent CNV discoveries that shed light on the molecular pathogenesis of GC, with a specific emphasis on CNVs that display diagnostic, prognostic or therapeutic significances in GC.
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