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1
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Biagioni A, Peri S, Versienti G, Fiorillo C, Becatti M, Magnelli L, Papucci L. Gastric Cancer Vascularization and the Contribution of Reactive Oxygen Species. Biomolecules 2023; 13:886. [PMID: 37371466 DOI: 10.3390/biom13060886] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 05/19/2023] [Accepted: 05/24/2023] [Indexed: 06/29/2023] Open
Abstract
Blood vessels are the most important way for cancer cells to survive and diffuse in the body, metastasizing distant organs. During the process of tumor expansion, the neoplastic mass progressively induces modifications in the microenvironment due to its uncontrolled growth, generating a hypoxic and low pH milieu with high fluid pressure and low nutrients concentration. In such a particular condition, reactive oxygen species play a fundamental role, enhancing tumor proliferation and migration, inducing a glycolytic phenotype and promoting angiogenesis. Indeed, to reach new sources of oxygen and metabolites, highly aggressive cancer cells might produce a new abnormal network of vessels independently from endothelial cells, a process called vasculogenic mimicry. Even though many molecular markers and mechanisms, especially in gastric cancer, are still unclear, the formation of such intricate, leaky and abnormal vessel networks is closely associated with patients' poor prognosis, and therefore finding new pharmaceutical solutions to be applied along with canonical chemotherapies in order to control and normalize the formation of such networks is urgent.
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Affiliation(s)
- Alessio Biagioni
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, 50134 Florence, Italy
| | - Sara Peri
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
| | - Giampaolo Versienti
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, 50134 Florence, Italy
| | - Claudia Fiorillo
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, 50134 Florence, Italy
| | - Matteo Becatti
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, 50134 Florence, Italy
| | - Lucia Magnelli
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, 50134 Florence, Italy
| | - Laura Papucci
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, 50134 Florence, Italy
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2
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Yoon K. Gastric Cancer: H. pylori and Macrophage Migration Inhibitory Factor. HELICOBACTER PYLORI 2023:321-326. [DOI: 10.1007/978-981-97-0013-4_25] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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3
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Yoon JH, Choi BJ, Nam SW, Park WS. Gastric cancer exosomes contribute to the field cancerization of gastric epithelial cells surrounding gastric cancer. Gastric Cancer 2022; 25:490-502. [PMID: 34993738 DOI: 10.1007/s10120-021-01269-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 11/14/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND A dynamic molecular interaction between cancer and the surrounding normal cells is mediated through exosomes. We investigated whether exosomes derived from gastric cancer cells affected the fate of the surrounding gastric epithelial cells. METHODS We analyzed the cell viability and immortalization of primary normal stomach epithelial cells (PNSECs) after treatment with exosomes derived from AGS gastric cancer cells and/or H. pylori CagA. Cell proliferation and apoptosis were analyzed by BrdU incorporation, flow-cytometry, and colony formation assays. We examined telomere length, expression and activity of telomerase, and expression of telomere-related genes in PNSECs treated with cancer exosomes, and in 60 gastric cancer and corresponding mucosal tissues. The differentially expressed genes and transcriptional regulation of telomere-related genes were verified using real-time qPCR and ChIP analyses, respectively. RESULTS Gastric cancer exosomes increased cell viability and the population-doubling levels but inhibited the cellular senescence and apoptosis of PNSECs. The internalization of cancer exosomes in PNSECs dramatically increased the number of surviving colonies and induced a multilayer growth and invasion into the scaffold. Treatment of PNSECs with cancer exosomes markedly increased the expression and activity of telomerase and the T/S ratio and regulated the expression of the telomere-associated genes, heat-shock genes, and hedgehog genes. Compared to gastric mucosae, gastric cancer showed increased hTERT expression, which was positively correlated with telomere length. Interestingly, seven (46.7%) of 15 non-cancerous gastric mucosae demonstrated strong telomerase activity. CONCLUSION These results suggest that gastric cancer exosomes induced the transformation and field cancerization of the surrounding non-cancerous gastric epithelial cells.
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Affiliation(s)
- Jung Hwan Yoon
- Department of Pathology, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, South Korea
- Functional RNomics Research Center, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, South Korea
| | - Byung Joon Choi
- Department of Pediatrics, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, South Korea
| | - Suk Woo Nam
- Department of Pathology, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, South Korea
- Functional RNomics Research Center, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, South Korea
| | - Won Sang Park
- Department of Pathology, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, South Korea.
- Functional RNomics Research Center, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, South Korea.
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4
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Contino KF, Yadav H, Shiozawa Y. The gut microbiota can be a potential regulator and treatment target of bone metastasis. Biochem Pharmacol 2022; 197:114916. [PMID: 35041811 PMCID: PMC8858876 DOI: 10.1016/j.bcp.2022.114916] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 01/10/2022] [Accepted: 01/10/2022] [Indexed: 02/08/2023]
Abstract
The gut microbiota, an often forgotten organ, have a tremendous impact on human health. It has long been known that the gut microbiota are implicated in cancer development, and more recently, the gut microbiota have been shown to influence cancer metastasis to distant organs. Although one of the most common sites of distant metastasis is the bone, and the skeletal system has been shown to be a subject of interactions with the gut microbiota to regulate bone homeostasis, little research has been done regarding how the gut microbiota control the development of bone metastasis. This review will discuss the mechanisms through which the gut microbiota and derived microbial compounds (i) regulate gastrointestinal cancer disease progression and metastasis, (ii) influence skeletal remodeling and potentially modulate bone metastasis, and (iii) affect and potentially enhance immunotherapeutic treatments for bone metastasis.
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Affiliation(s)
- Kelly F Contino
- Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest University Health Sciences, Winston-Salem, NC 27157, USA
| | - Hariom Yadav
- Department of Neurosurgery and Brain Repair and Institute for Microbiome, University of South Florida, Tampa, FL 33612, USA
| | - Yusuke Shiozawa
- Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest University Health Sciences, Winston-Salem, NC 27157, USA.
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5
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Targeting Cytotoxin-Associated Antigen A, a Virulent Factor of Helicobacter pylori-Associated Gastric Cancer: Structure-Based In Silico Screening of Natural Compounds. Molecules 2022; 27:molecules27030732. [PMID: 35164000 PMCID: PMC8838247 DOI: 10.3390/molecules27030732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 01/19/2022] [Accepted: 01/20/2022] [Indexed: 12/10/2022] Open
Abstract
Gastric cancer is the fifth most frequent cancer and the third major cause of mortality worldwide. Helicobacter pylori, a bacterial infection linked with GC, injects the cytotoxin-associated antigen A (CagA; an oncoprotein) into host cells. When the phosphorylated CagA protein enters the cell, it attaches to other cellular components, interfering with normal cellular signaling pathways. CagA plays an important role in the progression of GC by interacting with phosphatidylserine of the host cell membrane. Therefore, disrupting the CagA-phosphatidylserine connection using small molecules appears to be a promising therapeutic approach. In this report, we screened the natural compounds from ZINC database against the CagA protein using the bioinformatics tools. Hits were initially chosen based on their physicochemical, absorption, distribution, metabolism, excretion, and toxicity (ADMET) characteristics, as well as other drug-like characteristics. To locate safe and effective hits, the PAINS filter, binding affinities estimation, and interaction analysis were used. Three compounds with high binding affinity and specificity for the CagA binding pocket were discovered. The final hits, ZINC153731, ZINC69482055, and ZINC164387, were found to bind strongly with CagA protein, with binding energies of -11.53, -10.67, and -9.21 kcal/mol, respectively, which were higher than that of the control compound (-7.25 kcal/mol). Further, based on binding affinity and interaction pattern, two leads (ZINC153731, ZINC69482055) were chosen for molecular dynamics (MD) simulation analysis. MD results showed that they displayed stability in their vicinity at 100 ns. This study suggested that these compounds could be used as possible inhibitors of CagA protein in the fight against GC. However, additional benchwork tests are required to validate them as CagA protein inhibitors.
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Lin TY, Lan WH, Chiu YF, Feng CL, Chiu CH, Kuo CJ, Lai CH. Statins' Regulation of the Virulence Factors of Helicobacter pylori and the Production of ROS May Inhibit the Development of Gastric Cancer. Antioxidants (Basel) 2021; 10:1293. [PMID: 34439541 PMCID: PMC8389206 DOI: 10.3390/antiox10081293] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 08/12/2021] [Accepted: 08/13/2021] [Indexed: 12/13/2022] Open
Abstract
Conventionally, statins are used to treat high cholesterol levels. They exhibit pleiotropic effects, such as the prevention of cardiovascular disease and decreased cancer mortality. Gastric cancer (GC) is one of the most common cancers, ranking as the third leading global cause of cancer-related deaths, and is mainly attributed to chronic Helicobacter pylori infection. During their co-evolution with hosts, H. pylori has developed the ability to use the cellular components of the host to evade the immune system and multiply in intracellular niches. Certain H. pylori virulence factors, including cytotoxin-associated gene A (CagA), vacuolating cytotoxin A (VacA), and cholesterol-α-glucosyltransferase (CGT), have been shown to exploit host cholesterol during pathogenesis. Therefore, using statins to antagonize cholesterol synthesis might prove to be an ideal strategy for reducing the occurrence of H. pylori-related GC. This review discusses the current understanding of the interplay of H. pylori virulence factors with cholesterol and reactive oxygen species (ROS) production, which may prove to be novel therapeutic targets for the development of effective treatment strategies against H. pylori-associated GC. We also summarize the findings of several clinical studies on the association between statin therapy and the development of GC, especially in terms of cancer risk and mortality.
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Affiliation(s)
- Ting-Yu Lin
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (T.-Y.L.); (W.-H.L.); (Y.-F.C.); (C.-H.C.)
- Research Center for Emerging Viral, Infections Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan 33302, Taiwan
| | - Wen-Hsi Lan
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (T.-Y.L.); (W.-H.L.); (Y.-F.C.); (C.-H.C.)
- Research Center for Emerging Viral, Infections Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan 33302, Taiwan
| | - Ya-Fang Chiu
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (T.-Y.L.); (W.-H.L.); (Y.-F.C.); (C.-H.C.)
- Research Center for Emerging Viral, Infections Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan 33302, Taiwan
- Department of Medical Laboratory, Chang Gung Memorial Hospital at Linkou, Taoyuan 33305, Taiwan
| | - Chun-Lung Feng
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, China Medical University Hsinchu Hospital, Hsinchu 30272, Taiwan;
- Department of Internal Medicine, Department of Medical Research, School of Medicine, China Medical University and Hospital, Taichung 40447, Taiwan
| | - Cheng-Hsun Chiu
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (T.-Y.L.); (W.-H.L.); (Y.-F.C.); (C.-H.C.)
- Research Center for Emerging Viral, Infections Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan 33302, Taiwan
- Molecular Infectious Disease Research Center, Department of Pediatrics, Chang Gung Memorial Hospital at Linkou, Taoyuan 33305, Taiwan
- Chang Gung Microbiota Therapy Center, Chang Gung Memorial Hospital at Linkou, Taoyuan 33305, Taiwan
| | - Chia-Jung Kuo
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (T.-Y.L.); (W.-H.L.); (Y.-F.C.); (C.-H.C.)
- Chang Gung Microbiota Therapy Center, Chang Gung Memorial Hospital at Linkou, Taoyuan 33305, Taiwan
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital at Linkou, Taoyuan 33305, Taiwan
| | - Chih-Ho Lai
- Research Center for Emerging Viral, Infections Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan 33302, Taiwan
- Department of Internal Medicine, Department of Medical Research, School of Medicine, China Medical University and Hospital, Taichung 40447, Taiwan
- Molecular Infectious Disease Research Center, Department of Pediatrics, Chang Gung Memorial Hospital at Linkou, Taoyuan 33305, Taiwan
- Department of Nursing, Asia University, Taichung 41354, Taiwan
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7
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Evaluation of miR-21 Expression Level in Helicobacter pylori-Infected Gastric Mucosa. Jundishapur J Microbiol 2020. [DOI: 10.5812/jjm.100724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Background: Gastric cancer is one of the main causes of death worldwide. In this regard, Helicobacter pylori infection is considered as the main risk factor for gastric cancer. MicroRNA (mirNA) can interface with mRNA molecules as well as blocking their translation into proteins or inducing degradation. Objectives: The aim of this study was to compare the expression of mir-21 in biopsy samples of gastritis and healthy adjacent tissues. Methods: Between Feb-Dec 2017, 70 patients with dyspeptic symptoms from Taleghani Hospital were enrolled in this study. Accordingly, the expression level of mir-21 was evaluated using semi-quantitative RT-PCR in mucosal biopsy samples from those well-characterized patients. Moreover, the U6 gene was used as an internal control. Results: Our data indicated that mir-21 expression was significantly up-regulated in the infected samples with H. pylori compared to healthy samples. Conclusions: Our results confirm that H. pylori infection can alter the expression of mir-21 in gastric epithelial cells and gastric mucosal tissues. However, the exact role of the miRNA changes in H. pylori infection will require further experiments.
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8
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Handa O, Naito Y, Osawa M, Murao T, Matsumoto H, Umegaki E, Shiotani A. Nutrients and probiotics: current trends in their use to eradicate Helicobacter pylori. J Clin Biochem Nutr 2020; 67:26-28. [PMID: 32801465 PMCID: PMC7417805 DOI: 10.3164/jcbn.20-51] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 04/07/2020] [Indexed: 12/17/2022] Open
Abstract
Helicobacter pylori is a well-known bacterium that infects the human gastric mucosa and causes gastric inflammation, ultimately resulting in gastric cancer. To reduce the incidence of gastric cancer, eradication therapy is important. However, the rate of successful eradication gradually decreases due to increased antibiotic resistance to Helicobacter pylori. In order to increase the eradication rate and reduce gastric cancer incidence, food factors or probiotics are expected to play a beneficial role. Although several foods have been reported to inhibit bacterial load and gastric inflammation, further assessment on large population prospective studies in this field is warranted. Several food compounds, including phytochemicals, are reported to suppress the incidence of gastric cancer. Future evaluations should consider differences in geographic factors. Probiotics are effective and safe for use in Helicobacter pylori eradication therapy.
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Affiliation(s)
- Osamu Handa
- Department of Internal Medicine, Division of Gastroenterology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan
- Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyou-ku, Kyoto 602-8566, Japan
| | - Yuji Naito
- Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyou-ku, Kyoto 602-8566, Japan
| | - Motoyasu Osawa
- Department of Internal Medicine, Division of Gastroenterology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan
| | - Takahisa Murao
- Department of Internal Medicine, Division of Gastroenterology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan
| | - Hiroshi Matsumoto
- Department of Internal Medicine, Division of Gastroenterology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan
| | - Eiji Umegaki
- Department of Internal Medicine, Division of Gastroenterology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan
| | - Akiko Shiotani
- Department of Internal Medicine, Division of Gastroenterology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan
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Papaefthymiou A, Doulberis M, Katsinelos P, Liatsos C, Polyzos SA, Kotronis G, Papanikolaou K, Kountouras J. Impact of nitric oxide's bidirectional role on glaucoma: focus onHelicobacter pylori–related nitrosative stress. Ann N Y Acad Sci 2020; 1465:10-28. [DOI: 10.1111/nyas.14253] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 09/07/2019] [Accepted: 09/17/2019] [Indexed: 12/12/2022]
Affiliation(s)
| | - Michael Doulberis
- Department of Gastroenterology and HepatologyUniversity of Zurich Zurich Switzerland
- Department of Internal Medicine, Second Medical Clinic, Ippokration HospitalAristotle University of Thessaloniki Thessaloniki Macedonia Greece
| | - Panagiotis Katsinelos
- Department of Internal Medicine, Second Medical Clinic, Ippokration HospitalAristotle University of Thessaloniki Thessaloniki Macedonia Greece
| | - Christos Liatsos
- Department of Gastroenterology401 General Military Hospital of Athens Athens Greece
| | - Stergios A. Polyzos
- Department of Internal Medicine, Second Medical Clinic, Ippokration HospitalAristotle University of Thessaloniki Thessaloniki Macedonia Greece
- First Department of Pharmacology, School of MedicineAristotle University of Thessaloniki Thessaloniki Macedonia Greece
| | - Georgios Kotronis
- Department of Internal MedicineAgios Pavlos General Hospital Thessaloniki Macedonia Greece
| | - Katerina Papanikolaou
- Department of Internal Medicine, Second Medical Clinic, Ippokration HospitalAristotle University of Thessaloniki Thessaloniki Macedonia Greece
| | - Jannis Kountouras
- Department of Internal Medicine, Second Medical Clinic, Ippokration HospitalAristotle University of Thessaloniki Thessaloniki Macedonia Greece
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Yoon K, Kim N, Park Y, Kim BK, Park JH, Shin CM, Lee DH, Surh YJ. Correlation between macrophage migration inhibitory factor and autophagy in Helicobacter pylori-associated gastric carcinogenesis. PLoS One 2019; 14:e0211736. [PMID: 30742638 PMCID: PMC6370197 DOI: 10.1371/journal.pone.0211736] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Accepted: 01/18/2019] [Indexed: 02/06/2023] Open
Abstract
The role of macrophage migration inhibitory factor (MIF) and autophagy in gastric cancer is not clear. We determined H. pylori infection status of the subjects and investigated the expression of MIF and autophagy markers (Atg5, LC3A and LC3B) in human gastric tissue at baseline. Then H. pylori eradication was done for H. pylori positive patients and MIF and Atg5 levels were investigated on each follow-up for both H. pylori-eradicated and H. pylori negative patients. Baseline tissue mRNA expression of MIF, Atg5, LC3A and LC3B was measured by real-time PCR in 453 patients (control 165, gastric dysplasia 82, and gastric cancer 206). Three hundred three patients (66.9%) had H. pylori infection at the time of enrollment. Only within H. pylori-positive group, MIF level was significantly elevated in patients with cancer than in control or dysplasia groups (P<0.05). LC3A and LC3B levels also showed significant differences within H. pylori-positive subgroups. H. pylori-positive dysplasia subgroup showed significantly lower (LC3A) (P<0.05) and higher (LC3B) mRNA levels (P<0.05) than in other subgroups. On follow-up, within H. pylori-eradicated group, Atg5 expression increased sequentially from control to dysplasia and cancer subgroups. Multiple linear regression showed autophagy markers (LC3A, LC3B, and Atg5) directly predicted MIF level (adjusted R2 = 0.492, P<0.001). Serial follow-up showed longitudinal increase in Atg5 level in general, with constantly higher levels in H. pylori-eradicated group than in -negative group. Intestinal metaplasia (IM) group initially showed higher Atg5 expression than the IM-negative group. However, it was reversed between the groups eventually because of the lower rate of increase in IM group. These results suggest a role of MIF and autophagy markers and their interaction in H. pylori-associated gastric carcinogenesis.
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Affiliation(s)
- Kichul Yoon
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
- * E-mail:
| | - Youngmi Park
- Medical Research Collaborating Center, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Bo Kyung Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Ji Hyun Park
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Cheol Min Shin
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Dong Ho Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Young-Joon Surh
- Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea
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11
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Lian DW, Xu YF, Ren WK, Fu LJ, Chen FJ, Tang LY, Zhuang HL, Cao HY, Huang P. Unraveling the Novel Protective Effect of Patchouli Alcohol Against Helicobacter pylori-Induced Gastritis: Insights Into the Molecular Mechanism in vitro and in vivo. Front Pharmacol 2018; 9:1347. [PMID: 30524287 PMCID: PMC6262355 DOI: 10.3389/fphar.2018.01347] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2018] [Accepted: 10/31/2018] [Indexed: 12/18/2022] Open
Abstract
Patchouli alcohol (PA), a natural tricyclic sesquiterpene extracted from Pogostemon cablin (Blanco) Benth. (Labiatae), has been found to exhibit anti-Helicobacter pylori and anti-inflammatory properties. In this study, we investigated the protective effect of PA against H. pylori-induced gastritis in vitro and in vivo, and determined the underlying mechanism. In the in vivo experiment, a C57BL/6 mouse model of gastritis was established using H. pylori SS1, and treatments with standard triple therapy or 5, 10, and 20 mg/kg PA were performed for 2 weeks. Results indicated that PA effectively attenuated oxidative stress by decreasing contents of intracellular reactive oxygen species (ROS) and malonyldialdehyde (MDA), and increasing levels of non-protein sulfhydryl (NP-SH), catalase and glutathione (GSH)/glutathione disulphide (GSSG). Additionally, treatment with PA significantly attenuated the secretions of interleukin 1 beta (IL-1β), keratinocyte chemoattractant and interleukin 6 (IL-6). PA (20 mg/kg) significantly protected the gastric mucosa from H. pylori-induced damage. In the in vitro experiment, GES-1 cells were cocultured with H. pylori NCTC11637 at MOI = 100:1 and treated with different doses of PA (5, 10, and 20 μg/ml). Results indicated that PA not only significantly increased the cell viability and decreased cellular lactate dehydrogenase (LDH) leakage, but also markedly elevated the mitochondrial membrane potential and remarkably attenuated GES-1 cellular apoptosis, thereby protecting gastric epithelial cells against injuries caused by H. pylori. PA also inhibited the secretions of pro-inflammatory factors, such as monocyte chemotactic protein 1 (MCP-1), tumor necrosis factor-α (TNF-α) and IL-6. Furthermore, after PA treatment, the combination of NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) and cysteine-aspartic proteases 1 (CASPASE-1), the expression levels of NLRP3 inflammasome-related proteins, such as thioredoxin-interacting protein (TXNIP), pro-CASPASE-1, cle-CASPASE-1, and NLRP3 and genes (NLRP3 and CASPASE1) were significantly decreased as compared to the model group. In conclusion, treatment with PA for 2 weeks exhibited highly efficient protective effect against H. pylori-induced gastritis and related damages. The underlying mechanism might involve antioxidant activity, inhibition of pro-inflammatory factor and regulation of NLRP3 inflammasome function. PA exerted anti-H. pylori and anti-gastritis effects and thus had the potential to be a promising candidate for treatment of H. pylori-related diseases.
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Affiliation(s)
- Da-Wei Lian
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yi-Fei Xu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Wen-Kang Ren
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Li-Jun Fu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Fang-Jun Chen
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Li-Yao Tang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Hui-Ling Zhuang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Hong-Ying Cao
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ping Huang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
- Dongguan & Guangzhou University of Chinese Medicine Cooperative Academy of Mathematical Engineering for Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
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12
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Influence of Helicobacter pylori infection on gastrointestinal symptoms and complications in bariatric surgery patients: a review and meta-analysis. Surg Obes Relat Dis 2018; 14:1645-1657. [PMID: 30172695 DOI: 10.1016/j.soard.2018.06.020] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Revised: 06/22/2018] [Accepted: 06/27/2018] [Indexed: 12/17/2022]
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13
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Shi D, Liu Y, Wu D, Hu X. Transfection of the Helicobacter pylori CagA gene alters MUC5AC expression in human gastric cancer cells. Oncol Lett 2018; 15:5208-5212. [PMID: 29552159 DOI: 10.3892/ol.2018.7960] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Accepted: 08/24/2017] [Indexed: 12/22/2022] Open
Abstract
Helicobacter pylori, the primary causative agent of stomach cancer, is known to affect gastric mucin expression. However, the underlying molecular mechanisms mediating this H. pylori-dependent effect remain unknown. In the present study, the effect of exogenous expression of the H. pylori virulence factor, CagA, on mucin 5AC oligomeric muscus/gel-forming (MUC5AC) expression was investigated using an in vitro model of the gastric mucosa. AGS cells were either untreated or transfected by a vector control (pCDNA3.1) or heterologous DNA, which induced CagA overexpression (pCDNA3.1-CagA). The expression and functionality of MUC5AC was analyzed using the reverse transcription-quantitative polymerase chain reaction and immunofluorescence assays. The expression of H. pylori-CagA in AGS cells was able to significantly upregulate MUC5AC expression compared to the vector control. In addition, immunofluorescence assays were able to validate increased MUC5AC expression following exogenous expression of H. pylori-CagA. The results of the present study revealed that the H. pylori-derived virulence factor CagA was able to increase the expression of MUC5AC. As this mucin constitutes an important ecological niche for H. pylori, this response may be involved in H. pylori colonization of the stomach.
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Affiliation(s)
- Ding Shi
- Department of Gastroenterology, Ningbo No. 2 Hospital, Ningbo, Zhejiang 315000, P.R. China
| | - Yongpan Liu
- Department of Gastroenterology, First People's Hospital of Yuhang District, Hangzhou, Zhejiang 31100, P.R. China
| | - Dong Wu
- Department of Gastroenterology, Ningbo No. 2 Hospital, Ningbo, Zhejiang 315000, P.R. China
| | - Xujun Hu
- Department of Gastroenterology, Ningbo No. 2 Hospital, Ningbo, Zhejiang 315000, P.R. China
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14
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Sepulveda AR, J. Del Portillo A. Molecular Basis of Diseases of the Gastrointestinal Tract. MOLECULAR PATHOLOGY 2018:387-415. [DOI: 10.1016/b978-0-12-802761-5.00019-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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15
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Jones TA, Hernandez DZ, Wong ZC, Wandler AM, Guillemin K. The bacterial virulence factor CagA induces microbial dysbiosis that contributes to excessive epithelial cell proliferation in the Drosophila gut. PLoS Pathog 2017; 13:e1006631. [PMID: 29049360 PMCID: PMC5648253 DOI: 10.1371/journal.ppat.1006631] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Accepted: 09/06/2017] [Indexed: 02/07/2023] Open
Abstract
Gut microbiota facilitate many aspects of human health and development, but dysbiotic microbiota can promote hyperplasia and inflammation and contribute to human diseases such as cancer. Human patients infected with the gastric cancer-causing bacterium Helicobacter pylori have altered microbiota; however, whether dysbiosis contributes to disease in this case is unknown. Many H. pylori human disease phenotypes are associated with a potent virulence protein, CagA, which is translocated into host epithelial cells where it alters cell polarity and manipulates host-signaling pathways to promote disease. We hypothesized that CagA alone could contribute to H. pylori pathogenesis by inducing microbial dysbiosis that promotes disease. Here we use a transgenic Drosophila model of CagA expression to genetically disentangle the effects of the virulence protein CagA from that of H. pylori infection. We found that expression of CagA within Drosophila intestinal stem cells promotes excess cell proliferation and is sufficient to alter host microbiota. Rearing CagA transgenic flies germ-free revealed that the dysbiotic microbiota contributes to cell proliferation phenotypes and also elicits expression of innate immune components, Diptericin and Duox. Further investigations revealed interspecies interactions are required for this dysbiotic CagA-dependent microbiota to promote proliferation in CagA transgenic and healthy control Drosophila. Our model establishes that CagA can alter gut microbiota and exacerbate cell proliferation and immune phenotypes previously attributed to H. pylori infection. This work provides valuable new insights into the mechanisms by which interactions between a specific virulence factor and the resident microbiota can contribute to the development and progression of disease. Microbial communities in the gut, termed microbiota are important for human health, and when altered can sometimes promote disease. Infections, such as with the cancer-causing bacterium Helicobacter pylori, can cause altered gut microbiota, but why these alterations occur and whether the altered communities contribute to disease remain unknown. Here, we use Drosophila expressing the H. pylori disease-causing protein CagA, to model this virulence factor’s effect on host pathology and microbiota. We found that expression of CagA in the Drosophila gut causes excessive cell proliferation and immune activation, hallmarks of H. pylori infection. Notably, these traits did not occur when flies were reared in the absence of microbes. Further examination reveals that CagA-expressing flies have an altered gut microbial community that is sufficient to promote cell proliferation even in normal flies. This proliferative activity required the presence of two interacting bacteria, illustrating a new model for disease-promoting microbiota. This work demonstrates how a bacterial protein can cause disease indirectly through altering the microbial ecology of the host, and it suggests future treatments for infections that rely on manipulating the microbiota to mitigate disease pathology.
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Affiliation(s)
- Tiffani Alvey Jones
- Institute of Molecular Biology, University of Oregon, Eugene, OR, United States of America
| | - Diane Z. Hernandez
- Institute of Molecular Biology, University of Oregon, Eugene, OR, United States of America
| | - Zoë C. Wong
- Institute of Molecular Biology, University of Oregon, Eugene, OR, United States of America
| | - Anica M. Wandler
- Institute of Molecular Biology, University of Oregon, Eugene, OR, United States of America
| | - Karen Guillemin
- Institute of Molecular Biology, University of Oregon, Eugene, OR, United States of America
- Humans and the Microbiome Program, Canadian Institute for Advanced Research, Toronto, Ontario, Canada
- * E-mail:
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16
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Wang F, Qu N, Peng J, Yue C, Yuan L, Yuan Y. CagA promotes proliferation and inhibits apoptosis of GES-1 cells by upregulating TRAF1/4-1BB. Mol Med Rep 2017; 16:1262-1268. [PMID: 28627614 PMCID: PMC5561785 DOI: 10.3892/mmr.2017.6757] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Accepted: 03/30/2017] [Indexed: 02/06/2023] Open
Abstract
Cytotoxin-associated gene A (CagA) is one of the most important virulence factors of Helicobacter pylori, and serves a role in H. pylori‑mediated tumorigenesis in gastric cancer. However, the underlying molecular mechanism remains to be elucidated. The present study aimed to investigate the effects of CagA on the proliferation and apoptosis of GES‑1 cells, and the underlying mechanism. A CagA eukaryotic expression plasmid was constructed and transfected into GES‑1 cells. The mRNA and protein levels of CagA, tumor necrosis factor receptor‑associated factor 1 (TRAF1) and tumor necrosis factor receptor superfamily member 9 (4‑1BB) were determined using the reverse transcription‑quantitative polymerase chain reaction and western blot analysis, respectively. Western blot and ELISA analysis was used to detect the release of interleukin (IL)‑8. An MTT assay and flow cytometric analysis was used to assess cell viability and apoptosis, respectively. Ectopic expression of CagA markedly increased TRAF1 and 4‑1BB mRNA and protein levels in GES‑1 cells. CagA increased the expression and release of IL‑8 in GES‑1 cells. The expression of CagA significantly promoted the proliferation (P<0.05) and inhibited the apoptosis (P<0.05) of GES‑1 cells. In conclusion, CagA upregulated TRAF1/4‑1BB, thereby promoting the proliferation and inhibiting the apoptosis of GES-1 cells.
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Affiliation(s)
- Fen Wang
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
| | - Nanfang Qu
- Department of Gastroenterology, The Affiliated Hospital of Guilin Medical College, Guilin, Guangxi 541001, P.R. China
| | - Jin Peng
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
| | - Chun Yue
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
| | - Lingzhi Yuan
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
| | - Yi Yuan
- Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
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17
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Lee DY, Jung DE, Yu SS, Lee YS, Choi BK, Lee YC. Regulation of SIRT3 signal related metabolic reprogramming in gastric cancer by Helicobacter pylori oncoprotein CagA. Oncotarget 2017; 8:78365-78378. [PMID: 29108235 PMCID: PMC5667968 DOI: 10.18632/oncotarget.18695] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Accepted: 05/22/2017] [Indexed: 12/14/2022] Open
Abstract
Injection of the Helicobacter pylori cytotoxin-associated gene A (CagA) is closely associated with the development of chronic gastritis and gastric cancer. Individuals infected with H. pylori possessing the CagA protein produce more reactive oxygen species (ROS) and show an increased risk of developing gastric cancer. Sirtuins (SIRTs) are nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases and mitochondrial SIRT3 is known to be a tumor suppressor via its ability to suppress ROS and hypoxia inducible factor 1α (HIF-1α). However, it is unclear whether increased ROS production by H. pylori is regulated by SIRT3 followed by HIF-1α regulation and whether intracellular CagA acts as a regulator thereof. In this study, we investigated correlations among SIRT3, ROS, and HIF-1α in H. pylori-infected gastric epithelial cells. We observed that SIRT3-deficient AGS cells induce HIF-1α protein stabilization and augmented transcriptional activity under hypoxic conditions. In CagA+H. pylori infected cells, CagA protein localized to mitochondria where it subsequently suppressed SIRT3 proteins. CagA+H. pylori infection also increased HIF-1α activity through the ROS production induced by the downregulated SIRT3 activity, which is similar to the hypoxic condition in gastric epithelial cells. In contrast, overexpression of SIRT3 inhibited the HIF-1α protein stabilization and attenuated the increase in HIF-1α transcriptional activity under hypoxic conditions. Moreover, CagA+H. pylori attenuated HIF-1α stability and decreased transcriptional activity in SIRT3-overexpressing gastric epithelial cells. Taken together, these findings provide valuable insights into the potential role of SIRT3 in CagA+H. pylori-mediated gastric carcinogenesis and a possible target for cancer prevention via inhibition of HIF-1α.
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Affiliation(s)
- Do Yeon Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Dawoon E Jung
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Sung Sook Yu
- Department of Biomedical Science, Yonsei University College of Medicine, Seoul, Korea
| | | | - Beom Ku Choi
- Immune & Cell Therapy Branch, Division of Cancer Biology, National Cancer Center, Gyeonggi-do, Korea
| | - Yong Chan Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
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18
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Chen Z, Hu T, Zhu S, Mukaisho K, El-Rifai W, Peng DF. Glutathione peroxidase 7 suppresses cancer cell growth and is hypermethylated in gastric cancer. Oncotarget 2017; 8:54345-54356. [PMID: 28903346 PMCID: PMC5589585 DOI: 10.18632/oncotarget.17527] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Accepted: 04/14/2017] [Indexed: 01/06/2023] Open
Abstract
Gastric cancer (GC) is one of the most common cancers in the world, and remains the third leading cause of cancer-related deaths worldwide. Glutathione peroxidase 7 (GPX7) is a member of GPX family which is downregulated in some cancer types. In this study, we investigated the expression, regulation, and molecular function of GPX7 in gastric cancer using 2D and 3D in vitro models and de-identified human tissue samples. Quantitative real-time RT-PCR, immunofluorescence, Western blot, 3D organotypic cultures, and pyrosequencing assays were used. We detected downregulation of GPX7 in all 7 gastric cancer cell lines that we tested and in approximately half (22/45) of human gastric cancer samples, as compared to histologically normal gastric tissues. Quantitative bisulfite pyrosequencing methylation analysis demonstrated DNA hypermethylation (> 10% methylation level) of GPX7 promoter in all 7 gastric cancer cell lines and in 56% (25/45) of gastric cancer samples, as compared to only 13% (6/45) in normal samples (p < 0.0001). Treatment of AGS and SNU1 cells with 5-Aza-2′-deoxycytidine led to a significant demethylation of GPX7 promoter and restored the expression of GPX7. In vitro assays showed that reconstitution of GPX7 significantly suppressed gastric cancer cell growth in both 2D and 3D organotypic cell culture models. This growth suppression was associated with inhibition of cell proliferation and induction of cell death. We detected significant upregulation of p27 and cleaved PARP and downregulation of Cyclin D1 upon reconstitution of GPX7. Taken together, we conclude that epigenetic silencing of GPX7 could play an important role in gastric tumorigenesis and progression.
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Affiliation(s)
- Zheng Chen
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Tianling Hu
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Shoumin Zhu
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Kenichi Mukaisho
- Department of Pathology, Division of Molecular Diagnostic Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Wael El-Rifai
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.,Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.,Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA.,Department of Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, USA
| | - Dun-Fa Peng
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
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Butcher LD, den Hartog G, Ernst PB, Crowe SE. Oxidative Stress Resulting From Helicobacter pylori Infection Contributes to Gastric Carcinogenesis. Cell Mol Gastroenterol Hepatol 2017; 3:316-322. [PMID: 28462373 PMCID: PMC5404027 DOI: 10.1016/j.jcmgh.2017.02.002] [Citation(s) in RCA: 156] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2016] [Accepted: 02/11/2017] [Indexed: 12/12/2022]
Abstract
Helicobacter pylori is a gram-negative, microaerophilic bacterium that infects the stomach and can lead to, among other disorders, the development of gastric cancer. The inability of the host to clear the infection results in a chronic inflammatory state with continued oxidative stress within the tissue. Reactive oxygen species and reactive nitrogen species produced by the immune and epithelial cells damage the host cells and can result in DNA damage. H pylori has evolved to evoke this damaging response while blunting the host's efforts to kill the bacteria. This long-lasting state with inflammation and oxidative stress can result in gastric carcinogenesis. Continued efforts to better understand the bacterium and the host response will serve to prevent or provide improved early diagnosis and treatment of gastric cancer.
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Key Words
- AP Endonuclease
- APE1, apurinic/apyrimidinic endonuclease 1
- BabA, blood group antigen binding adhesion
- CagA, cytotoxin-associated gene A
- DNA Damage
- Gastric Cancer
- H pylori
- IL, interleukin
- NADPH, nicotinamide adenine dinucleotide phosphate
- NapA, neutrophil activating factor A
- Nox, nicotinamide adenine dinucleotide phosphate oxidase
- O2-, superoxide
- OH, hydroxyl radical
- Oxidative Stress
- RNS, reactive nitrogen species
- ROS, reactive oxygen species
- TGF-β, transforming growth factor β
- VacA, vacuolating cytotoxin A
- iNOS, inducible nitric oxide synthase
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Affiliation(s)
- Lindsay D. Butcher
- Department of Medicine, University of California, San Diego, La Jolla, California
| | - Gerco den Hartog
- Department of Medicine, University of California, San Diego, La Jolla, California
| | - Peter B. Ernst
- Department of Pathology, University of California, San Diego, La Jolla, California
| | - Sheila E. Crowe
- Department of Medicine, University of California, San Diego, La Jolla, California
- Correspondence Address correspondence to: Sheila E. Crowe, MD, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0063. fax: (858) 246-1788.Department of MedicineUniversity of CaliforniaSan Diego9500 Gilman DriveLa JollaCalifornia 92093-0063
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20
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Yoon K. Gastric Cancer: H. pylori and Macrophage Migration Inhibitory Factor. HELICOBACTER PYLORI 2016:269-274. [DOI: 10.1007/978-981-287-706-2_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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21
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Libânio D, Dinis-Ribeiro M, Pimentel-Nunes P. Helicobacter pylori and microRNAs: Relation with innate immunity and progression of preneoplastic conditions. World J Clin Oncol 2015; 6:111-132. [PMID: 26468448 PMCID: PMC4600186 DOI: 10.5306/wjco.v6.i5.111] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2015] [Revised: 06/22/2015] [Accepted: 08/04/2015] [Indexed: 02/06/2023] Open
Abstract
The accepted paradigm for intestinal-type gastric cancer pathogenesis is a multistep progression from chronic gastritis induced by Helicobacter pylori (H. pylori) to gastric atrophy, intestinal metaplasia, dysplasia and ultimately gastric cancer. The genetic and molecular mechanisms underlying disease progression are still not completely understood as only a fraction of colonized individuals ever develop neoplasia suggesting that bacterial, host and environmental factors are involved. MicroRNAs are noncoding RNAs that may influence H. pylori-related pathology through the regulation of the transcription and expression of various genes, playing an important role in inflammation, cell proliferation, apoptosis and differentiation. Indeed, H. pylori have been shown to modify microRNA expression in the gastric mucosa and microRNAs are involved in the immune host response to the bacteria and in the regulation of the inflammatory response. MicroRNAs have a key role in the regulation of inflammatory pathways and H. pylori may influence inflammation-mediated gastric carcinogenesis possibly through DNA methylation and epigenetic silencing of tumor suppressor microRNAs. Furthermore, microRNAs influenced by H. pylori also have been found to be involved in cell cycle regulation, apoptosis and epithelial-mesenchymal transition. Altogether, microRNAs seem to have an important role in the progression from gastritis to preneoplastic conditions and neoplastic lesions and since each microRNA can control the expression of hundreds to thousands of genes, knowledge of microRNAs target genes and their functions are of paramount importance. In this article we present a comprehensive review about the role of microRNAs in H. pylori gastric carcinogenesis, identifying the microRNAs downregulated and upregulated in the infection and clarifying their biological role in the link between immune host response, inflammation, DNA methylation and gastric carcinogenesis.
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22
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Morphological changes in human gastric epithelial cells induced by nuclear targeting of Helicobacter pylori urease subunit A. J Microbiol 2015; 53:406-14. [PMID: 26025173 DOI: 10.1007/s12275-015-5085-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2015] [Revised: 05/14/2015] [Accepted: 05/15/2015] [Indexed: 12/20/2022]
Abstract
Nuclear targeting of bacterial proteins and their pathological effects on host cells are an emerging pathogenic mechanism in bacteria. We have previously reported that urease subunit A (UreA) of Helicobacter pylori targets the nuclei of COS-7 cells through nuclear localization signals (NLSs). This study further investigated whether UreA of H. pylori targets the nuclei of gastric epithelial cells and then induces molecular and cellular changes in the host cells. H. pylori 26695 strain produced and secreted outer membrane vesicles (OMVs). UreA was translocated into gastric epithelial AGS cells through outer membrane vesicles (OMVs) and then targeted the nuclei of AGS cells. Nuclear targeting of rUreA did not induce host cell death, but resulted in morphological changes, such as cellular elongation, in AGS cells. In contrast, AGS cells treated with rUreA?NLS proteins did not show this morphological change. Next generation sequencing revealed that nuclear targeting of UreA differentially regulated 102 morphogenesis- related genes, of which 67 and 35 were up-regulated and down-regulated, respectively. Our results suggest that nuclear targeting of H. pylori UreA induces both molecular and cellular changes in gastric epithelial cells.
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23
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Teymournejad O, Shokoohizadeh L, Mohabati Mobarez A, Amini M. Helicobacter Pylori and CagA: Relationships With Esophageal and Gastroduodenal Disorders in Iranian Patients. INTERNATIONAL JOURNAL OF ENTERIC PATHOGENS 2015. [DOI: 10.17795/ijep25022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
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24
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Shu X, Yang Z, Li ZH, Chen L, Zhou XD, Xie Y, Lu NH. Helicobacter pylori Infection Activates the Akt-Mdm2-p53 Signaling Pathway in Gastric Epithelial Cells. Dig Dis Sci 2015; 60:876-886. [PMID: 25480405 DOI: 10.1007/s10620-014-3470-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2014] [Accepted: 11/27/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUNDS AND AIMS Although Helicobacter pylori is widely accepted as a causative factor of many gastric diseases, the signaling pathways affected by H. pylori and subsequent effects on cell apoptosis and proliferation remain unclear. Here, we investigated the molecular mechanisms mediating H. pylori infection in gastric epithelial cells. METHODS Tissues from 160 patients with various gastric diseases with or without H. pylori infection were obtained and analyzed by immunohistochemistry for Akt, pAkt, Mdm2, p53, and Bax expression. In vitro, human gastric epithelial cells, GES-1, were incubated with H. pylori culture filtrates. Cell viability was measured by MTT assay. Apoptosis was evaluated by Annexin V/PI double staining followed by flow cytometry, DNA electrophoresis, and comet assay. mRNA and protein expression was assessed by RT-PCR and Western blot analysis. RESULTS In patient tissues, H. pylori infection was associated with significantly elevated levels of pAkt in chronic nonatrophic gastritis (CNAG), Mdm2 in dysplasia, p53 in metaplastic atrophy (MA), and Bax in CNAG and MA. In vitro, H. pylori culture filtrates reduced GES-1 cell viability in a time- and dose-dependent manner, induced G0/G1 arrest, triggered apoptosis, and increased DNA fragmentation. Mdm2 and Bax mRNA expression and pAkt, Mdm2, p53, and Bax protein expression were significantly upregulated when treated with H. pylori culture filtrates. Akt inhibition by LY294002 decreased Mdm2 expression, upregulated p53, and enhanced H. pylori-induced growth inhibition of GES-1 cells. CONCLUSIONS These findings suggest that Akt-Mdm2-p53 signaling is involved in the molecular response of GES-1 cells to H. pylori infection.
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Affiliation(s)
- Xu Shu
- Department of Gastroenterology, The First Affiliated Hospital, Nanchang University, Nanchang, 330006, Jiangxi, China,
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25
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Moridi K, Hosseini Doust R, Goudarzi Z, Lashini H, Esmaeili D, Saberfar E. Investigation of Helicobacter pylori in Laryngeal Papillomatosis. INTERNATIONAL JOURNAL OF ENTERIC PATHOGENS 2015. [DOI: 10.17795/ijep22392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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26
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Kang MJ, Song EJ, Kim BY, Kim DJ, Park JH. Helicobacter pylori induces vascular endothelial growth factor production in gastric epithelial cells through hypoxia-inducible factor-1α-dependent pathway. Helicobacter 2014; 19:476-83. [PMID: 25231285 DOI: 10.1111/hel.12169] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
BACKGROUND Although Helicobacter pylori have been known to induce vascular endothelial growth factor (VEGF) production in gastric epithelial cells, the precise mechanism for cellular signaling is incompletely understood. In this study, we investigated the role of bacterial virulence factor and host cellular signaling in VEGF production of H. pylori-infected gastric epithelial cells. MATERIALS AND METHODS We evaluated production of VEGF, activation of nuclear factor nuclear factor-kappaB (NF-κB) and mitogen-activated protein kinases (MAPKs) and hypoxia-inducible factor-1α (HIF-1α) stabilization in gastric epithelial cells infected with H. pylori WT or isogenic mutants deficient in type IV secretion system (T4SS). RESULTS H. pylori induced VEGF production in gastric epithelial cells via both T4SS-dependent and T4SS-independent pathways, although T4SS-independent pathway seems to be the dominant signaling. The inhibitor assay implicated that activation of NF-κB and MAPKs is dispensable for H. pylori-induced VEGF production in gastric epithelial cells. H. pylori led to HIF-1α stabilization in gastric epithelial cells independently of T4SS, NF-κB, and MAPKs, which was essential for VEGF production in these cells. N-acetyl-cysteine (NAC), a reactive oxygen species (ROS) inhibitor, treatment impaired H. pylori-induced HIF-1α stabilization and VEGF production in gastric epithelial cells. CONCLUSION We defined the important role of ROS-HIF-1α axis in VEGF production of H. pylori-infected gastric epithelial cells, and bacterial T4SS has a minor role in H. pylori-induced VEGF production of gastric epithelial cells.
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Affiliation(s)
- Min-Jung Kang
- Department of Biochemistry, College of Medicine, Konyang University, Daejeon, Korea; World Class Institute, Korea Research Institute of Bioscience and Biotechnology, Ochang-Eup, Cheongwon-Gun, Choongbuk, Korea
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27
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Yoon JH, Seo HS, Choi SS, Chae HS, Choi WS, Kim O, Ashktorab H, Smoot DT, Nam SW, Lee JY, Park WS. Gastrokine 1 inhibits the carcinogenic potentials of Helicobacter pylori CagA. Carcinogenesis 2014; 35:2619-2629. [PMID: 25239641 PMCID: PMC4303776 DOI: 10.1093/carcin/bgu199] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2014] [Revised: 08/25/2014] [Accepted: 09/10/2014] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori CagA directly injected by the bacterium into epithelial cells via a type IV secretion system, leads to cellular changes such as morphology, apoptosis, proliferation and cell motility, and stimulates gastric carcinogenesis. We investigated the effects of cytotoxin-associated gene A (CagA) and gastrokine 1 (GKN1) on cell proliferation, apoptosis, reactive oxygen species (ROS) production, epithelial-mesenchymal transition (EMT) and cell migration in CagA- or GKN1-transfected gastric epithelial cells and mucosal tissues from humans and mice infected with H.pylori. On the molecular level, H.pylori CagA induced increased cell proliferation, ROS production, antiapoptotic activity, cell migration and invasion. Moreover, CagA induced activation of NF-κB and PI3K/Akt signaling pathways and EMT-related proteins. In addition, H.pylori CagA reduced GKN1 gene copy number and expression in gastric cells and mucosal tissues of humans and mice. However, GKN1 overexpression successfully suppressed the carcinogenic effects of CagA through binding to CagA. These results suggest that GKN1 might be a target to inhibit the effects from H.pylori CagA.
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Affiliation(s)
| | - Ho Suk Seo
- Department of General Surgery, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul 137-701, South Korea
| | - Sung Sook Choi
- College of Pharmacy, Sahmyook University, Hwarangro 815, Nowon-gu, Seoul 139-742, South Korea
| | - Hyun Suk Chae
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul 137-701, South Korea
| | | | | | - Hassan Ashktorab
- Department of Medicine, Howard University, Washington, DC 20060, USA
| | - Duane T Smoot
- Department of Internal Medicine, Meharry Medical College, Nashville, TN 37208, USA and
| | - Suk Woo Nam
- Department of Pathology and Functional RNomics Research Center, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul 137-701, South Korea
| | - Jung Young Lee
- Department of Pathology and Functional RNomics Research Center, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul 137-701, South Korea
| | - Won Sang Park
- Department of Pathology and Functional RNomics Research Center, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul 137-701, South Korea
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28
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Computational approaches for evaluating the effect of sequence variations and the intrinsically disordered C-terminal region of the Helicobacter pylori CagA protein on the interaction with tyrosine kinase Src. J Mol Model 2014; 20:2406. [DOI: 10.1007/s00894-014-2406-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2013] [Accepted: 07/29/2014] [Indexed: 01/25/2023]
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29
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Shim JH, Yoon JH, Choi SS, Ashktorab H, Smoot DT, Song KY, Nam SW, Lee JY, Park CH, Park WS. The effect of Helicobacter pylori CagA on the HER-2 copy number and expression in gastric cancer. Gene 2014; 546:288-296. [PMID: 24879917 PMCID: PMC4286173 DOI: 10.1016/j.gene.2014.05.064] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Revised: 04/15/2014] [Accepted: 05/23/2014] [Indexed: 01/26/2023]
Abstract
We investigated whether Helicobacter pylori (H. pylori) CagA contributes to the DNA copy change and mRNA transcript expression of the HER-2 gene and, consequently, affects HER-2 protein expression to evaluate the significance of CagA and HER-2 amplification in gastric cancer. We used the AGS and MKN1 gastric cancer and HFE-145 immortalized non-neoplastic gastric mucosa cell lines. We also confirmed the effects of CagA on HER-2 expression in human gastric cancer tissues and gastric mucosal tissues of H. pylori infected C57BL/6 mice. Ectopic CagA expression in AGS, MKN1 and HFE-145 cells showed a significant increase in HER-2 gene copy number and expression. The gastric mucosae of H. pylori infected C57BL/6 mice also showed increased HER-2 DNA copy number and protein expression. In addition, CagA expression was detected in 17 (56.7%) of 30 gastric cancer tissues, and eight (47%) of them showed HER-2 DNA amplification of more than two-fold. In immunohistochemistry, HER-2 overexpression was detected in 12 (40%) of 30 gastric cancers and a positive correlation was observed among DNA copy number, the mRNA transcript, and protein expression of the HER-2 gene in gastric cancer (P<0.05). These results suggest that H. pylori CagA may induce overexpression of the HER-2 protein by increasing HER-2 DNA and mRNA copy number.
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MESH Headings
- Animals
- Antigens, Bacterial/genetics
- Antigens, Bacterial/metabolism
- Bacterial Proteins/genetics
- Bacterial Proteins/metabolism
- Cell Line, Tumor
- Female
- Gastric Mucosa/metabolism
- Gastric Mucosa/pathology
- Gene Dosage
- Gene Expression Regulation, Neoplastic
- Helicobacter pylori/genetics
- Helicobacter pylori/metabolism
- Humans
- Male
- Mice
- RNA, Messenger/biosynthesis
- RNA, Messenger/genetics
- RNA, Neoplasm/biosynthesis
- RNA, Neoplasm/genetics
- Receptor, ErbB-2/biosynthesis
- Receptor, ErbB-2/genetics
- Stomach Neoplasms/genetics
- Stomach Neoplasms/metabolism
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Affiliation(s)
- Jung Ho Shim
- Division of Gastrointestinal Surgery, Department of Surgery, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Jung Hwan Yoon
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Sung Sook Choi
- College of Pharmacy, Sahmyook University, Hwarangro 815, Nowon-gu, Seoul 139-742, South Korea
| | - Hassan Ashktorab
- Department of Medicine, Howard University, Washington, DC 20060, USA
| | - Duane T Smoot
- Department of Medicine, Howard University, Washington, DC 20060, USA
| | - Kyo Young Song
- Division of Gastrointestinal Surgery, Department of Surgery, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Suk Woo Nam
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Jung Young Lee
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Cho Hyun Park
- Division of Gastrointestinal Surgery, Department of Surgery, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Won Sang Park
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
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30
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Rahimi HR, Rasouli M, Jamshidzadeh A, Farshad S, Firoozi MS, Taghavi AR, Kiany S. New immunological investigations on Helicobacter pylori-induced gastric ulcer in patients. Microbiol Immunol 2014; 57:455-62. [PMID: 23773024 DOI: 10.1111/1348-0421.12056] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2012] [Revised: 04/03/2013] [Accepted: 04/05/2013] [Indexed: 01/22/2023]
Abstract
Although Helicobacter pylori (Hp) plays an important role in the pathogenesis of chronic gastritis and gastric ulcer, little is known about the probable mechanisms of these types of gastrointestinal damage. To determine the precise mechanisms involved in ulcer formation, immune responses in patients with gastric ulcer (GUP) caused by Hp infection (Hp(+)) were compared with those of other gastritis patients (GP). The sensitivity and proliferation of peripheral blood mononuclear cells (PBMNCs) obtained from patients were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay against exposure with complex Hp crude antigen (HPCA) and mitogen (phytohemagglutinin, PHA). Production of inflammatory cytokines, including interleukin (IL)-1β and IL-8, in serum and supernatants of PBMNCs were then measured by ELISA. It was found that, after stimulation with PHA, both IL-8 and IL-1β concentrations in sera and supernatants as well as proliferation and sensitivity were statistically greater in GUP Hp(+) than GP Hp(-) . Furthermore, HPCA inhibited the proliferation of PBMNCs dose-dependently; however, it stimulated IL-8 and IL-1β production in supernatants of mononuclear cells. Therefore, the up-regulated concentrations of IL-8 and IL-1β may have been caused by increase in the size of mononuclear cell subpopulations or in their cytokine secretory activity, indicating the greatest cell responsiveness in GUP Hp(+) patients. These results suggest that tissue damage and ulcers occur in patients who produce more IL-8 and IL-1β than patients who do not develop ulcers; the former consequently have more activated immune cells at the site of infection. Therefore, both host responses and Hp virulence factors may be involved in the development of gastric ulcers.
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Affiliation(s)
- Hamid Reza Rahimi
- Department of Immunology, Professor Alborzi Clinical Microbiology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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31
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Esmaeili D, Hatami S, Bahador A. Risk of cagA DNA in H. Pylori Patients. INTERNATIONAL JOURNAL OF ENTERIC PATHOGENS 2013. [DOI: 10.17795/ijep15466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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32
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Abstract
Some host-adapted bacterial pathogens are capable of causing persistent infections in humans. For example, Helicobacter pylori inhabits the human gastric mucosa and persistence can be lifelong. Salmonella enterica serovar Typhi causes systemic infections that involve colonization of the reticuloendothelial system and some individuals become lifelong carriers. In this review, I compare and contrast the different lifestyles of Helicobacter and Salmonella within the host and the strategies they have evolved to persist in mammalian hosts. Persistently infected carriers serve as the reservoirs for these pathogens, and the carrier state is an essential feature that is required for survival of the bacteria within a restricted host population. Therefore, investigating the chronic carrier state should provide insight into bacterial survival strategies, as well as new therapeutic approaches for treatments.
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Affiliation(s)
- Denise M Monack
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California 94305
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33
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Wang C, Huang XY, Yao JG, Huang BC, Huang CH, Liao P, Long XD. XRCC7 rs#7003908 Polymorphism and Helicobacter pylori Infection-Related Gastric Antrum Adenocarcinoma. Int J Genomics 2013; 2013:124612. [PMID: 24319674 PMCID: PMC3844259 DOI: 10.1155/2013/124612] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2013] [Accepted: 09/29/2013] [Indexed: 02/06/2023] Open
Abstract
The X-ray repair cross-complementing group 7 (XRCC7) plays a key role in DNA repair that protects against genetic instability and carcinogenesis. To determine whether XRCC7 rs#7003908 polymorphism (XRCC7P) is associated with Helicobacter pylori (H. pylori) infection-related gastric antrum adenocarcinoma (GAA) risk, we conducted a hospital-based case-control study, including 642 patients with pathologically confirmed GAA and 927 individually matched controls without any evidence of tumours or precancerous lesions, among Guangxi population. Increased risks of GAA were observed for individuals with cagA positive (odds ratio (OR) 6.38; 95% confidence interval (CI) 5.03-8.09). We also found that these individuals with the genotypes of XRCC7 rs#7003908 G alleles (XRCC7-TG or -GG) featured increasing risk of GAA (ORs 2.80 and 5.13, resp.), compared with the homozygote of XRCC7 rs#7003908 T alleles (XRCC7-TT). GAA risk, moreover, did appear to differ more significantly among individuals featuring cagA-positive status, whose adjusted ORs (95% CIs) were 15.74 (10.89-22.77) for XRCC7-TG and 38.49 (22.82-64.93) for XRCC7-GG, respectively. Additionally, this polymorphism multiplicatively interacted with XRCC3 codon 241 polymorphism with respect to HCC risk (ORinteraction = 1.49). These results suggest that XRCC7P may be associated with the risk of Guangxiese GAA related to cagA.
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Affiliation(s)
- Chao Wang
- Department of Medicine, The Affiliated Hospital of Youjiang Medical College for Nationalities (AHYMCN), Baise 533000, China
| | - Xiao-Ying Huang
- Department of Pathology, The Affiliated Hospital of Youjiang Medical College for Nationalities (AHYMCN), Baise 533000, China
| | - Jin-Guang Yao
- Department of Pathology, The Affiliated Hospital of Youjiang Medical College for Nationalities (AHYMCN), Baise 533000, China
| | - Bing-Chen Huang
- Department of Pathology, The Affiliated Hospital of Youjiang Medical College for Nationalities (AHYMCN), Baise 533000, China
| | - Cen-Han Huang
- Department of Medicine, The Affiliated Hospital of Youjiang Medical College for Nationalities (AHYMCN), Baise 533000, China
| | - Pinhu Liao
- Department of Medicine, The Affiliated Hospital of Youjiang Medical College for Nationalities (AHYMCN), Baise 533000, China
| | - Xi-Dai Long
- Department of Pathology, The Affiliated Hospital of Youjiang Medical College for Nationalities (AHYMCN), Baise 533000, China
- Department of Liver Surgery, The Affiliated Ren Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
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34
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Wu J, Xu S, Zhu Y. Helicobacter pylori CagA: a critical destroyer of the gastric epithelial barrier. Dig Dis Sci 2013; 58:1830-7. [PMID: 23423500 DOI: 10.1007/s10620-013-2589-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2012] [Accepted: 01/24/2013] [Indexed: 12/15/2022]
Abstract
The destruction of the integrity of the gastric epithelial barrier underlies the pathology of many gastric diseases, including gastric tumors. The Helicobacter pylori virulence factor CagA is one of the main destroyers of the gastric epithelial barrier. There are differences among CagA proteins that originate from different isolates. CagA translocated into the gastric epithelial cells causes significant changes in cell signaling pathways in phosphorylation-dependent and phosphorylation-independent manners, leading to cell morphological changes and host cell epithelial barrier injury, which lay the foundation for the occurrence of related diseases. As a newly identified pathogenic mechanism of CagA, miRNA is involved in the remodeling of the gastric epithelial barrier. Both the eradication of H. pylori infection and interventions against CagA-induced gastric epithelial barrier lesions may contribute to the prevention of the development of gastric tumors.
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Affiliation(s)
- Jia Wu
- Department of Gastroenterology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
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35
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Zhang X, Yang Y, Zhu R, Bai J, Tian Y, Li X, Peng Z, He Y, Chen L, Fang D, Chen W, Zou Q, Mao X, Wang R. H. pylori induces the expression of Hath1 in gastric epithelial cells via interleukin-8/STAT3 phosphorylation while suppressing Hes1. J Cell Biochem 2013; 113:3740-51. [PMID: 22786753 DOI: 10.1002/jcb.24248] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Chronic gastritis associated with Helicobacter pylori is a leading cause of gastric intestinal metaplasia (IM), which arises from abnormal cell differentiation of the epithelium in the gastric mucosa. However, the mechanisms involved in H. pylori-mediated IM remain elusive. The aim of our study was to explore the effects and the underlying mechanisms of H. pylori on the abnormal expression of Hath1 and Sox2 and to reveal its relationship to the development of gastric IM. We found that Hath1 and Sox2 were overexpressed in gastric IM tissue. Hath1 expression was up-regulated, whereas Sox2 expression, which was independent of the CagA virulence factor, was down-regulated in gastric epithelial cells and coincided with increased IL-6 and IL-8 levels in the culture media. Stimulation with H. pylori-related cytokine IL-8, but not IL-6 or IL-1β, was induced by Hath1 expression in the gastric epithelial cells. Although IL-8 and IL-6 levels correlated with STAT3 (signal transducer and activator of transcription) phosphorylation before and after H. pylori eradication in the gastric mucosa, only the blocking of IL-8-induced STAT3 activation using AG490 or STAT3-targeting RNA interference altered Hath1 expression. Additionally, we found that H. pylori down-regulated Hes1, which is a direct downstream target gene of Notch signaling and a repressor of Hath1 expression. These findings suggest that H. pylori induced inflammation up-regulate Hath1 expression via interleukin-8/STAT3 (IL-8) phosphorylation while suppressing Hes1, which provides a novel molecular connection between a H. pylori infection and intestinal metaplasia.
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Affiliation(s)
- Xin Zhang
- Department of Gastroenterology, Southwest Hospital, Chongqing 400038, People's Republic of China
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36
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Abstract
Helicobacter pylori infection leads to long-lasting chronic inflammation and represents the most common risk factor underlying gastric cancer. Recently, new insights into the mechanisms through which H. pylori and mucosal inflammation lead to cancer development have emerged. H. pylori virulence factors, in particular specific CagA genotypes, represent main factors in gastric cancer, inducing altered intracellular signaling in epithelial cells. The chronic nature of H. pylori infection appears to relate to the VacA virulence factor and Th17/Treg mechanisms. A role of H. pylori infection in epigenetic and microRNA deregulation has been shown. Mutation of the epithelial cell genome, a hallmark of cancer, was demonstrated to accumulate in H. pylori infected stomach partly due to inadequate DNA repair. Gastric stem cells were shown to be targets of oxidative injury in the Helicobacter-inflammatory milieu. Recent advances emphasizing the contribution of bacterial factors, inflammatory mediators, and the host epithelial response in gastric carcinogenesis are reviewed.
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37
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Up-regulation of neutrophil activating protein in Helicobacter pylori under high-salt stress: structural and phylogenetic comparison with bacterial iron-binding ferritins. Biochimie 2013; 95:1136-45. [PMID: 23352965 DOI: 10.1016/j.biochi.2012.12.017] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2012] [Accepted: 12/30/2012] [Indexed: 02/08/2023]
Abstract
It is generally accepted that most gastrointestinal diseases are probably caused by the bacterial pathogen Helicobacter pylori (H. pylori). In this study we have focused on the comparison of protein expression profiles of H. pylori grown under normal and high-salt conditions by a proteomics approach. We have identified about 190 proteins whose expression levels changed after growth at high salt concentration. Among these proteins, neutrophil-activating protein (NapA) was found to be consistently up-regulated under osmotic stress brought by high salts. We have investigated the effect of high salt on secondary and tertiary structures of NapA by circular dichroism spectroscopy followed by analytical ultracentrifugation to monitor the change of quaternary structure of recombinant NapA with increasing salt concentration. The loss of iron-binding activity of NapA coupled with noticeable energetic variation in protein association of NapA as revealed by isothermal titration calorimetry was found under high salt condition. The phylogenetic tree analysis based on sequence comparison of 16 protein sequences encompassing NapA proteins and ferritin of H. pylori and other prokaryotic organisms pointed to the fact that all H. pylori NapA proteins of human origin are more homologous to NapA of Helicobacter genus than to other bacterial NapA. Based on computer modeling, NapA proteins from H. pylori of human isolates are found more similar to ferritin from H. pylori than to NapA from other species of bacteria. Taken together, these results suggested that divergent evolution of NapA and ferritin possessing dissimilar and diverse sequences follows a path distinct from that of convergent evolution of NapA and ferritin with similar dual functionality of iron-binding and ferroxidase activities.
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38
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Silencing of glutathione peroxidase 3 through DNA hypermethylation is associated with lymph node metastasis in gastric carcinomas. PLoS One 2012; 7:e46214. [PMID: 23071548 PMCID: PMC3468580 DOI: 10.1371/journal.pone.0046214] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2012] [Accepted: 08/29/2012] [Indexed: 01/06/2023] Open
Abstract
Gastric cancer remains the second leading cause of cancer-related death in the world. H. pylori infection, a major risk factor for gastric cancer, generates high levels of reactive oxygen species (ROS). Glutathione peroxidase 3 (GPX3), a plasma GPX member and a major scavenger of ROS, catalyzes the reduction of hydrogen peroxide and lipid peroxides by reduced glutathione. To study the expression and gene regulation of GPX3, we examined GPX3 gene expression in 9 gastric cancer cell lines, 108 primary gastric cancer samples and 45 normal gastric mucosa adjacent to cancers using quantitative real-time RT-PCR. Downregulation or silencing of GPX3 was detected in 8 of 9 cancer cell lines, 83% (90/108) gastric cancers samples, as compared to non-tumor adjacent normal gastric samples (P<0.0001). Examination of GPX3 promoter demonstrated DNA hypermethylation (≥10% methylation level determined by Bisulfite Pyrosequencing) in 6 of 9 cancer cell lines and 60% of gastric cancer samples (P = 0.007). We also detected a significant loss of DNA copy number of GPX3 in gastric cancers (P<0.001). Treatment of SNU1 and MKN28 cells with 5-Aza-2′ Deoxycytidine restored the GPX3 gene expression with a significant demethylation of GPX3 promoter. The downregulation of GPX3 expression and GPX3 promoter hypermethylation were significantly associated with gastric cancer lymph node metastasis (P = 0.018 and P = 0.029, respectively). We also observed downregulation, DNA copy number losses, and promoter hypermethylation of GPX3 in approximately one-third of tumor-adjacent normal gastric tissue samples, suggesting the presence of a field defect in areas near tumor samples. Reconstitution of GPX3 in AGS cells reduced the capacity of cell migration, as measured by scratch wound healing assay. Taken together, the dysfunction of GPX3 in gastric cancer is mediated by genetic and epigenetic alterations, suggesting impairment of mechanisms that regulate ROS and its possible involvement in gastric tumorigenesis and metastasis.
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Cheung DY, Kim TH. [Helicobacter pylori in human stomach: can it be called mutualism or a disease?]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2012; 59:329-37. [PMID: 22617526 DOI: 10.4166/kjg.2012.59.5.329] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Helicobacter pylori (H. pylori) has been a major concern as a gastric pathogen with unique features since discovered in the end of the 20th century. Recent data on comparative genome study have revealed that H. pylori has successfully survived with its host though over 58,000 years of evolution and migration from continent to continent. To maintain the symbiotic relationship with human, H. pylori has come up with ways to induce host tolerance as well as exert harmful injuries. Studies about H. pylori have accumulated the knowledge about how the cellular and molecular interactions are controlled and regulated to decide whether the symbiotic relationship is directed to diseases or peaceful mutualism. We reviewed recent literatures and research outcomes about the H. pylori and host interaction in molecular and cellular basis.
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Affiliation(s)
- Dae Young Cheung
- Department of Internal Medicine, Bucheon St. Mary's Hospital, The Catholic University of Korea, College of Medicine, 327 Sosa-ro, Wonmi-gu, Bucheon 420-717, Korea
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40
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Targosz A, Brzozowski T, Pierzchalski P, Szczyrk U, Ptak-Belowska A, Konturek SJ, Pawlik W. Helicobacter pylori promotes apoptosis, activates cyclooxygenase (COX)-2 and inhibits heat shock protein HSP70 in gastric cancer epithelial cells. Inflamm Res 2012; 61:955-66. [PMID: 22610150 PMCID: PMC3418497 DOI: 10.1007/s00011-012-0487-x] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2012] [Revised: 03/05/2012] [Accepted: 05/02/2012] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVE Apoptosis plays an important role in the regulation of gastric epithelial cell number and gastrointestinal disorders induced by Helicobacter pylori (Hp). Heat shock proteins (HSPs) are involved in cell integrity, cell growth and in gastric mucosa colonized by Hp. COX-2 was implicated in Hp-induced carcinogenesis but the effects of this germ and CagA cytotoxin on HSP70, COX-2, Bax and Bcl-2 in gastric cancer epithelial cells have been little studied. MATERIAL AND METHODS We determined the expression for HSP70, Bax and Bcl-2 in human gastric epithelial MKN7 cells incubated with live strain Hp (cagA + vacA+) with or without co-incubation with exogenous CagA and NS-398, the selective COX-2 inhibitor. After 3-48 h of incubation, the expression of HSP70, COX-2, Bax and Bcl-2 mRNA and proteins were determined by RT-PCR and immunoprecipitation. RESULTS Hp inhibited expression for HSP70 and this was significantly potentiated by exogenous CagA. Co-incubation of epithelial cells with Hp, without or with CagA increased Bax expression and simultaneously decreased expression for Bcl-2. The increase in COX-2 mRNA and Bax expression were significantly inhibited by NS-398. We conclude that Hp promotes apoptosis in adenocarcinoma gastric epithelial cells in vitro and this is associated with activation of COX-2 and inhibition of HSP70.
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Affiliation(s)
- Aneta Targosz
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Str., 31-531 Cracow, Poland
| | - Tomasz Brzozowski
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Str., 31-531 Cracow, Poland
| | - Piotr Pierzchalski
- Department of Medical Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, Cracow, Poland
| | - Urszula Szczyrk
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Str., 31-531 Cracow, Poland
| | - Agata Ptak-Belowska
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Str., 31-531 Cracow, Poland
| | - Stanislaw Jan Konturek
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Str., 31-531 Cracow, Poland
| | - Wieslaw Pawlik
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Str., 31-531 Cracow, Poland
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41
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Chang YJ, Byun SW, Kim HK, Cho YS, Kim SS, Kim JI, Kim JK, Jung ES. [DNA double strand breaks in gastric epithelium with Helicobacter pylori infection]. THE KOREAN JOURNAL OF GASTROENTEROLOGY = TAEHAN SOHWAGI HAKHOE CHI 2012; 60:79-85. [PMID: 22926118 DOI: 10.4166/kjg.2012.60.2.79] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
BACKGROUND/AIMS DNA double strand breaks (DSB) is one of the critical types of DNA damage. If unrepaired, DSB is accumulated in the nucleus of cells, the cells become apoptotic or transform to tumor by way of genomic instability. Some of malignant cancers and its premalignant lesions were proven to have DSB in their nuclei. There was no report that Helicobacter pylori (H. pylori), the gastric carcinogen, induce DNA DSB in gastric epithelium in vivo. The aim of this study was to investigate whether H. pylori induce DSB in the gastric epithelial cells of chronic gastritis. METHODS Immunohistochemical stains were performed for the DSB markers, phospho-53BP1 and gH2AX, in the gastric epithelium derived from 44 peptic ulcer disease patients before and after H. pylori eradication. DNA fragmentation assay was performed in the cell line to investigate the DNA damage by H. pylori infection. RESULTS The mean expression score of gH2AX was significantly higher in the H. pylori infected gastric epithelium as compared to the H. pylori eradicated gastric epithelium (8.8±5.5 vs. 6.2±5.3 respectively; p=0.008). The expression score of phospho-53BP1 between before and after eradication of H. pylori was not statistically different, but tended to be higher in H. pylori infection. DNA fragmentation was developed significantly more in the cell lines after infection with H. pylori. CONCLUSIONS DSB of DNA damage was typical feature of H. pylori infection in the gastric epithelium.
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Affiliation(s)
- Young Jun Chang
- Department of Internal Medicine, The Catholic University of Korea Uijongbu St. Mary's Hospital, 271 Cheonbo-ro, Uijeongbu 480-717, Korea
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42
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Yang JJ, Cho LY, Ko KP, Shin A, Ma SH, Choi BY, Han DS, Song KS, Kim YS, Lee JY, Han BG, Chang SH, Shin HR, Kang D, Yoo KY, Park SK. Genetic susceptibility on CagA-interacting molecules and gene-environment interaction with phytoestrogens: a putative risk factor for gastric cancer. PLoS One 2012; 7:e31020. [PMID: 22383989 PMCID: PMC3286459 DOI: 10.1371/journal.pone.0031020] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2011] [Accepted: 12/29/2011] [Indexed: 12/23/2022] Open
Abstract
OBJECTIVES To evaluate whether genes that encode CagA-interacting molecules (SRC, PTPN11, CRK, CRKL, CSK, c-MET and GRB2) are associated with gastric cancer risk and whether an interaction between these genes and phytoestrogens modify gastric cancer risk. METHODS In the discovery phase, 137 candidate SNPs in seven genes were analyzed in 76 incident gastric cancer cases and 322 matched controls from the Korean Multi-Center Cancer Cohort. Five significant SNPs in three genes (SRC, c-MET and CRK) were re-evaluated in 386 cases and 348 controls in the extension phase. Odds ratios (ORs) for gastric cancer risk were estimated adjusted for age, smoking, H. pylori seropositivity and CagA strain positivity. Summarized ORs in the total study population (462 cases and 670 controls) were presented using pooled- and meta-analysis. Plasma concentrations of phytoestrogens (genistein, daidzein, equol and enterolactone) were measured using the time-resolved fluoroimmunoassay. RESULTS SRC rs6122566, rs6124914, c-MET rs41739, and CRK rs7208768 showed significant genetic effects for gastric cancer in both the pooled and meta-analysis without heterogeneity (pooled OR = 3.96 [95% CI 2.05-7.65], 1.24 [95% CI = 1.01-1.53], 1.19 [95% CI = 1.01-1.41], and 1.37 [95% CI = 1.15-1.62], respectively; meta OR = 4.59 [95% CI 2.74-7.70], 1.36 [95% CI = 1.09-1.70], 1.20 [95% CI = 1.00-1.44], and 1.32 [95% CI = 1.10-1.57], respectively). Risk allele of CRK rs7208768 had a significantly increased risk for gastric cancer at low phytoestrogen levels (p interaction<0.05). CONCLUSIONS Our findings suggest that SRC, c-MET and CRK play a key role in gastric carcinogenesis by modulating CagA signal transductions and interaction between CRK gene and phytoestrogens modify gastric cancer risk.
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Affiliation(s)
- Jae Jeong Yang
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
- Cancer Research Institute, Seoul National University, Seoul, Korea
| | - Lisa Y. Cho
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
- Cancer Research Institute, Seoul National University, Seoul, Korea
| | - Kwang-Pil Ko
- Department of Preventive Medicine, Gachon University of Medicine and Science, Incheon, Korea
| | - Aesun Shin
- Cancer Epidemiology Branch, National Cancer Center, Goyang-si, Korea
| | - Seung Hyun Ma
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
- Cancer Research Institute, Seoul National University, Seoul, Korea
| | - Bo Youl Choi
- Department of Preventive Medicine, Hanyang University College of Medicine, Seoul, Korea
| | - Dong Soo Han
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
| | - Kyu Sang Song
- Department of Pathology, Chungnam National University College of Medicine, Daejeon, Korea
| | - Yong Sung Kim
- Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea
| | - Jong-Young Lee
- Center for Genome Science, Korea National Institute of Health, Osong, Korea
| | - Bok Ghee Han
- Center for Genome Science, Korea National Institute of Health, Osong, Korea
| | - Soung-Hoon Chang
- Department of Preventive Medicine, Konkuk University, Chungju, Korea
| | - Hai-Rim Shin
- Cancer Epidemiology Branch, National Cancer Center, Goyang-si, Korea
- Non Communicable Diseases and Health Promotion, World Health Organization, Western Pacific Regional Office, Manila, Philippines
| | - Daehee Kang
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
- Cancer Research Institute, Seoul National University, Seoul, Korea
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea
| | - Keun-Young Yoo
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Sue K. Park
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
- Cancer Research Institute, Seoul National University, Seoul, Korea
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea
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Tsolaki F, Gogaki E, Sakkias F, Skatharoudi C, Lopatatzidi C, Tsoulopoulos V, Lampoura S, Topouzis F, Tsolaki M, Kountouras J. Helicobacter pylori infection and primary open-angle glaucoma: is there a connection? Clin Ophthalmol 2012; 6:45-7. [PMID: 22259235 PMCID: PMC3259099 DOI: 10.2147/opth.s26659] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Glaucoma, the most common form of which is primary open-angle glaucoma (POAG), is a neurodegenerative disease which is the second most common cause of blindness worldwide. Among the factors that have been implicated in the pathophysiology of this disease is infection with Helicobacter pylori. This alleged association has caused a great deal of scientific discussion during the past decade, as the establishment of such a correlation might lead to therapeutic applications for all glaucoma patients. In this review, we assess all relevant major studies and trials in an effort to elucidate the issue.
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Affiliation(s)
- Fani Tsolaki
- Ophthalmology Department, Hippokrateion Hospital of Thessaloniki, Thessaloniki, Greece
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Huang CH, Chiou SH. Proteomic analysis of upregulated proteins in Helicobacter pylori under oxidative stress induced by hydrogen peroxide. Kaohsiung J Med Sci 2011; 27:544-53. [DOI: 10.1016/j.kjms.2011.06.019] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2010] [Accepted: 04/18/2011] [Indexed: 01/03/2023] Open
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45
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Zhao L, Long XD, Yao JG, Wang C, Ma Y, Huang YZ, Li YQ, Wang MF, Fu GH. Genetic polymorphism of XRCC3 codon 241 and Helicobacter pylori infection-related gastric antrum adenocarcinoma in Guangxi Population, China: a hospital-based case-control study. Cancer Epidemiol 2011; 35:564-568. [PMID: 21937297 DOI: 10.1016/j.canep.2011.03.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2010] [Revised: 03/07/2011] [Accepted: 03/16/2011] [Indexed: 12/14/2022]
Abstract
BACKGROUND The relationship between Helicobacter pylori infection and gastric antrum adenocarcinoma (GAA) has previously been demonstrated and supported with strong epidemiological evidence. However, the role of genetic polymorphism of X-ray cross-complementing group 3 (XRCC3) Thr241Met (rs#861539), which may be involved in the repair of DNA double-strand breaks caused by carcinogens such as CagA, a protein produced by H. pylori, has been less well elaborated. METHODS We conducted a hospital-based case-control study, including 721 patients with pathologically confirmed GAA and 989 individually matched controls without any evidence of tumors or precancerous lesions to evaluate the associations between this polymorphism and GAA risk in the Guangxi population. XRCC3 codon 241 genotypes and CagA status were determined using TaqMan-PCR and PCR, respectively. RESULTS Increased risks of GAA were found for cagA-positive individuals [odds ratio (OR), 7.31; 95% confidence interval (CI), 5.87-9.09]. We also found that individuals with the XRCC3 genotypes with codon 241 Met (namely XRCC3-TM or XRCC3-MM) had an increased risk of GAA compared with those with the homozygote of XRCC3 codon 241 Thr alleles (namely XRCC3-TT, adjusted ORs 1.76 and 3.73; 95% CIs 1.37-2.24 and 2.66-5.23, respectively). The risk of GAA, moreover, appeared to differ more significantly among individuals featuring cagA-positive status, whose adjusted ORs (95% CIs) were 11.31 (8.34-15.33) and 27.48 (15.17-49.78), respectively. CONCLUSION These results suggest that XRCC3 Thr241Met polymorphism may be associated with the risk of GAA related to CagA.
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Affiliation(s)
- Lei Zhao
- Department of Pathology, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
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46
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Wang H, Han J, Chen D, Duan X, Gao X, Wang X, Shao S. Characterization of CagI in the cag pathogenicity island of Helicobacter pylori. Curr Microbiol 2011; 64:191-6. [PMID: 22109855 DOI: 10.1007/s00284-011-0043-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2011] [Accepted: 10/24/2011] [Indexed: 02/06/2023]
Abstract
Helicobacter pylori is a highly successful human-specific gastric pathogen that infects up to 50% of the world's population. Virulent H. pylori isolates harbor the cytotoxin-associated genes pathogenicity island (cag-PAI), which encodes a type IV secretion system that translocates bacterial effector (e.g., CagA oncoprotein) molecules into host cells. Although some cag-PAI genes are shown to be required for CagA delivery or localization, the majority have no known function. In the current study, the authors performed a cell components fractionation assay and showed that CagI, one of the cag-PAI proteins located in the bacterial membrane, was not translocated into host cells. The homologous recombination method then was used to construct the isogenic mutant of H. pylori cagI, and the translocation assay was performed. The results showed that the isogenic mutant of H. pylori NCTC 11637 cagI could cause a reduction in the degree of CagA translocation. Overall, the results suggested that CagI might be an accessory component of the CagA secretion system not translocated into host cells and that it is located in the bacterial membrane.
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Affiliation(s)
- Hua Wang
- School of Medical Science and Laboratory Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013 Jiangsu, People's Republic of China
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Wessler S, Gimona M, Rieder G. Regulation of the actin cytoskeleton in Helicobacter pylori-induced migration and invasive growth of gastric epithelial cells. Cell Commun Signal 2011; 9:27. [PMID: 22044652 PMCID: PMC3214149 DOI: 10.1186/1478-811x-9-27] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2011] [Accepted: 11/01/2011] [Indexed: 02/08/2023] Open
Abstract
Dynamic rearrangement of the actin cytoskeleton is a significant hallmark of Helicobacter pylori (H. pylori) infected gastric epithelial cells leading to cell migration and invasive growth. Considering the cellular mechanisms, the type IV secretion system (T4SS) and the effector protein cytotoxin-associated gene A (CagA) of H. pylori are well-studied initiators of distinct signal transduction pathways in host cells targeting kinases, adaptor proteins, GTPases, actin binding and other proteins involved in the regulation of the actin lattice. In this review, we summarize recent findings of how H. pylori functionally interacts with the complex signaling network that controls the actin cytoskeleton of motile and invasive gastric epithelial cells.
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Affiliation(s)
- Silja Wessler
- Division of Molecular Biology, Department of Microbiology, University of Salzburg, Salzburg, Austria.
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48
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Matsui H, Nagano Y, Shimokawa O, Kaneko T, Rai K, Udo J, Hirayama A, Nakamura Y, Indo HP, Majima HJ, Hyodo I. Gastric acid induces mitochondrial superoxide production and lipid peroxidation in gastric epithelial cells. J Gastroenterol 2011; 46:1167-76. [PMID: 21789481 DOI: 10.1007/s00535-011-0434-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2011] [Accepted: 06/06/2011] [Indexed: 02/04/2023]
Abstract
BACKGROUND Gastric hydrochloric acid (HCl) has been regarded as an inciting factor in gastric mucosal injuries and has been reported to induce lipid peroxidation in vitro. However, because HCl is not an oxidant per se, the exact mechanism by which the acid induces lipid peroxidation is unknown. We hypothesized that gastric acid may disrupt mitochondrial transmembrane potential and induce the production of superoxide in mitochondria, which subsequently may induce lipid peroxidation and apoptosis in gastric mucosal cells. METHODS Firstly we treated gastric epithelial RGM1 cells with solutions containing various concentrations of HCl (i.e., of varying pH), and examined cellular injury, lipid peroxidation, and apoptosis with specific fluorescent dyes. Secondly, we performed electron paramagnetic resonance (EPR) spectroscopy of isolated, acid-exposed mitochondria from the cells, using a spin-trapping reagent for superoxide, 5-(2,2-dimethyl-1,3-propoxy cyclophosphoryl)-5-methyl-1-pyrroline N-oxide (CYPMPO). Finally, we established novel RGM1 cells that overexpressed manganese superoxide dismutase (MnSOD), which removes superoxide from mitochondria, and examined the effect of acid treatment on cellular membrane lipid peroxidation. RESULTS The results indicated that the exposure to acid indeed induced cellular injury, cellular lipid peroxidation, apoptosis, and the demonstration of the exact superoxide spectra on EPR spectroscopy in gastric epithelial cells, and that overexpression of MnSOD decreased superoxide production and prevented cellular lipid peroxidation. CONCLUSION These results suggested that gastric acid, like nonsteroidal anti-inflammatory drugs (NSAIDs), induces mitochondrial superoxide production, which induces gastric cellular injury by triggering cellular lipid peroxidation and apoptosis.
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Affiliation(s)
- Hirofumi Matsui
- The Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
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Wang H, Sun Y, Liu S, Yu H, Li W, Zeng J, Chen C, Jia J. Upregulation of progranulin by Helicobacter pylori in human gastric epithelial cells via p38MAPK and MEK1/2 signaling pathway: role in epithelial cell proliferation and migration. ACTA ACUST UNITED AC 2011; 63:82-92. [PMID: 21707777 DOI: 10.1111/j.1574-695x.2011.00833.x] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Helicobacter pylori is a major human pathogen associated with gastric diseases such as chronic active gastritis, peptic ulcer, and gastric carcinoma. The growth factor progranulin (PGRN) is a secreted glycoprotein that functions as an important regulator of cell growth, migration, and transformation. We aimed to determine the molecular mechanisms by which H. pylori upregulates the expression of PGRN and the relationship between H. pylori infection and production of PGRN in controlling cell proliferation and migration. Levels of PGRN were examined in gastric tissues from patients and in vitro in gastric epithelial cells. Cell proliferation was measured by colony formation assay. Cell migration was monitored by wound healing migration assay. PGRN protein levels were increased in patients with gastritis and gastric cancer tissue. Infection of gastric epithelial cells with H. pylori significantly increased PGRN expression in a time-dependent manner. Blockade of the p38 and MEK1/2 pathway by inhibitor inhibited H. pylori-mediated PGRN upregulation. Activation of p38 and MEK1/2 pathway by H. pylori was also identified. Knockdown of PGRN attenuated the H. pylori-induced proliferative activity and migration of cancer cells. These findings suggest that the upregulation of PGRN in H. pylori-infected gastric epithelial cells may contribute to the carcinogenic process.
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Affiliation(s)
- Hongyan Wang
- Department of Microbiology, Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan, Shandong, China
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50
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Alkylhydroperoxide reductase of Helicobacter pylori as a biomarker for gastric patients with different pathological manifestations. Biochimie 2011; 93:1115-23. [DOI: 10.1016/j.biochi.2011.03.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2010] [Accepted: 03/17/2011] [Indexed: 12/25/2022]
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