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He L, Zhang X, Zhang S, Wang Y, Hu W, Li J, Liu Y, Liao Y, Peng X, Li J, Zhao H, Wang L, Lv Y, Hu C, Yang S. H. Pylori-Facilitated TERT/Wnt/β-Catenin Triggers Spasmolytic Polypeptide-Expressing Metaplasia and Oxyntic Atrophy. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2401227. [PMID: 39587848 PMCID: PMC11744579 DOI: 10.1002/advs.202401227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 10/23/2024] [Indexed: 11/27/2024]
Abstract
Persistent H. pylori infection triggers the repair program of the mucosa, such as spasmolytic polypeptide-expressing metaplasia (SPEM). However, the mechanism underlying the initiation of SPEM in gastric tissues by H. pylori remains unclear. Here, an increase in telomerase reverse transcriptase (TERT) protein expression is observed in chief cells upon infection with cagA-positive H. pylori. Tert knockout significantly ameliorated H. pylori-induced SPEM and single-cell RNA sequencing demonstrated that the Wnt/β-Catenin pathway is suppressed in gastric cells with Tert knockout. Mechanism study revealed that CagA elevated TERT abundance by disrupting the interaction between TERT and its novel E3 ligase, SYVN1. Interestingly, Nitazoxanide effectively relieved SPEM via inhibition of the Wnt/β-Catenin signaling in vivo. This results clarified the mechanism underlying which CagA activated the TERT/Wnt/β-Catenin pathway, thus promoting the dedifferentiation of chief cells and the occurrence of SPEM in gastric mucosa. This highlights a molecular basis for targeting CagA-activated Wnt signaling in chief cells for the treatment of gastric precancerous lesions.
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Affiliation(s)
- Lijiao He
- Department of GastroenterologyThe Second Affiliated Hospital of Army Medical UniversityChongqing400037China
| | - Xiao Zhang
- Department of GastroenterologyThe Second Affiliated Hospital of Army Medical UniversityChongqing400037China
- Cancer Center of Daping HospitalArmy Medical UniversityChongqing400000China
| | - Shengwei Zhang
- Department of GastroenterologyThe Second Affiliated Hospital of Army Medical UniversityChongqing400037China
- Department of GastroenterologyThe 987th Hospital of the Joint Logistics Support Force of the People's Liberation Army of China, BaojiShaanxi721000China
| | - Yi Wang
- Department of GastroenterologyThe Second Affiliated Hospital of Army Medical UniversityChongqing400037China
- Biological Science Research CenterSouthwest UniversityChongqing400715China
| | - Weichao Hu
- Department of GastroenterologyThe Second Affiliated Hospital of Army Medical UniversityChongqing400037China
| | - Jie Li
- Department of GastroenterologyThe Second Affiliated Hospital of Army Medical UniversityChongqing400037China
| | - Yunyi Liu
- Department of GastroenterologyThe Second Affiliated Hospital of Army Medical UniversityChongqing400037China
| | - Yu Liao
- Department of GastroenterologyThe Second Affiliated Hospital of Army Medical UniversityChongqing400037China
| | - Xue Peng
- Department of GastroenterologyThe Second Affiliated Hospital of Army Medical UniversityChongqing400037China
| | - Jianjun Li
- Department of GastroenterologyThe Second Affiliated Hospital of Army Medical UniversityChongqing400037China
| | - Haiyan Zhao
- Department of GastroenterologyThe Second Affiliated Hospital of Army Medical UniversityChongqing400037China
| | - Liting Wang
- Department of GastroenterologyThe Second Affiliated Hospital of Army Medical UniversityChongqing400037China
- Central LaboratoryArmy Medical UniversityChongqing400038China
| | - Yang‐Fan Lv
- Department of PathologyThe Second Affiliated Hospital of Army Medical UniversityChongqing400037China
| | - Chang‐Jiang Hu
- Department of GastroenterologyThe Second Affiliated Hospital of Army Medical UniversityChongqing400037China
| | - Shi‐Ming Yang
- Department of GastroenterologyThe Second Affiliated Hospital of Army Medical UniversityChongqing400037China
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Kuang W, Xu J, Xu F, Huang W, Majid M, Shi H, Yuan X, Ruan Y, Hu X. Current study of pathogenetic mechanisms and therapeutics of chronic atrophic gastritis: a comprehensive review. Front Cell Dev Biol 2024; 12:1513426. [PMID: 39720008 PMCID: PMC11666564 DOI: 10.3389/fcell.2024.1513426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Accepted: 11/25/2024] [Indexed: 12/26/2024] Open
Abstract
Chronic atrophic gastritis (CAG) is a prevalent digestive system disease characterized by atrophy of the gastric mucosa and the disappearance of inherent gastric glands. According to the theory of Correa's cascade, CAG is an important pathological stage in the transformation from normal condition to gastric carcinoma. In recent years, the global incidence of CAG has been increasing due to pathogenic factors, including Helicobacter pylori infection, bile reflux, and the consumption of processed meats. In this review, we comprehensively described the etiology and clinical diagnosis of CAG. We focused on elucidating the regulatory mechanisms and promising therapeutic targets in CAG, with the expectation of providing insights and theoretical support for future research on CAG.
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Affiliation(s)
- Weihong Kuang
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Dongguan, China
- Dongguan Key Laboratory of Traditional Chinese Medicines for Prevention and Treatment of Digestive Diseases, Guangdong Medical University, Dongguan, China
- Dongguan Key Laboratory of Chronic Inflammatory Diseases, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
| | - Jialin Xu
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Dongguan, China
- Dongguan Key Laboratory of Traditional Chinese Medicines for Prevention and Treatment of Digestive Diseases, Guangdong Medical University, Dongguan, China
| | - Fenting Xu
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Dongguan, China
- Dongguan Key Laboratory of Traditional Chinese Medicines for Prevention and Treatment of Digestive Diseases, Guangdong Medical University, Dongguan, China
| | - Weizhen Huang
- Cancer Center, The First Huizhou Affiliated Hospital, Guangdong Medical University, Huizhou, China
| | - Muhammad Majid
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Dongguan, China
- Dongguan Key Laboratory of Traditional Chinese Medicines for Prevention and Treatment of Digestive Diseases, Guangdong Medical University, Dongguan, China
| | - Hui Shi
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Dongguan, China
- Dongguan Key Laboratory of Traditional Chinese Medicines for Prevention and Treatment of Digestive Diseases, Guangdong Medical University, Dongguan, China
| | - Xia Yuan
- Cancer Center, The First Huizhou Affiliated Hospital, Guangdong Medical University, Huizhou, China
| | - Yongdui Ruan
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Dongguan, China
- Dongguan Key Laboratory of Traditional Chinese Medicines for Prevention and Treatment of Digestive Diseases, Guangdong Medical University, Dongguan, China
- Cancer Center, The First Huizhou Affiliated Hospital, Guangdong Medical University, Huizhou, China
| | - Xianjing Hu
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Dongguan, China
- Dongguan Key Laboratory of Traditional Chinese Medicines for Prevention and Treatment of Digestive Diseases, Guangdong Medical University, Dongguan, China
- Dongguan Key Laboratory of Chronic Inflammatory Diseases, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
- Department of Acupuncture, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
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Men X, Shi X, Xu Q, Liu M, Yang H, Wang L, Men X, Xu H. Exploring the pathogenesis of chronic atrophic gastritis with atherosclerosis via microarray data analysis. Medicine (Baltimore) 2024; 103:e37798. [PMID: 38640295 PMCID: PMC11029937 DOI: 10.1097/md.0000000000037798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Revised: 02/26/2024] [Accepted: 03/14/2024] [Indexed: 04/21/2024] Open
Abstract
Although several studies have reported a link between chronic atrophic gastritis (CAG) and atherosclerosis, the underlying mechanisms have not been elucidated. The present study aimed to investigate the molecular mechanisms common to both diseases from a bioinformatics perspective. Gene expression profiles were obtained from the Gene Expression Omnibus database. Data on atherosclerosis and CAG were downloaded from the GSE28829 and GSE60662 datasets, respectively. We identified the differentially expressed genes co-expressed in CAG and atherosclerosis before subsequent analyses. We constructed and identified the hub genes and performed functional annotation. Finally, the transcription factor (TF)-target genes regulatory network was constructed. In addition, we validated core genes and certain TFs. We identified 116 common differentially expressed genes after analyzing the 2 datasets (GSE60662 and GSE28829). Functional analysis highlighted the significant contribution of immune responses and the positive regulation of tumor necrosis factor production and T cells. In addition, phagosomes, leukocyte transendothelial migration, and cell adhesion molecules strongly correlated with both diseases. Furthermore, 16 essential hub genes were selected with cytoHubba, including PTPRC, TYROBP, ITGB2, LCP2, ITGAM, FCGR3A, CSF1R, IRF8, C1QB, TLR2, IL10RA, ITGAX, CYBB, LAPTM5, CD53, CCL4, and LY86. Finally, we searched for key gene-related TFs, especially SPI1. Our findings reveal a shared pathogenesis between CAG and atherosclerosis. Such joint pathways and hub genes provide new insights for further studies.
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Affiliation(s)
- Xiaoxiao Men
- Department of Gastroenterology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xiuju Shi
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Qianqian Xu
- Department of Gastroenterology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Mingyue Liu
- Department of Gastroenterology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Hongli Yang
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Ling Wang
- Hunan Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha, PR China
| | - Xiaoju Men
- Hunan Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha, PR China
| | - Hongwei Xu
- Department of Gastroenterology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
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He Y, Liu HH, Zhou XL, He TT, Zhang AZ, Wang X, Wei SZ, Li HT, Chen LS, Chang L, Zhao YL, Jing MY. Rutaecarpine Ameliorates Murine N-Methyl-N'-Nitro-N-Nitrosoguanidine-Induced Chronic Atrophic Gastritis by Sonic Hedgehog Pathway. Molecules 2023; 28:6294. [PMID: 37687125 PMCID: PMC10489734 DOI: 10.3390/molecules28176294] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 07/25/2023] [Accepted: 08/18/2023] [Indexed: 09/10/2023] Open
Abstract
CAG is a burdensome and progressive disease. Numerous studies have shown the effectiveness of RUT in digestive system diseases. The therapeutic effects of RUT on MNNG-induced CAG and the potential mechanisms were probed. MNNG administration was employed to establish a CAG model. The HE and ELISA methods were applied to detect the treatment effects. WB, qRT-PCR, immunohistochemistry, TUNEL, and GES-1 cell flow cytometry approaches were employed to probe the mechanisms. The CAG model was successfully established. The ELISA and HE staining data showed that the RUT treatment effects on CAG rats were reflected by the amelioration of histological damage. The qRT-PCR and WB analyses indicated that the protective effect of RUT is related to the upregulation of the SHH pathway and downregulation of the downstream of apoptosis to improve gastric cellular survival. Our data suggest that RUT induces a gastroprotective effect by upregulating the SHH signaling pathway and stimulating anti-apoptosis downstream.
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Affiliation(s)
- Yong He
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (Y.H.); (X.W.)
| | - Hong-Hong Liu
- Department of Pharmacy, Chinese PLA General Hospital, Beijing 100039, China
| | - Xue-Lin Zhou
- Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing 100039, China
| | - Ting-Ting He
- Department of Pharmacy, Chinese PLA General Hospital, Beijing 100039, China
| | - Ao-Zhe Zhang
- Department of Pharmacy, Chinese PLA General Hospital, Beijing 100039, China
| | - Xin Wang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (Y.H.); (X.W.)
| | - Shi-Zhang Wei
- Department of Pharmacy, Chinese PLA General Hospital, Beijing 100039, China
| | - Hao-Tian Li
- Department of Pharmacy, Chinese PLA General Hospital, Beijing 100039, China
| | - Li-Sheng Chen
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (Y.H.); (X.W.)
| | - Lei Chang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Yan-Ling Zhao
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (Y.H.); (X.W.)
- Department of Pharmacy, Chinese PLA General Hospital, Beijing 100039, China
| | - Man-Yi Jing
- Department of Pharmacy, Chinese PLA General Hospital, Beijing 100039, China
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Chi ZC. Hedgehog/GLI and gastric cancer: Research progress and current status. Shijie Huaren Xiaohua Zazhi 2023; 31:389-396. [DOI: 10.11569/wcjd.v31.i10.389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/26/2023] Open
Abstract
Hedgehog/GLI (Hh/GLI) is an important signaling pathway. It has been confirmed in various cancer studies that mutated or dysregulated Hh signals may be the behavioral phenotype of tumors, leading to the occurrence of various cancers. The abnormally activated Hh pathway endows tumor cells with a tendency to occur, proliferate, and migrate. In recent years, studies have found that the Hh signaling pathway induces gastric cancer (GC) invasion and epithelial mesenchymal transition. This article reviews the research progress and current status of Hh/GLI related to GC. Unveiling the new veil of GC occurrence will open a new approach for targeted therapy of this malignancy.
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Wen J, Xuan B, Liu Y, Wang L, He L, Meng X, Zhou T, Wang Y. NLRP3 inflammasome-induced pyroptosis in digestive system tumors. Front Immunol 2023; 14:1074606. [PMID: 37081882 PMCID: PMC10110858 DOI: 10.3389/fimmu.2023.1074606] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Accepted: 03/03/2023] [Indexed: 04/07/2023] Open
Abstract
Programmed cell death (PCD) refers to cell death in a manner that depends on specific genes encoding signals or activities. PCD includes apoptosis, pyroptosis, autophagy and necrosis (programmed necrosis). Among these mechanisms, pyroptosis is mediated by the gasdermin family and is accompanied by inflammatory and immune responses. When pathogens or other danger signals are detected, cytokine action and inflammasomes (cytoplasmic multiprotein complexes) lead to pyroptosis. The relationship between pyroptosis and cancer is complex and the effect of pyroptosis on cancer varies in different tissue and genetic backgrounds. On the one hand, pyroptosis can inhibit tumorigenesis and progression; on the other hand, pyroptosis, as a pro-inflammatory death, can promote tumor growth by creating a microenvironment suitable for tumor cell growth. Indeed, the NLRP3 inflammasome is known to mediate pyroptosis in digestive system tumors, such as gastric cancer, pancreatic ductal adenocarcinoma, gallbladder cancer, oral squamous cell carcinoma, esophageal squamous cell carcinoma, in which a pyroptosis-induced cellular inflammatory response inhibits tumor development. The same process occurs in hepatocellular carcinoma and some colorectal cancers. The current review summarizes mechanisms and pathways of pyroptosis, outlining the involvement of NLRP3 inflammasome-mediated pyroptosis in digestive system tumors.
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Affiliation(s)
- Jiexia Wen
- Department of Central Laboratory, The First Hospital of Qinhuangdao, Hebei Medical University, Qinhuangdao, Hebei, China
| | - Bin Xuan
- Department of General Surgery, The First Hospital of Qinhuangdao, Hebei Medical University, Qinhuangdao, Hebei, China
| | - Yang Liu
- Department of General Surgery, The First Hospital of Qinhuangdao, Hebei Medical University, Qinhuangdao, Hebei, China
| | - Liwei Wang
- Department of General Surgery, The First Hospital of Qinhuangdao, Hebei Medical University, Qinhuangdao, Hebei, China
| | - Li He
- Department of General Surgery, The First Hospital of Qinhuangdao, Hebei Medical University, Qinhuangdao, Hebei, China
| | - Xiangcai Meng
- Department of General Surgery, The First Hospital of Qinhuangdao, Hebei Medical University, Qinhuangdao, Hebei, China
| | - Tao Zhou
- Department of General Surgery, The First Hospital of Qinhuangdao, Hebei Medical University, Qinhuangdao, Hebei, China
| | - Yimin Wang
- Department of Central Laboratory, The First Hospital of Qinhuangdao, Hebei Medical University, Qinhuangdao, Hebei, China
- Department of General Surgery, The First Hospital of Qinhuangdao, Hebei Medical University, Qinhuangdao, Hebei, China
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IL-1β, an important cytokine affecting Helicobacter pylori-mediated gastric carcinogenesis. Microb Pathog 2023; 174:105933. [PMID: 36494022 DOI: 10.1016/j.micpath.2022.105933] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 12/01/2022] [Accepted: 12/05/2022] [Indexed: 12/12/2022]
Abstract
Infection with Helicobacter pylori (H. pylori) is prevalent around the world and responsible for gastric cancer (GC). The development of GC from gastritis is closely associated with the bacterial virulence and the body's immune response ability. In this process, interleukin-1β (IL-1β) plays an important role. Under H. pylori infection, IL-1β is highly expressed that result in gastric acid inhibition, GC-related gene methylations and disfunctions, angiogenesis. Nod-like receptor pyrin domain containing 3 (NLRP3) inflammasome mediates IL-1β maturation in cells such as macrophages, neutrophils and dendritic cells. But how does IL-1β get released across the cell membrane still unclear. In this review, we focus on the secretion mechanism of IL-1β across the membrane, and to explore the role of IL-1β in the progression of GC.
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Abstract
Like most solid tumours, the microenvironment of epithelial-derived gastric adenocarcinoma (GAC) consists of a variety of stromal cell types, including fibroblasts, and neuronal, endothelial and immune cells. In this article, we review the role of the immune microenvironment in the progression of chronic inflammation to GAC, primarily the immune microenvironment driven by the gram-negative bacterial species Helicobacter pylori. The infection-driven nature of most GACs has renewed awareness of the immune microenvironment and its effect on tumour development and progression. About 75-90% of GACs are associated with prior H. pylori infection and 5-10% with Epstein-Barr virus infection. Although 50% of the world's population is infected with H. pylori, only 1-3% will progress to GAC, with progression the result of a combination of the H. pylori strain, host susceptibility and composition of the chronic inflammatory response. Other environmental risk factors include exposure to a high-salt diet and nitrates. Genetically, chromosome instability occurs in ~50% of GACs and 21% of GACs are microsatellite instability-high tumours. Here, we review the timeline and pathogenesis of the events triggered by H. pylori that can create an immunosuppressive microenvironment by modulating the host's innate and adaptive immune responses, and subsequently favour GAC development.
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Hoffmann W. Self-Renewal and Cancers of the Gastric Epithelium: An Update and the Role of the Lectin TFF1 as an Antral Tumor Suppressor. Int J Mol Sci 2022; 23:ijms23105377. [PMID: 35628183 PMCID: PMC9141172 DOI: 10.3390/ijms23105377] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 05/09/2022] [Accepted: 05/10/2022] [Indexed: 11/16/2022] Open
Abstract
In 2020, gastric cancer was the fourth leading cause of cancer deaths globally. About 90% of gastric cancers are sporadic and the vast majority are correlated with Helicobacter pylori infection; whereas familial clustering is observed in about 10% of cases. Gastric cancer is now considered to be a disease originating from dysregulated self-renewal of the gastric glands in the setting of an inflammatory environment. The human stomach contains two types of gastric units, which show bi-directional self-renewal from a complex variety of stem cells. This review focuses on recent progress concerning the characterization of the different stem cell populations and the mainly mesenchymal signals triggering their stepwise differentiation as well as the genesis of pre-cancerous lesions and carcinogenesis. Furthermore, a model is presented (Lectin-triggered Receptor Blocking Hypothesis) explaining the role of the lectin TFF1 as an antral tumor suppressor possibly regulating Lgr5+ antral stem cells in a paracrine or maybe autocrine fashion, with neighboring antral gland cells having a role as niche cells.
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Affiliation(s)
- Werner Hoffmann
- Institute of Molecular Biology and Medicinal Chemistry, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany
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Frauenlob T, Neuper T, Mehinagic M, Dang HH, Boraschi D, Horejs-Hoeck J. Helicobacter pylori Infection of Primary Human Monocytes Boosts Subsequent Immune Responses to LPS. Front Immunol 2022; 13:847958. [PMID: 35309333 PMCID: PMC8924073 DOI: 10.3389/fimmu.2022.847958] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 02/14/2022] [Indexed: 12/04/2022] Open
Abstract
Infection with Helicobacter pylori (H. pylori) affects almost half of the world's population and is a major cause of stomach cancer. Although immune cells react strongly to this gastric bacterium, H. pylori is still one of the rare pathogens that can evade elimination by the host and cause chronic inflammation. In the present study, we characterized the inflammatory response of primary human monocytes to repeated H. pylori infection and their responsiveness to an ensuing bacterial stimulus. We show that, although repeated stimulations with H. pylori do not result in an enhanced response, H. pylori-primed monocytes are hyper-responsive to an Escherichia coli-lipopolysaccharide (LPS) stimulation that takes place shortly after infection. This hyper-responsiveness to bacterial stimuli is observed upon infection with viable H. pylori only, while heat-killed H. pylori fails to boost both cytokine secretion and STAT activation in response to LPS. When the secondary challenge occurs several days after the primary infection with live bacteria, H. pylori-infected monocytes lose their hyper-responsiveness. The observation that H. pylori makes primary human monocytes more susceptible to subsequent/overlapping stimuli provides an important basis to better understand how H. pylori can maintain chronic inflammation and thus contribute to gastric cancer progression.
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Affiliation(s)
- Tobias Frauenlob
- Department of Biosciences, University of Salzburg, Salzburg, Austria
- Cancer Cluster Salzburg (CCS), Salzburg, Austria
| | - Theresa Neuper
- Department of Biosciences, University of Salzburg, Salzburg, Austria
| | - Muamera Mehinagic
- Department of Biosciences, University of Salzburg, Salzburg, Austria
| | - Hieu-Hoa Dang
- Department of Biosciences, University of Salzburg, Salzburg, Austria
| | - Diana Boraschi
- Institute of Biochemistry and Cell Biology (IBBC), National Research Council (CNR), Napoli, Italy
- Department of Biology and Evolution of Marine Organisms, Napoli, Italy
- Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences (CAS), Shenzhen, China
| | - Jutta Horejs-Hoeck
- Department of Biosciences, University of Salzburg, Salzburg, Austria
- Cancer Cluster Salzburg (CCS), Salzburg, Austria
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Duan S, Rico K, Merchant JL. Gastrin: From Physiology to Gastrointestinal Malignancies. FUNCTION (OXFORD, ENGLAND) 2021; 3:zqab062. [PMID: 35330921 PMCID: PMC8788842 DOI: 10.1093/function/zqab062] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 11/14/2021] [Accepted: 11/16/2021] [Indexed: 01/07/2023]
Abstract
Abetted by widespread usage of acid-suppressing proton pump inhibitors (PPIs), the mitogenic actions of the peptide hormone gastrin are being revisited as a recurring theme in various gastrointestinal (GI) malignancies. While pathological gastrin levels are intricately linked to hyperplasia of enterochromaffin-like cells leading to carcinoid development, the signaling effects exerted by gastrin on distinct cell types of the gastric mucosa are more nuanced. Indeed, mounting evidence suggests dichotomous roles for gastrin in both promoting and suppressing tumorigenesis. Here, we review the major upstream mediators of gastrin gene regulation, including inflammation secondary to Helicobacter pylori infection and the use of PPIs. We further explore the molecular biology of gastrin in GI malignancies, with particular emphasis on the regulation of gastrin in neuroendocrine neoplasms. Finally, we highlight tissue-specific transcriptional targets as an avenue for targetable therapeutics.
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Affiliation(s)
- Suzann Duan
- Department of Medicine, Division of Gastroenterology and Hepatology, Arizona Comprehensive Cancer Center, University of Arizona, Tucson, AZ 85724, USA
| | - Karen Rico
- Department of Medicine, Division of Gastroenterology and Hepatology, Arizona Comprehensive Cancer Center, University of Arizona, Tucson, AZ 85724, USA
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Ding L, Sontz EA, Saqui-Salces M, Merchant JL. Interleukin-1β Suppresses Gastrin via Primary Cilia and Induces Antral Hyperplasia. Cell Mol Gastroenterol Hepatol 2021; 11:1251-1266. [PMID: 33347972 PMCID: PMC8005816 DOI: 10.1016/j.jcmgh.2020.12.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 12/10/2020] [Accepted: 12/11/2020] [Indexed: 01/02/2023]
Abstract
BACKGROUND & AIMS Helicobacter pylori infection in humans typically begins with colonization of the gastric antrum. The initial Th1 response occasionally coincides with an increase in gastrin secretion. Subsequently, the gastritis segues to chronic atrophic gastritis, metaplasia, dysplasia and distal gastric cancer. Despite these well characterized clinical events, the link between inflammatory cytokines and non-cardia gastric cancer remains difficult to study in mouse models. Prior studies have demonstrated that overexpression of the Hedgehog (HH) effector GLI2 induces loss of gastrin (atrophy) and antral hyperplasia. To determine the link between specific cytokines, HH signaling and pre-neoplastic changes in the gastric antrum. METHODS Mouse lines were created to conditionally direct IL1β or IFN-γ to the antrum using the Gastrin-CreERT2 and Tet activator. Primary cilia, which transduces HH signaling, on G cells were disrupted by deleting the ciliary motor protein KIF3a. Phenotypic changes were assessed by histology and western blots. A subclone of GLUTag enteroendocrine cells selected for gastrin expression and the presence of primary cilia was treated with recombinant SHH, IL1β or IFN-γ with or without kif3a siRNA. RESULTS IFN-γ increased gastrin and induced antral hyperplasia. However, antral expression of IL1β suppressed tissue and serum gastrin, while also inducing antral hyperplasia. IFN-γ treatment of GLUTAg cells suppressed GLI2 and induced gastrin, without affecting cilia length. By contrast, IL1β treatment doubled primary cilia length, induced GLI2 and suppressed gastrin gene expression. Knocking down kif3a in GLUTAg cells mitigated SHH or IL1β suppression of gastrin. CONCLUSIONS Overexpression of IL1β in the antrum was sufficient to induce antral hyperplasia coincident with suppression of gastrin via primary cilia. ORCID: #0000-0002-6559-8184.
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Affiliation(s)
- Lin Ding
- Department of Internal Medicine-Gastroenterology, University of Michigan, Ann Arbor, Michigan; Department of Medicine-Gastroenterology, University of Arizona, Tucson, Arizona
| | - Erica A Sontz
- Department of Medicine-Gastroenterology, University of Arizona, Tucson, Arizona
| | | | - Juanita L Merchant
- Department of Internal Medicine-Gastroenterology, University of Michigan, Ann Arbor, Michigan; Department of Medicine-Gastroenterology, University of Arizona, Tucson, Arizona.
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Analysis of Gastrointestinal Responses Revealed Both Shared and Specific Targets of Zinc Oxide and Carbadox in Weaned Pigs. Antibiotics (Basel) 2020; 9:antibiotics9080463. [PMID: 32751572 PMCID: PMC7460413 DOI: 10.3390/antibiotics9080463] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 07/20/2020] [Accepted: 07/29/2020] [Indexed: 12/28/2022] Open
Abstract
Antibiotics and pharmacological zinc supplementation were commonly used as growth promoters for several decades in the swine industry before being limited because of public health and environmental concerns. Further, the physiological and metabolic responses associated with their growth promotion effects are unclear. To characterize these responses induced by pharmacological zinc supplementation (2500 mg/kg) and carbadox (55 mg/kg), 192 post-weaning pigs were fed basal and test diets for 43 days. Compared with basal, pharmacological zinc and carbadox independently improved growth performance. Pharmacological zinc increased gastric mucosa thickness compared with basal zinc, while carbadox increased intestinal villus:crypt ratio compared with non-carbadox. Pharmacological zinc and carbadox independently reduced interleukin (IL)-1β concentration compared with basal zinc and non-carbadox. Pharmacological zinc increased IL-1RA:IL-1 ratio by 42% compared with basal zinc, while carbadox tended to increase the IL-10 and IL10:IL-12 ratio compared with non-carbadox. Carbadox increased fecal concentrations of histidine and lysine compared with non-carbadox. The independent effect of pharmacological zinc and carbadox on morphology and nutrient metabolism, and their shared effect on immunity may contribute to the additive effect on growth promotion. These results further confirmed the concept that growth promotion is multifactorial intervention. Therefore, elucidating growth-promoting effects and searching for alternatives should include wide-spectrum evaluation.
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Engevik AC, Kaji I, Goldenring JR. The Physiology of the Gastric Parietal Cell. Physiol Rev 2020; 100:573-602. [PMID: 31670611 PMCID: PMC7327232 DOI: 10.1152/physrev.00016.2019] [Citation(s) in RCA: 143] [Impact Index Per Article: 28.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 10/10/2019] [Accepted: 10/13/2019] [Indexed: 12/11/2022] Open
Abstract
Parietal cells are responsible for gastric acid secretion, which aids in the digestion of food, absorption of minerals, and control of harmful bacteria. However, a fine balance of activators and inhibitors of parietal cell-mediated acid secretion is required to ensure proper digestion of food, while preventing damage to the gastric and duodenal mucosa. As a result, parietal cell secretion is highly regulated through numerous mechanisms including the vagus nerve, gastrin, histamine, ghrelin, somatostatin, glucagon-like peptide 1, and other agonists and antagonists. The tight regulation of parietal cells ensures the proper secretion of HCl. The H+-K+-ATPase enzyme expressed in parietal cells regulates the exchange of cytoplasmic H+ for extracellular K+. The H+ secreted into the gastric lumen by the H+-K+-ATPase combines with luminal Cl- to form gastric acid, HCl. Inhibition of the H+-K+-ATPase is the most efficacious method of preventing harmful gastric acid secretion. Proton pump inhibitors and potassium competitive acid blockers are widely used therapeutically to inhibit acid secretion. Stimulated delivery of the H+-K+-ATPase to the parietal cell apical surface requires the fusion of intracellular tubulovesicles with the overlying secretory canaliculus, a process that represents the most prominent example of apical membrane recycling. In addition to their unique ability to secrete gastric acid, parietal cells also play an important role in gastric mucosal homeostasis through the secretion of multiple growth factor molecules. The gastric parietal cell therefore plays multiple roles in gastric secretion and protection as well as coordination of physiological repair.
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Affiliation(s)
- Amy C Engevik
- Departments of Surgery and of Cell and Developmental Biology and the Epithelial Biology Center, Vanderbilt University School of Medicine, Vanderbilt University Medical Center and the Nashville VA Medical Center, Nashville, Tennessee
| | - Izumi Kaji
- Departments of Surgery and of Cell and Developmental Biology and the Epithelial Biology Center, Vanderbilt University School of Medicine, Vanderbilt University Medical Center and the Nashville VA Medical Center, Nashville, Tennessee
| | - James R Goldenring
- Departments of Surgery and of Cell and Developmental Biology and the Epithelial Biology Center, Vanderbilt University School of Medicine, Vanderbilt University Medical Center and the Nashville VA Medical Center, Nashville, Tennessee
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15
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van Niekerk G, Meaker C, Engelbrecht AM. Nutritional support in sepsis: when less may be more. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2020; 24:53. [PMID: 32059698 PMCID: PMC7023788 DOI: 10.1186/s13054-020-2771-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Accepted: 02/10/2020] [Indexed: 12/28/2022]
Abstract
Despite sound basis to suspect that aggressive and early administration of nutritional support may hold therapeutic benefits during sepsis, recommendations for nutritional support have been somewhat underwhelming. Current guidelines (ESPEN and ASPEN) recognise a lack of clear evidence demonstrating the beneficial effect of nutritional support during sepsis, raising the question: why, given the perceived low efficacy of nutritionals support, are there no high-quality clinical trials on the efficacy of permissive underfeeding in sepsis? Here, we review clinically relevant beneficial effects of permissive underfeeding, motivating the urgent need to investigate the clinical benefits of delaying nutritional support during sepsis.
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Affiliation(s)
- Gustav van Niekerk
- Department of Physiological Sciences, Stellenbosch University, Stellenbosch, South Africa.
| | - Charné Meaker
- Department of Physiological Sciences, Stellenbosch University, Stellenbosch, South Africa
| | - Anna-Mart Engelbrecht
- Department of Physiological Sciences, Stellenbosch University, Stellenbosch, South Africa
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16
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Associations of Interleukin-1 β with H. pylori-Induced Gastric Atrophy and Syndrome of Dampness-Heat in the Spleen and Stomach in Subjects with H. pylori-Related Gastric Diseases. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:6409485. [PMID: 32382299 PMCID: PMC7187723 DOI: 10.1155/2020/6409485] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Accepted: 01/10/2020] [Indexed: 01/10/2023]
Abstract
H. pylori-related gastric diseases (HPGD) are a series of gastric mucosal benign and malignant lesions associated with H. pylori infection. Exploring the pathogenesis of HPGD will be of great significance to prevent and treat gastric malignancy. Traditional Chinese medicine (TCM) syndrome is the essence of TCM, reflecting the state of whole body. Potential similarities of TCM syndrome may provide a new perspective in understanding development and treatment of diseases. To seek an early warning signal for gastric malignant pathology and similarities of TCM syndrome from the viewpoint of molecular biology, we examined the relationships among H. pylori, gastric pathology, and TCM syndrome and effects of Interleukin-1β (IL-1β) gene polymorphisms and expression on gastric pathology and TCM syndrome in HPGD. The results indicated that detection of H. pylori with differentiation of TCM syndrome may have a predictive function to gastric pathology. H. pylori may lead to gastric atrophy via enhancing IL-1β mRNA expression, and IL-1β mRNA overexpression in gastric mucosa may be one of the generality characteristics for H. pylori-negative subjects with syndrome of dampness-heat in the spleen and stomach.
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Xu Y, Song S, Wang Z, Ajani JA. The role of hedgehog signaling in gastric cancer: molecular mechanisms, clinical potential, and perspective. Cell Commun Signal 2019; 17:157. [PMID: 31775795 PMCID: PMC6882007 DOI: 10.1186/s12964-019-0479-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 11/11/2019] [Indexed: 02/07/2023] Open
Abstract
Patients with advanced gastric cancer usually have a poor prognosis and limited therapeutic options. Overcoming this challenge requires novel targets and effective drugs. The Hedgehog (Hh) signaling pathway plays a crucial role in the development of the gastrointestinal tract and maintenance of the physiologic function of the stomach. Aberrantly activated Hh signaling is implicated in carcinogenesis as well as maintenance of cancer stem cells. Somatic mutations in the components of Hh signaling (PTCH1 and SMO) have been shown to be a major cause of basal cell carcinoma, and dozens of Hh inhibitors have been developed. To date, two inhibitors (GDC-0449 and LDE225) have been approved by the U.S. Food and Drug Administration to treat basal cell carcinoma and medulloblastoma. Here, we review the role of the Hh signaling in the carcinogenesis and progression of gastric cancer and summarize recent findings on Hh inhibitors in gastric cancer. Hedgehog signaling is often aberrantly activated and plays an important role during inflammation and carcinogenesis of gastric epithelial cells. Further study of the precise mechanisms of Hh signaling in this disease is needed for the validation of therapeutic targets and evaluation of the clinical utility of Hh inhibitors for gastric cancer.
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Affiliation(s)
- Yan Xu
- Department of Gastrointestinal Medical Oncology, Unit 426, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030-4009, USA.,Department of Surgical Oncology and General Surgery, First Hospital of China Medical University, 155 North Nanjing Street, Shenyang, 110001, People's Republic of China
| | - Shumei Song
- Department of Gastrointestinal Medical Oncology, Unit 426, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030-4009, USA.
| | - Zhenning Wang
- Department of Surgical Oncology and General Surgery, First Hospital of China Medical University, 155 North Nanjing Street, Shenyang, 110001, People's Republic of China.
| | - Jaffer A Ajani
- Department of Gastrointestinal Medical Oncology, Unit 426, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030-4009, USA.
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Holokai L, Chakrabarti J, Broda T, Chang J, Hawkins JA, Sundaram N, Wroblewski LE, Peek RM, Wang J, Helmrath M, Wells JM, Zavros Y. Increased Programmed Death-Ligand 1 is an Early Epithelial Cell Response to Helicobacter pylori Infection. PLoS Pathog 2019; 15:e1007468. [PMID: 30703170 PMCID: PMC6380601 DOI: 10.1371/journal.ppat.1007468] [Citation(s) in RCA: 135] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 02/19/2019] [Accepted: 11/13/2018] [Indexed: 12/24/2022] Open
Abstract
Helicobacter pylori (H. pylori) is the major risk factor for the development of gastric cancer. Our laboratory has reported that the Sonic Hedgehog (Shh) signaling pathway is an early response to infection that is fundamental to the initiation of H. pylori-induced gastritis. H. pylori also induces programmed death ligand 1 (PD-L1) expression on gastric epithelial cells, yet the mechanism is unknown. We hypothesize that H. pylori-induced PD-L1 expression within the gastric epithelium is mediated by the Shh signaling pathway during infection. To identify the role of Shh signaling as a mediator of H. pylori-induced PD-L1 expression, human gastric organoids generated from either induced pluripotent stem cells (HGOs) or tissue (huFGOs) were microinjected with bacteria and treated with Hedgehog/Gli inhibitor GANT61. Gastric epithelial monolayers generated from the huFGOs were also infected with H. pylori and treated with GANT61 to study the role of Hedgehog signaling as a mediator of induced PD-1 expression. A patient-derived organoid/autologous immune cell co-culture system infected with H. pylori and treated with PD-1 inhibitor (PD-1Inh) was developed to study the protective mechanism of PD-L1 in response to bacterial infection. H. pylori significantly increased PD-L1 expression in organoid cultures 48 hours post-infection when compared to uninfected controls. The mechanism was cytotoxic associated gene A (CagA) dependent. This response was blocked by pretreatment with GANT61. Anti-PD-L1 treatment of H. pylori infected huFGOs, co-cultured with autologous patient cytotoxic T lymphocytes and dendritic cells, induced organoid death. H. pylori-induced PD-L1 expression is mediated by the Shh signaling pathway within the gastric epithelium. Cells infected with H. pylori that express PD-L1 may be protected from the immune response, creating premalignant lesions progressing to gastric cancer.
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Affiliation(s)
- Loryn Holokai
- Department of Molecular Genetics, Biochemistry, and Microbiology, Cincinnati OH, United States of America
| | - Jayati Chakrabarti
- Department of Pharmacology and Systems Physiology, University of Cincinnati, Cincinnati OH, United States of America
| | - Taylor Broda
- Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati OH, United States of America
- Center for Stem Cell and Organoid Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati OH, United States of America
| | - Julie Chang
- Department of Biomedical Engineering, University of Cincinnati, Cincinnati OH, United States of America
| | - Jennifer A. Hawkins
- Department of Pediatric Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati OH, United States of America
| | - Nambirajan Sundaram
- Department of Pediatric Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati OH, United States of America
| | - Lydia E. Wroblewski
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States of America
| | - Richard M. Peek
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States of America
| | - Jiang Wang
- Department of Pathology and Lab Medicine, University of Cincinnati College of Medicine, Cincinnati OH, United States of America
| | - Michael Helmrath
- Department of Pediatric Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati OH, United States of America
| | - James M. Wells
- Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati OH, United States of America
- Center for Stem Cell and Organoid Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati OH, United States of America
| | - Yana Zavros
- Department of Pharmacology and Systems Physiology, University of Cincinnati, Cincinnati OH, United States of America
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Chen ST, Ni YH, Li CC, Liu SH. Hepcidin correlates with interleukin-1β and interleukin-6 but not iron deficiency in children with Helicobacter pylori infection. Pediatr Neonatol 2018; 59:611-617. [PMID: 29548703 DOI: 10.1016/j.pedneo.2018.02.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Revised: 12/26/2017] [Accepted: 02/07/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Helicobacter pylori infection is associated with iron deficiency (ID) in children. Inflammatory cytokine reactions could influence the consequences of H. pylori infection. Hepcidin is an important regulator in iron homeostasis and could be induced by chronic inflammation. The relationship between hepcidin and cytokine levels in children infected with H. pylori remains controversial. METHODS Based on serology testing for anti-H. pylori IgG, participants (43 seropositive and 43 seronegative) aged 10-18 years were enrolled. Serum hepcidin levels and iron profiles, including iron, ferritin, and total iron-binding capacity, were measured. ID is defined as iron saturation less than 15%. Seropositive children were divided into low hepcidin (n = 22) and high hepcidin (n = 21) groups. IL-1β, IL-6, and IL-8 serum levels were compared. RESULTS Serum IL-1β and IL-6 levels were comparable between H. pylori seropositive and seronegative children, as were the median serum hepcidin levels (6.5 ng/mL versus 8.6 ng/mL; P = 0.1318). Median levels of serum iron, ferritin, and iron saturation were significantly lower in seropositive children with low hepcidin than in those with high hepcidin (P = 0.0123, P = 0.0001, and P = 0.0004, respectively). The prevalence of ID was significantly higher in those with low serum hepcidin levels (33.3% versus 4.5%; P = 0.015). Compared to the high hepcidin seropositive group, the low hepcidin group had significantly lower median serum levels of cytokines IL-1β and IL-6, but not IL-8 (P = 0.0151 and P = 0.0015, respectively). CONCLUSIONS Inflammatory cytokines IL-1β and IL-6, but not IL-8, might be associated with increased hepcidin levels among H. pylori-seropositive children. Further studies are needed to clarify the role of hepcidin.
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Affiliation(s)
- Szu-Ta Chen
- Department of Pediatrics, National Taiwan University Hospital Yun-Lin Branch, National Taiwan University, Taiwan; Department of Pediatrics, National Taiwan University Children's Hospital, National Taiwan University, Taiwan; Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taiwan; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Yen-Hsuan Ni
- Department of Pediatrics, National Taiwan University Children's Hospital, National Taiwan University, Taiwan
| | - Chuan-Chun Li
- Department of Laboratory Medicine, National Taiwan University Hospital Yun-Lin Branch, National Taiwan University, Taiwan
| | - Shing-Hwa Liu
- Department of Pediatrics, National Taiwan University Children's Hospital, National Taiwan University, Taiwan; Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.
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20
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Ferrandis Vila M, Trudeau MP, Hung YT, Zeng Z, Urriola PE, Shurson GC, Saqui-Salces M. Dietary fiber sources and non-starch polysaccharide-degrading enzymes modify mucin expression and the immune profile of the swine ileum. PLoS One 2018; 13:e0207196. [PMID: 30408134 PMCID: PMC6224153 DOI: 10.1371/journal.pone.0207196] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Accepted: 10/27/2018] [Indexed: 12/15/2022] Open
Abstract
Due to their complex chemical and physical properties, the effects and mechanisms of action of natural sources of dietary fiber on the intestine are unclear. Pigs are commonly fed high-fiber diets to reduce production costs and non-starch polysaccharide (NSP)-degrading enzymes have been used to increase fiber digestibility. We evaluated the expression of mucin 2 (MUC2), presence of goblet cells, and ileal immune profile of pigs housed individually for 28 days and fed either a low fiber diet based on corn-soybean meal (CSB, n = 9), or two high fiber diets formulated adding 40% corn distillers' dried grains with solubles (DDGS, n = 9) or 30% wheat middlings (WM, n = 9) to CSB-based diet. Pigs were also fed those diets supplemented with a NSP enzymes mix (E) of xylanase, β-glucanase, mannanase, and galactosidase (n = 8, 10, and 9 for CSB+E, DDGS+E and WM+E, respectively). Feeding DDGS and WM diets increased ileal MUC2 expression compared with CSB diet, and this effect was reversed by the addition of enzymes. There were no differences in abundance of goblet cells among treatments. In general, enzyme supplementation increased gene expression and concentrations of IL-1β, and reduced the concentrations of IL-4, IL-17A and IL-11. The effects of diet-induced cytokines on modulating intestinal MUC2 were assessed in vitro by treating mouse and swine enteroids with 1 ng/ml of IL-4 and IL-1β. In accordance with previous studies, treatment with Il-4 induced Muc2 and expansion of goblet cells in mouse enteroids. However, swine enteroids did not change MUC2 expression or number of goblet cells when treated with IL-4 or IL-1β. Our results suggest that mucin and immune profile are regulated by diet in the swine intestine, but by mechanisms different to mouse, emphasizing the need for using appropriate models to study responses to dietary fiber in swine.
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Affiliation(s)
- Marta Ferrandis Vila
- Department of Animal Science, University of Minnesota, St. Paul, Minnesota, United States of America
| | - Michaela P. Trudeau
- Department of Animal Science, University of Minnesota, St. Paul, Minnesota, United States of America
| | - Yuan-Tai Hung
- Department of Animal Science, University of Minnesota, St. Paul, Minnesota, United States of America
| | - Zhikai Zeng
- Department of Animal Science, University of Minnesota, St. Paul, Minnesota, United States of America
| | - Pedro E. Urriola
- Department of Animal Science, University of Minnesota, St. Paul, Minnesota, United States of America
- Veterinary Population Medicine, University of Minnesota, St. Paul, Minnesota, United States of America
| | - Gerald C. Shurson
- Department of Animal Science, University of Minnesota, St. Paul, Minnesota, United States of America
| | - Milena Saqui-Salces
- Department of Animal Science, University of Minnesota, St. Paul, Minnesota, United States of America
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Sáenz JB, Mills JC. Acid and the basis for cellular plasticity and reprogramming in gastric repair and cancer. Nat Rev Gastroenterol Hepatol 2018; 15:257-273. [PMID: 29463907 PMCID: PMC6016373 DOI: 10.1038/nrgastro.2018.5] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Subjected to countless daily injuries, the stomach still functions as a remarkably efficient digestive organ and microbial filter. In this Review, we follow the lead of the earliest gastroenterologists who were fascinated by the antiseptic and digestive powers of gastric secretions. We propose that it is easiest to understand how the stomach responds to injury by stressing the central role of the most important gastric secretion, acid. The stomach follows two basic patterns of adaptation. The superficial response is a pattern whereby the surface epithelial cells migrate and rapidly proliferate to repair erosions induced by acid or other irritants. The stomach can also adapt through a glandular response when the source of acid is lost or compromised (that is, the process of oxyntic atrophy). We primarily review the mechanisms governing the glandular response, which is characterized by a metaplastic change in cellular differentiation known as spasmolytic polypeptide-expressing metaplasia (SPEM). We propose that the stomach, like other organs, exhibits marked cellular plasticity: the glandular response involves reprogramming mature cells to serve as auxiliary stem cells that replace lost cells. Unfortunately, such plasticity might mean that the gastric epithelium undergoes cycles of differentiation and de-differentiation that increase the risk of accumulating cancer-predisposing mutations.
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Affiliation(s)
- José B. Sáenz
- Division of Gastroenterology, Department of Internal Medicine, Washington University School of Medicine
| | - Jason C. Mills
- Division of Gastroenterology, Department of Internal Medicine, Washington University School of Medicine
- Department of Developmental Biology, Washington University School of Medicine
- Department of Pathology and Immunology, Washington University School of Medicine
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22
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Li T, Liu X, Riederer B, Nikolovska K, Singh AK, Mäkelä KA, Seidler A, Liu Y, Gros G, Bartels H, Herzig KH, Seidler U. Genetic ablation of carbonic anhydrase IX disrupts gastric barrier function via claudin-18 downregulation and acid backflux. Acta Physiol (Oxf) 2018; 222:e12923. [PMID: 28748627 PMCID: PMC5901031 DOI: 10.1111/apha.12923] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2016] [Revised: 11/21/2016] [Accepted: 07/24/2017] [Indexed: 12/28/2022]
Abstract
Aim This study aimed to explore the molecular mechanisms for the parietal cell loss and fundic hyperplasia observed in gastric mucosa of mice lacking the carbonic anhydrase 9 (CAIX). Methods We assessed the ability of CAIX‐knockout and WT gastric surface epithelial cells to withstand a luminal acid load by measuring the pHi of exteriorized gastric mucosa in vivo using two‐photon confocal laser scanning microscopy. Cytokines and claudin‐18A2 expression was analysed by RT‐PCR. Results CAIX‐knockout gastric surface epithelial cells showed significantly faster pHi decline after luminal acid load compared to WT. Increased gastric mucosal IL‐1β and iNOS, but decreased claudin‐18A2 expression (which confer acid resistance) was observed shortly after weaning, prior to the loss of parietal and chief cells. At birth, neither inflammatory cytokines nor claudin‐18 expression were altered between CAIX and WT gastric mucosa. The gradual loss of acid secretory capacity was paralleled by an increase in serum gastrin, IL‐11 and foveolar hyperplasia. Mild chronic proton pump inhibition from the time of weaning did not prevent the claudin‐18 decrease nor the increase in inflammatory markers at 1 month of age, except for IL‐1β. However, the treatment reduced the parietal cell loss in CAIX‐KO mice in the subsequent months. Conclusions We propose that CAIX converts protons that either backflux or are extruded from the cells rapidly to CO2 and H2O, contributing to tight junction protection and gastric epithelial pHi regulation. Lack of CAIX results in persistent acid backflux via claudin‐18 downregulation, causing loss of parietal cells, hypergastrinaemia and foveolar hyperplasia.
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Affiliation(s)
- T. Li
- Department of Gastroenterology; Hannover Medical School; Hannover Germany
| | - X. Liu
- Department of Gastroenterology; Hannover Medical School; Hannover Germany
- Department of Department of Gastroenterology; Affiliated Hospital of Zunyi Medical College; Zunyi China
| | - B. Riederer
- Department of Gastroenterology; Hannover Medical School; Hannover Germany
| | - K. Nikolovska
- Department of Gastroenterology; Hannover Medical School; Hannover Germany
| | - A. K. Singh
- Department of Gastroenterology; Hannover Medical School; Hannover Germany
| | - K. A. Mäkelä
- Institute of Biomedicine and Biocenter of Oulu; Oulu University; Finland
| | - A. Seidler
- Department of Gastroenterology; Hannover Medical School; Hannover Germany
| | - Y. Liu
- Department of Gastroenterology; Hannover Medical School; Hannover Germany
| | - G. Gros
- Department of Physiology; Hannover Medical School; Hannover Germany
| | - H. Bartels
- Department of Anatomy; Hannover Medical School; Hannover Germany
| | - K. H. Herzig
- Institute of Biomedicine and Biocenter of Oulu; Oulu University; Finland
| | - U. Seidler
- Department of Gastroenterology; Hannover Medical School; Hannover Germany
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Affiliation(s)
- Juanita L. Merchant
- Correspondence Address correspondence to: Juanita L. Merchant, MD, PhD, 109 Zina Pitcher Place, BSRB 2051, Ann Arbor, Michigan 48109-2200.
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Potential Association of IL1B Polymorphism With Iron Deficiency Risk in Childhood Helicobacter pylori Infection. J Pediatr Gastroenterol Nutr 2018; 66:e36-e40. [PMID: 28727656 DOI: 10.1097/mpg.0000000000001687] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
OBJECTIVE Helicobacter pylori infection occurs predominantly in childhood. Host immune response gene polymorphism is reported to affect the susceptibility to H pylori infection and the outcome of H pylori-related gastric cancer. Not all H pylori-infected patients, however, exhibit iron deficiency (ID). The relationship between host genetic polymorphisms and ID mediated by H pylori infection is not well understood. METHODS Subjects (n = 644) from the general population of age 10 to 18 years were divided into 2 groups based on serology testing for anti-H pylori IgG: seropositive study group; and seronegative control group. Five single nucleotide polymorphisms (SNPs) in IL1B (rs1143627 and rs16944), IL8 (rs4073), IL10 (rs1800896), and ABO (rs505922), were genotyped and the iron status of the 2 groups was compared. RESULTS The seroprevalence rate for H pylori was 10.7% in this study. Infected subjects were significantly older and had lower serum iron levels than uninfected subjects (P = 0.0195 and 0.0059, respectively). Multivariate analysis revealed a significantly higher frequency of the T allele of rs505922 (odds ratio [OR] = 6.128; P < 0.001) and lower frequency of the T allele of rs1143627 (OR = 0.846; P = 0.014) in seropositive subjects. Among 59 seropositive subjects, the T allele frequency of rs1143627 was significantly higher in those with ID (OR = 3.156; P = 0.043), compared with those without ID. CONCLUSIONS ABO (rs505922) and IL1B (rs1143627) may affect H pylori infection susceptibility, and IL1B (rs1143627) may also influence ID risk in infected children.
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Díaz P, Valenzuela Valderrama M, Bravo J, Quest AFG. Helicobacter pylori and Gastric Cancer: Adaptive Cellular Mechanisms Involved in Disease Progression. Front Microbiol 2018; 9:5. [PMID: 29403459 PMCID: PMC5786524 DOI: 10.3389/fmicb.2018.00005] [Citation(s) in RCA: 155] [Impact Index Per Article: 22.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Accepted: 01/04/2018] [Indexed: 12/13/2022] Open
Abstract
Helicobacter pylori (H. pylori) infection is the major risk factor associated with the development of gastric cancer. The transition from normal mucosa to non-atrophic gastritis, triggered primarily by H. pylori infection, initiates precancerous lesions which may then progress to atrophic gastritis and intestinal metaplasia. Further progression to dysplasia and gastric cancer is generally believed to be attributable to processes that no longer require the presence of H. pylori. The responses that develop upon H. pylori infection are directly mediated through the action of bacterial virulence factors, which drive the initial events associated with transformation of infected gastric cells. Besides genetic and to date poorly defined environmental factors, alterations in gastric cell stress-adaptive mechanisms due to H. pylori appear to be crucial during chronic infection and gastric disease progression. Firstly, H. pylori infection promotes gastric cell death and reduced epithelial cell turnover in the majority of infected cells, resulting in primary tissue lesions associated with an initial inflammatory response. However, in the remaining gastric cell population, adaptive responses are induced that increase cell survival and proliferation, resulting in the acquisition of potentially malignant characteristics that may lead to precancerous gastric lesions. Thus, deregulation of these intrinsic survival-related responses to H. pylori infection emerge as potential culprits in promoting disease progression. This review will highlight the most relevant cellular adaptive mechanisms triggered upon H. pylori infection, including endoplasmic reticulum stress and the unfolded protein response, autophagy, oxidative stress, and inflammation, together with a subsequent discussion on how these factors may participate in the progression of a precancerous lesion. Finally, this review will shed light on how these mechanisms may be exploited as pharmacological targets, in the perspective of opening up new therapeutic alternatives for non-invasive risk control in gastric cancer.
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Affiliation(s)
- Paula Díaz
- Cellular Communication Laboratory, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.,Advanced Center for Chronic Diseases, Facultad de Medicina, Universidad de Chile, Santiago, Chile.,Center for Molecular Studies of the Cell, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Manuel Valenzuela Valderrama
- Cellular Communication Laboratory, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.,Advanced Center for Chronic Diseases, Facultad de Medicina, Universidad de Chile, Santiago, Chile.,Instituto de Investigación e Innovación en Salud, Facultad de Ciencias de la Salud, Universidad Central de Chile, Santiago, Chile
| | - Jimena Bravo
- Cellular Communication Laboratory, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.,Advanced Center for Chronic Diseases, Facultad de Medicina, Universidad de Chile, Santiago, Chile.,Center for Molecular Studies of the Cell, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Andrew F G Quest
- Cellular Communication Laboratory, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.,Advanced Center for Chronic Diseases, Facultad de Medicina, Universidad de Chile, Santiago, Chile.,Center for Molecular Studies of the Cell, Facultad de Medicina, Universidad de Chile, Santiago, Chile
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26
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Mommersteeg MC, Yu J, Peppelenbosch MP, Fuhler GM. Genetic host factors in Helicobacter pylori-induced carcinogenesis: Emerging new paradigms. Biochim Biophys Acta Rev Cancer 2017; 1869:42-52. [PMID: 29154808 DOI: 10.1016/j.bbcan.2017.11.003] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Revised: 11/13/2017] [Accepted: 11/13/2017] [Indexed: 02/09/2023]
Abstract
Helicobacter Pylori is a gram negative rod shaped microaerophilic bacterium that colonizes the stomach of approximately half the world's population. Infection with c may cause chronic gastritis which via a quite well described process known as Correas cascade can progress through sequential development of atrophic gastritis, intestinal metaplasia and dysplasia to gastric cancer. H. pylori is currently the only bacterium that is classified as a class 1 carcinogen by the WHO, although the exact mechanisms by which this bacterium contributes to gastric carcinogenesis are still poorly understood. Only a minority of H. pylori-infected patients will eventually develop gastric cancer, suggesting that host factors may be important in determining the outcome of H. pylori infection. This is supported by a growing body of evidence suggesting that the host genetic background contributes to risk of H. pylori infection and gastric carcinogenesis. In particular single nucleotide polymorphisms in genes that influence bacterial handling via pattern recognition receptors appear to be involved, further strengthening the link between host risk factors, H. pylori incidence and cancer. Many of these genes influence cellular pathways leading to inflammatory signaling, inflammasome formation and autophagy. In this review we summarize known carcinogenic effects of H. pylori, and discuss recent findings that implicate host genetic pattern recognition pathways in the development of gastric cancer and their relation with H. pylori.
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Affiliation(s)
- Michiel C Mommersteeg
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical center Rotterdam, Office NA-619, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
| | - Jun Yu
- Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences and CUHK-Shenzhen Research Institute, Rm 707A, 7/F., Li Ka Shing Medical Science Building, The Chinese University of Hong Kong, Hong Kong.
| | - Maikel P Peppelenbosch
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical center Rotterdam, Office NA-619, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
| | - Gwenny M Fuhler
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical center Rotterdam, Office NA-619, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
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27
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Ballweg R, Schozer F, Elliott K, Kuhn A, Spotts L, Aihara E, Zhang T. Multiscale positive feedbacks contribute to unidirectional gastric disease progression induced by helicobacter pylori infection. BMC SYSTEMS BIOLOGY 2017; 11:111. [PMID: 29166909 PMCID: PMC5700561 DOI: 10.1186/s12918-017-0497-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/17/2017] [Accepted: 11/13/2017] [Indexed: 12/27/2022]
Abstract
Background Helicobacter Pylori (HP) is the most common risk factor for gastric cancer. Nearly half the world’s population is infected with HP, but only a small percentage of those develop significant pathology. The bacteria itself does not directly cause cancer; rather it promotes an environment that is conducive to tumor formation. Upon infection, HP induces transcriptional changes in the host, leading to enhanced proliferation and host immune response. In addition, HP causes direct damage to gastric epithelial cells. Results We present a multiscale mechanistic model of HP induced changes. The model includes four modules representing the host transcriptional changes in response to infection, gastric atrophy, the Hedgehog pathway response, and the restriction point that controls cell cycle. This model was able to recapture a number of literature reported observations and was used as an “in silico” representation of the biological system for further analysis. Dynamical analysis of the model revealed that HP might induce the activation of multiple interplayed positive feedbacks, which in turn might result in a “ratchet ladder” system that promotes a unidirectional progression of gastric disease. Conclusions The current multiscale model is able to recapitulate the observed experimental features of HP host interactions and provides dynamic insights on the epidemiologically observed heterogeneity in disease progression. This model provides a solid framework that can be further expanded and validated to include additional experimental evidence, to understand the complex multi-pathway interactions characterizing HP infection, and to design novel treatment protocols for HP induced diseases. Electronic supplementary material The online version of this article (10.1186/s12918-017-0497-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Richard Ballweg
- Department of Molecular and Cellular Physiology, College of Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Frederick Schozer
- Department of Molecular and Cellular Physiology, College of Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Kelsey Elliott
- Division of Plastic Surgery, Department of Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.,Division of Developmental Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Alexander Kuhn
- Department of Molecular and Cellular Physiology, College of Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Logan Spotts
- Department of Molecular and Cellular Physiology, College of Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Eitaro Aihara
- Department of Molecular and Cellular Physiology, College of Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Tongli Zhang
- Department of Molecular and Cellular Physiology, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
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28
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Mechanisms of angiogenesis in microbe-regulated inflammatory and neoplastic conditions. Angiogenesis 2017; 21:1-14. [PMID: 29110215 DOI: 10.1007/s10456-017-9583-4] [Citation(s) in RCA: 103] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2017] [Accepted: 10/24/2017] [Indexed: 12/19/2022]
Abstract
Commensal microbiota inhabit all the mucosal surfaces of the human body. It plays significant roles during homeostatic conditions, and perturbations in numbers and/or products are associated with several pathological disorders. Angiogenesis, the process of new vessel formation, promotes embryonic development and critically modulates several biological processes during adulthood. Indeed, deregulated angiogenesis can induce or augment several pathological conditions. Accumulating evidence has implicated the angiogenic process in various microbiota-associated human diseases. Herein, we critically review diseases that are regulated by microbiota and are affected by angiogenesis, aiming to provide a broad understanding of how angiogenesis is involved and how microbiota regulate angiogenesis in microbiota-associated human conditions.
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29
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Goldenring JR. The AGA/Funderburg Award in Gastric Cancer: Twenty-five Years of Advances in Gastric Cancer Research. Gastroenterology 2017; 152:1262-1266. [PMID: 28327368 DOI: 10.1053/j.gastro.2017.03.010] [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: 12/19/2022]
Affiliation(s)
- James R Goldenring
- Nashville VA Medical Center and Vanderbilt University Medical Center, Nashville, Tennessee
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30
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Ma J, Wu D, Hu X, Li J, Cao M, Dong W. Associations between cytokine gene polymorphisms and susceptibility to Helicobacter pylori infection and Helicobacter pylori related gastric cancer, peptic ulcer disease: A meta-analysis. PLoS One 2017; 12:e0176463. [PMID: 28453551 PMCID: PMC5409176 DOI: 10.1371/journal.pone.0176463] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Accepted: 04/11/2017] [Indexed: 12/20/2022] Open
Abstract
Objectives The aim of this study is to clarify the associations between IL-1B31C/T, IL-1B-511C/T, IL-8-251T/A gene polymorphisms and the risk of Helicobacter pylori (H. pylori) infection together with H. pylori-related gastric cancer (GC), peptic ulcer disease (PUD). Methods All eligible literature published up to July 2016 were identified by searching Pubmed, Embase, Web of Science and CNKI. Pooled odds ratio (OR) and 95% confidence interval (95% CI) were calculated using a fixed or random effects model. Results 29 case-control studies were eligible, and each of them may focus on more than one gene polymorphism. Ultimately, there were 21 studies (3159 cases and 2816 controls) for IL-1B-31C/T, 16 studies (2486 cases and 1989 controls) for IL-1B-511C/T polymorphisms, 9 studies (1963 cases and 1205 controls) for IL-8-251T/A polymorphisms. Overall, an increased risk of H. pylori infection was found for IL-1B-31C/T polymorphisms in total population [OR = 1.134, 95%CI = 1.008–1.275 for recessive model; OR = 1.145, 95%CI = 1.007–1.301 for TT vs CC model]. While, for IL-1B-511C/T and IL8-251T/A polymorphisms, no evidence indicated that they were associated with the risk of H. pylori infection in all genetic models. Furthermore, we found an increased risk of H. pylori-related GC with IL-1B-511C/T polymorphisms [OR = 1.784, 95%CI = 1.289–2.469 for recessive model; OR = 1.772, 95%CI = 1.210–2.594 for TT vs CC model] and IL8-251A/T polymorphisms [OR = 1.810, 95%CI = 1.229–2.667 for recessive model; OR = 1.717, 95%CI = 1.143–2.580 for TT vs AA model], an increased risk of H. pylori-related PUD with IL8-251T/A polymorphisms [OR = 1.364, 95%CI = 1.010–1.843 for recessive model; OR = 1.427, 95%CI = 1.039–1.959 for AA vs TT model]. Conclusions IL-1B-31C/T gene polymorphisms might increase H. pylori infection risk. IL-1B-511-C/T and IL-8-251T/A gene polymorphisms might act as a risk factor to H. pylori-related diseases including GC or PUD
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Affiliation(s)
- Jingjing Ma
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Dandan Wu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Xue Hu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Jiao Li
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Mingwei Cao
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Weiguo Dong
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
- * E-mail:
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31
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Wessler S, Krisch LM, Elmer DP, Aberger F. From inflammation to gastric cancer - the importance of Hedgehog/GLI signaling in Helicobacter pylori-induced chronic inflammatory and neoplastic diseases. Cell Commun Signal 2017; 15:15. [PMID: 28427431 PMCID: PMC5397778 DOI: 10.1186/s12964-017-0171-4] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Accepted: 04/07/2017] [Indexed: 02/07/2023] Open
Abstract
Infections with the human pathogen Helicobacter pylori (H. pylori) are closely associated with the development of inflammatory disorders and neoplastic transformation of the gastric epithelium. Drastic changes in the micromilieu involve a complex network of H. pylori-regulated signal transduction pathways leading to the release of proinflammatory cytokines, gut hormones and a wide range of signaling molecules. Besides controlling embryonic development, the Hedgehog/GLI signaling pathway also plays important roles in epithelial proliferation, differentiation, and regeneration of the gastric physiology, but also in the induction and progression of inflammation and neoplastic transformation in H. pylori infections. Here, we summarize recent findings of H. pylori-associated Hedgehog/GLI signaling in gastric homeostasis, malignant development and the modulation of the gastric tumor microenvironment.
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Affiliation(s)
- Silja Wessler
- Division of Microbiology, Cancer Cluster Salzburg, Department of Molecular Biology, Paris-Lodron University of Salzburg, Billroth Strasse 11, A-5020, Salzburg, Austria.
| | - Linda M Krisch
- Division of Microbiology, Cancer Cluster Salzburg, Department of Molecular Biology, Paris-Lodron University of Salzburg, Billroth Strasse 11, A-5020, Salzburg, Austria
| | - Dominik P Elmer
- Division of Molecular Tumor Biology, Cancer Cluster Salzburg, Department of Molecular Biology, Paris-Lodron University of Salzburg, Hellbrunner Strasse 34, A-5020, Salzburg, Austria
| | - Fritz Aberger
- Division of Molecular Tumor Biology, Cancer Cluster Salzburg, Department of Molecular Biology, Paris-Lodron University of Salzburg, Hellbrunner Strasse 34, A-5020, Salzburg, Austria.
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32
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Merchant JL, Ding L. Hedgehog Signaling Links Chronic Inflammation to Gastric Cancer Precursor Lesions. Cell Mol Gastroenterol Hepatol 2017; 3:201-210. [PMID: 28275687 PMCID: PMC5331830 DOI: 10.1016/j.jcmgh.2017.01.004] [Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2016] [Accepted: 01/11/2017] [Indexed: 12/24/2022]
Abstract
Since its initial discovery in Drosophila, Hedgehog (HH) signaling has long been associated with foregut development. The mammalian genome expresses 3 HH ligands, with sonic hedgehog (SHH) levels highest in the mucosa of the embryonic foregut. More recently, interest in the pathway has shifted to improving our understanding of its role in gastrointestinal cancers. The use of reporter mice proved instrumental in our ability to probe the expression pattern of SHH ligand and the cell types responding to canonical HH signaling during homeostasis, inflammation, and neoplastic transformation. SHH is highly expressed in parietal cells and is required for these cells to produce gastric acid. Furthermore, myofibroblasts are the predominant cell type responding to HH ligand in the uninfected stomach. Chronic infection caused by Helicobacter pylori and associated inflammation induces parietal cell atrophy and the expansion of metaplastic cell types, a precursor to gastric cancer in human subjects. During Helicobacter infection in mice, canonical HH signaling is required for inflammatory cells to be recruited from the bone marrow to the stomach and for metaplastic development. Specifically, polarization of the invading myeloid cells to myeloid-derived suppressor cells requires the HH-regulated transcription factor GLI1, thereby creating a microenvironment favoring wound healing and neoplastic transformation. In mice, GLI1 mediates the phenotypic shift to gastric myeloid-derived suppressor cells by directly inducing Schlafen 4 (slfn4). However, the human homologs of SLFN4, designated SLFN5 and SLFN12L, also correlate with intestinal metaplasia and could be used as biomarkers to predict the subset of individuals who might progress to gastric cancer and benefit from treatment with HH antagonists.
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Key Words
- ATPase, adenosine triphosphatase
- DAMP, damage-associated molecular pattern
- DAMPs
- GLI, glioma-associated protein
- GLI1
- Gr-MDSC, granulocytic myeloid-derived suppressor cell
- HH, hedgehog
- HHIP, hedgehog-interacting protein
- IFN, interferon
- IL, interleukin
- MDSC, myeloid-derived suppressor cell
- MDSCs
- Metaplasia
- Mo-MDSC, monocytic myeloid-derived suppressor cell
- PTCH, Patched
- SHH
- SHH, sonic hedgehog
- SLFN4, Schlafen 4
- SMO, Smoothened
- SP, spasmolytic polypeptide
- SPEM
- SPEM, spasmolytic polypeptide–expressing mucosa
- SST, somatostatin
- TLR, Toll-like receptor
- mRNA, messenger RNA
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Affiliation(s)
- Juanita L. Merchant
- Department of Internal Medicine-Gastroenterology, University of Michigan, Ann Arbor, Michigan,Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan,Correspondence Address correspondence to: Juanita L. Merchant, MD, PhD, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, Michigan 48109-2200. fax: (734) 763-4686.University of Michigan109 Zina Pitcher PlaceAnn ArborMichigan 48109-2200
| | - Lin Ding
- Department of Internal Medicine-Gastroenterology, University of Michigan, Ann Arbor, Michigan
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33
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Zhang XY, Zhang PY, Aboul-Soud MAM. From inflammation to gastric cancer: Role of Helicobacter pylori. Oncol Lett 2016; 13:543-548. [PMID: 28356927 PMCID: PMC5351277 DOI: 10.3892/ol.2016.5506] [Citation(s) in RCA: 89] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Accepted: 12/08/2016] [Indexed: 12/20/2022] Open
Abstract
Gastric cancer is a multifactorial disease and a leading cause of mortality and the risk factors for this include environmental factors and factors that influence host-pathogen interaction and complex interplay between these factors. Gastric adenocarcinomas are of two types, namely intestinal and diffuse type, and Helicobacter pylori (H. pylori) infection has been suspected of being causally linked to the initiation of chronic active gastritis, which leads to adenocarcinoma of the intestinal type. Even though most individuals with H. pylori infection do not show any clinical symptoms, long-term infection leads to inflammation of gastric epithelium and approximately 10% of infected patients develop peptic ulcers and 1–3% of patients develop gastric adenocarcinoma. Among the several mechanisms involved in tumorigenesis, CagA and peptidoglycan of H. pylori, which enter the infected gastric epithelial cells play an important role by triggering oncogenic pathways. Inflammation induced by H. pylori in gastric epithelium, which involves the cyclooxygenase-2/prostaglandin E2 pathway and IL-1β, is also an important factor that triggers chronic active gastritis and adenocarcinoma. H. pylori infection induced oxidative stress and dysregulated E-cadherin/β-catenin/p120 interactions and function also play a critical role in tumorigenesis. Environmental and dietary factors, in particular salt intake, are known to modify the pathogenesis induced by H. pylori. Gastric cancer induced by H. pylori appears to involve several mechanisms, making this mode of tumorigenesis a highly complicated process. Nevertheless, there are many events in this tumorigenesis that remain to be clarified and investigated.
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Affiliation(s)
- Xiao-Ying Zhang
- Nanjing University of Chinese Medicine, Information Institute, Nanjing, Jiangsu 221009, P.R. China
| | - Pei-Ying Zhang
- Department of Cardiology, Xuzhou Central Hospital, The Affiliated Xuzhou Hospital of Medical College of Southeast University, Xuzhou, Jiangsu 221009, P.R. China
| | - Mourad A M Aboul-Soud
- Chair of Medical and Molecular Genetics Research, Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh 11433, Kingdom of Saudi Arabia
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Konstantinou D, Bertaux-Skeirik N, Zavros Y. Hedgehog signaling in the stomach. Curr Opin Pharmacol 2016; 31:76-82. [PMID: 27750091 PMCID: PMC5154826 DOI: 10.1016/j.coph.2016.09.003] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Accepted: 09/21/2016] [Indexed: 02/06/2023]
Abstract
The Hedgehog (Hh) signaling pathway not only plays a key part in controlling embryonic development, but in the adult stomach governs important cellular events such as epithelial cell differentiation, proliferation, gastric disease, and regeneration. In particular, Sonic Hedgehog (Shh) signaling has been well studied for its role in gastric physiology and pathophysiology. Shh is secreted from the gastric parietal cells and contributes to the regeneration of the epithelium in response to injury, or the development of gastritis during Helicobacter pylori infection. Dysregulation of the Shh signaling pathway leads to the disruption of gastric differentiation, loss of gastric acid secretion and the development of cancer. In this chapter, we will review the most recent findings that reveal the role of Shh as a regulator of gastric physiology, regeneration, and disease.
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Affiliation(s)
- Daniel Konstantinou
- Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, OH, USA
| | - Nina Bertaux-Skeirik
- Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, OH, USA
| | - Yana Zavros
- Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, OH, USA.
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Ding L, Hayes MM, Photenhauer A, Eaton KA, Li Q, Ocadiz-Ruiz R, Merchant JL. Schlafen 4-expressing myeloid-derived suppressor cells are induced during murine gastric metaplasia. J Clin Invest 2016; 126:2867-80. [PMID: 27427984 DOI: 10.1172/jci82529] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Accepted: 05/19/2016] [Indexed: 12/29/2022] Open
Abstract
Chronic Helicobacter pylori infection triggers neoplastic transformation of the gastric mucosa in a small subset of patients, but the risk factors that induce progression to gastric metaplasia have not been identified. Prior to cancer development, the oxyntic gastric glands atrophy and are replaced by metaplastic cells in response to chronic gastritis. Previously, we identified schlafen 4 (Slfn4) as a GLI1 target gene and myeloid differentiation factor that correlates with spasmolytic polypeptide-expressing metaplasia (SPEM) in mice. Here, we tested the hypothesis that migration of SLFN4-expressing cells from the bone marrow to peripheral organs predicts preneoplastic changes in the gastric microenvironment. Lineage tracing in Helicobacter-infected Slfn4 reporter mice revealed that SLFN4+ cells migrated to the stomach, where they exhibited myeloid-derived suppressor cell (MDSC) markers and acquired the ability to inhibit T cell proliferation. SLFN4+ MDSCs were not observed in infected GLI1-deficient mice. Overexpression of sonic hedgehog ligand (SHH) in infected WT mice accelerated the appearance of SLFN4+ MDSCs in the gastric corpus. Similarly, in the stomachs of H. pylori-infected patients, the human SLFN4 ortholog SLFN12L colocalized to cells that expressed MDSC surface markers CD15+CD33+HLA-DRlo. Together, these results indicate that SLFN4 marks a GLI1-dependent population of MDSCs that predict a shift in the gastric mucosa to a metaplastic phenotype.
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36
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Poh AR, O'Donoghue RJJ, Ernst M, Putoczki TL. Mouse models for gastric cancer: Matching models to biological questions. J Gastroenterol Hepatol 2016; 31:1257-72. [PMID: 26809278 PMCID: PMC5324706 DOI: 10.1111/jgh.13297] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2015] [Revised: 01/12/2016] [Accepted: 01/14/2016] [Indexed: 02/06/2023]
Abstract
Gastric cancer is the third leading cause of cancer-related mortality worldwide. This is in part due to the asymptomatic nature of the disease, which often results in late-stage diagnosis, at which point there are limited treatment options. Even when treated successfully, gastric cancer patients have a high risk of tumor recurrence and acquired drug resistance. It is vital to gain a better understanding of the molecular mechanisms underlying gastric cancer pathogenesis to facilitate the design of new-targeted therapies that may improve patient survival. A number of chemically and genetically engineered mouse models of gastric cancer have provided significant insight into the contribution of genetic and environmental factors to disease onset and progression. This review outlines the strengths and limitations of current mouse models of gastric cancer and their relevance to the pre-clinical development of new therapeutics.
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Affiliation(s)
- Ashleigh R Poh
- Department of Medical BiologyUniversity of MelbourneMelbourneVictoriaAustralia
- The Walter and Eliza Hall Institute of Medical ResearchMelbourneVictoriaAustralia
| | - Robert J J O'Donoghue
- School of Cancer MedicineLa Trobe University, Olivia Newton‐John Cancer Research InstituteMelbourneVictoriaAustralia
| | - Matthias Ernst
- School of Cancer MedicineLa Trobe University, Olivia Newton‐John Cancer Research InstituteMelbourneVictoriaAustralia
| | - Tracy L Putoczki
- Department of Medical BiologyUniversity of MelbourneMelbourneVictoriaAustralia
- The Walter and Eliza Hall Institute of Medical ResearchMelbourneVictoriaAustralia
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KLF4 deletion alters gastric cell lineage and induces MUC2 expression. Cell Death Dis 2016; 7:e2255. [PMID: 27277677 PMCID: PMC5143387 DOI: 10.1038/cddis.2016.158] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Revised: 04/15/2016] [Accepted: 05/06/2016] [Indexed: 12/16/2022]
Abstract
Gastric cancer is one of the most common types of cancer in the world, particularly in underdeveloped countries. The mechanism of gastric cancer is less understood compared with other types of gastrointestinal (GI) cancers. Krüppel-like factor 4 (KLF4) is a zinc-finger transcription factor and is a potential tumor suppressor in GI cancers. In this study, we have generated two mouse models, Rosa-Cre;Klf4fl/fl and Lgr5-Cre;Klf4fl/fl. KLF4 was deleted by Rosa-Cre in the gastric epithelia cells or by Lgr5-Cre in the antral stem cells in the adult mice. KLF4 deletion resulted in increased proliferating cells and decreased pit mucous cells. Surprisingly, the intestinal goblet cell marker, MUC2, which is not expressed in normal gastric tissues, was strongly induced at the base of the KLF4-deleted antral glands. To understand the clinical relevance of these findings, we analyzed the expression of KLF4 and MUC2 in human gastric cancer. In a subset of human gastric cancer, the expression of KLF4 is negatively associated with MUC2 expression. In conclusion, KLF4 is essential for normal homeostasis of antral stem cells; loss of KLF4 and expression of MUC2 could be important markers for gastric cancer diagnosis.
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Lisovsky A, Zhang DKY, Sefton MV. Effect of methacrylic acid beads on the sonic hedgehog signaling pathway and macrophage polarization in a subcutaneous injection mouse model. Biomaterials 2016; 98:203-14. [PMID: 27264502 DOI: 10.1016/j.biomaterials.2016.04.033] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Revised: 04/14/2016] [Accepted: 04/20/2016] [Indexed: 12/23/2022]
Abstract
Poly(methacrylic acid-co-methyl methacrylate) (MAA) beads promote a vascular regenerative response when used in diabetic wound healing. Previous studies reported that MAA beads modulated the expression of sonic hedgehog (Shh) and inflammation related genes in diabetic wounds. The aim of this work was to follow up on these observations in a subcutaneous injection model to study the host response in the absence of the confounding factors of diabetic wound healing. In this model, MAA beads improved vascularization in healthy mice of both sexes compared to control poly(methyl methacrylate) (MM) beads, with a stronger effect seen in males than females. MAA-induced vessels were perfusable, as evidenced from the CLARITY-processed images. In Shh-Cre-eGFP/Ptch1-LacZ non-diabetic transgenic mice, the increased vessel formation was accompanied by a higher density of cells expressing GFP (Shh) and β-Gal (patched 1, Ptch1) suggesting MAA enhanced the activation of the Shh pathway. Ptch1 is the Shh receptor and a target of the pathway. MAA beads also modulated the inflammatory cell infiltrate in CD1 mice: more neutrophils and more macrophages were noted with MAA relative to MM beads at days 1 and 7, respectively. In addition, MAA beads biased macrophages towards a MHCII-CD206+ ("M2") polarization state. This study suggests that the Shh pathway and an altered inflammatory response are two elements of the complex mechanism whereby MAA-based biomaterials effect vascular regeneration.
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Affiliation(s)
- Alexandra Lisovsky
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, 164 College Street, Suite 407, Toronto, Ontario, Canada M5S 3G9
| | - David K Y Zhang
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, 164 College Street, Suite 407, Toronto, Ontario, Canada M5S 3G9
| | - Michael V Sefton
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, 164 College Street, Suite 407, Toronto, Ontario, Canada M5S 3G9; Department of Chemical Engineering and Applied Chemistry, University of Toronto, 164 College Street, Suite 407, Toronto, Ontario, Canada M5S 3G9.
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Sun Z, Meng Y, Liu G, Jiang Y, Meng Q, Hu S. Effect of interleukin-1β and tumor necrosis factor α gene silencing on mouse gastric cancer cell proliferation and migration. Oncol Lett 2016; 11:2559-2565. [PMID: 27073517 DOI: 10.3892/ol.2016.4253] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2014] [Accepted: 01/29/2016] [Indexed: 12/22/2022] Open
Abstract
The aim of the present study was to investigate the effect of interleukin-1β (IL-1β) and tumor necrosis factor α (TNFα) gene co-silencing in mouse gastric cancer (GC) cells. Respectively, three pairs of liposome-encapsulated IL-1β and TNFα small interfering RNA (siRNA) were transfected into the mouse GC cell line MFC. The most effective siRNA, as identified by reverse transcription-polymerase chain reaction, was used for co-suppression of IL-1β and TNFα genes. The activities of cell proliferation, colony formation and migration were determined by the Cell Counting Kit 8 method, colony formation assay and Transwell assay, respectively. Protein array analysis was performed to identify the differentially expressed factors. The possible signaling pathways of the various factors targeting the genes were identified by pathway enrichment analysis using KOBAS 2.0. siRNA1 and siRNAc were the most effective interference sequences for IL-1β and TNFα, respectively. Following co-transfection of siRNA1 and siRNAc, the expression of IL-1β and TNFα was inhibited at the mRNA and protein levels, and the cell proliferation, colony forming and migration abilities were reduced (P<0.05). The expression of inflammatory factors, including chemokine ligand 5, cyclooxygenase-2, IL-6, transforming growth factor β, IL-17A, matrix metallopeptidase 9 and stromal cell-derived factor 1α were also inhibited (P<0.05). These factors are mainly involved in the rheumatoid arthritis pathway, the intestinal immune network for IgA production, the TNF signaling pathway and the inflammatory bowel disease pathway. IL-1β and TNFα gene silencing inhibits the proliferation and migration of MFC. The mechanisms may involve multiple inflammatory factors that participate in the signaling pathways of tumor tissue inflammation, the immune network and TNF.
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Affiliation(s)
- Zhongwei Sun
- Gastrointestinal Surgery Department, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250012, P.R. China
| | - Yan Meng
- Operating Department, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250012, P.R. China
| | - Guoqin Liu
- Gastrointestinal Surgery Department, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250012, P.R. China
| | - Yongsheng Jiang
- Gastrointestinal Surgery Department, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250012, P.R. China
| | - Qinghua Meng
- Gastrointestinal Surgery Department, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250012, P.R. China
| | - Sanyuan Hu
- General Surgery Department, Qilu Hospital Affiliated to Shandong University, Jinan, Shandong 250012, P.R. China
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Recapitulating Human Gastric Cancer Pathogenesis: Experimental Models of Gastric Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 908:441-78. [PMID: 27573785 DOI: 10.1007/978-3-319-41388-4_22] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
This review focuses on the various experimental models to study gastric cancer pathogenesis, with the role of genetically engineered mouse models (GEMMs) used as the major examples. We review differences in human stomach anatomy compared to the stomachs of the experimental models, including the mouse and invertebrate models such as Drosophila and C. elegans. The contribution of major signaling pathways, e.g., Notch, Hedgehog, AKT/PI3K is discussed in the context of their potential contribution to foregut tumorigenesis. We critically examine the rationale behind specific GEMMs, chemical carcinogens, dietary promoters, Helicobacter infection, and direct mutagenesis of relevant oncogenes and tumor suppressor that have been developed to study gastric cancer pathogenesis. Despite species differences, more efficient and effective models to test specific genes and pathways disrupted in human gastric carcinogenesis have yet to emerge. As we better understand these species differences, "humanized" versions of mouse models will more closely approximate human gastric cancer pathogenesis. Towards that end, epigenetic marks on chromatin, the gut microbiota, and ways of manipulating the immune system will likely move center stage, permitting greater overlap between rodent and human cancer phenotypes thus providing a unified progression model.
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Hong JB, Zuo W, Wang AJ, Lu NH. Helicobacter pylori Infection Synergistic with IL-1β Gene Polymorphisms Potentially Contributes to the Carcinogenesis of Gastric Cancer. Int J Med Sci 2016; 13:298-303. [PMID: 27076787 PMCID: PMC4829543 DOI: 10.7150/ijms.14239] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2015] [Accepted: 03/31/2016] [Indexed: 12/14/2022] Open
Abstract
Helicobacter pylori (H. pylori) infection is the most common chronic bacterial infection in the world and the etiological agent for most gastric cancer (GC). Interleukin-1β (IL-1β) is a potent proinflammatory cytokine, and its deregulation is closely associated with the tumorigenesis of several cancers. Recent studies have revealed that the IL-1β-31 and -511T alleles are closely associated with gastric carcinogenesis due to their roles in the induction of gastric precancerous lesions and hypochlorhydria. Furthermore, H. pylori infection has a synergistic effect on the development of GC with IL-1β gene polymorphisms, and the highest prevalence of severe gastric abnormalities are found in patients with both host and bacterial high-risk genotypes (cagA(+)/vacAs1(+)/IL-1β-511T). Therefore, these recent advances demonstrate that H. pylori synergistic with IL-1β gene polymorphisms contribute to the gastric carcinogenesis by their involvement in precancerous gastric lesions and low gastric acid secretion.
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Affiliation(s)
- Jun-Bo Hong
- 1. Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China
| | - Wei Zuo
- 2. Department of Respiratory Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China
| | - An-Jiang Wang
- 1. Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China
| | - Nong-Hua Lu
- 1. Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China
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Hoffmann W. [Continual self-renewal of the gastric epithelium by cell differentiation: implications for carcinogenesis]. DER PATHOLOGE 2015; 35 Suppl 2:202-6. [PMID: 25394968 DOI: 10.1007/s00292-014-1996-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND The gastric mucosa and its glands represent a close interactive barrier to the outside world. This delicate surface is protected by a multilayered mucus barrier which contains among others the mucins MUC5AC and MUC6 and the trefoil factor family peptide TFF2. Furthermore, two types of gastric glands form delicate homeostatic systems, i.e. the fundic and antral glands, which show continual bidirectional self-renewal via differentiation from stem and progenitor cells. It was the aim of this study to analyze the self-renewal of these gastric units. MATERIAL AND METHODS Three characteristic regions (i.e. foveolar, proliferative zone and lower gland regions) were isolated from fundic and antral units by the use of laser microdissection and expression profiles concerning known marker genes were generated by reverse transcription polymerase chain reaction (RT-PCR) analysis. RESULTS The surface mucous cells (SMCs) of fundic and antral units characteristically differed in the expression of certain secretory genes. Furthermore, the maturation of mucous neck cells and their trans-differentiation into chief cells as well as the maturation of antral SMCs and antral gland cells occurred in a stepwise manner. DISCUSSION The correct maturation particularly of mucous neck cells and their trans-differentiation into chief cells is critical for homeostatic self-renewal of fundic units. Dysregulation of this multistep process can result in generation of the spasmolytic polypeptide-expressing metaplasia (SPEM) lineage which is characterized by its strong ectopic TFF2 expression. Chronic inflammation is known to support SPEM formation. The SPEM lineage is a precancerous lesion which can further differentiate into intestinal metaplasia.
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Affiliation(s)
- W Hoffmann
- Institut für Molekularbiologie und Medizinische Chemie, Medizinische Fakultät, Otto-von-Guericke-Universität, Leipziger Str. 44, 39120, Magdeburg, Deutschland,
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Gall A, Fero J, McCoy C, Claywell BC, Sanchez CA, Blount PL, Li X, Vaughan TL, Matsen FA, Reid BJ, Salama NR. Bacterial Composition of the Human Upper Gastrointestinal Tract Microbiome Is Dynamic and Associated with Genomic Instability in a Barrett's Esophagus Cohort. PLoS One 2015; 10:e0129055. [PMID: 26076489 PMCID: PMC4468150 DOI: 10.1371/journal.pone.0129055] [Citation(s) in RCA: 96] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Accepted: 05/04/2015] [Indexed: 12/19/2022] Open
Abstract
Background The incidence of esophageal adenocarcinoma (EAC) has increased nearly five-fold over the last four decades in the United States. Barrett’s esophagus, the replacement of the normal squamous epithelial lining with a mucus-secreting columnar epithelium, is the only known precursor to EAC. Like other parts of the gastrointestinal (GI) tract, the esophagus hosts a variety of bacteria and comparisons among published studies suggest bacterial communities in the stomach and esophagus differ. Chronic infection with Helicobacter pylori in the stomach has been inversely associated with development of EAC, but the mechanisms underlying this association remain unclear. Methodology The bacterial composition in the upper GI tract was characterized in a subset of participants (n=12) of the Seattle Barrett’s Esophagus Research cohort using broad-range 16S PCR and pyrosequencing of biopsy and brush samples collected from squamous esophagus, Barrett’s esophagus, stomach corpus and stomach antrum. Three of the individuals were sampled at two separate time points. Prevalence of H. pylori infection and subsequent development of aneuploidy (n=339) and EAC (n=433) was examined in a larger subset of this cohort. Results/Significance Within individuals, bacterial communities of the stomach and esophagus showed overlapping community membership. Despite closer proximity, the stomach antrum and corpus communities were less similar than the antrum and esophageal samples. Re-sampling of study participants revealed similar upper GI community membership in two of three cases. In this Barrett’s esophagus cohort, Streptococcus and Prevotella species dominate the upper GI and the ratio of these two species is associated with waist-to-hip ratio and hiatal hernia length, two known EAC risk factors in Barrett’s esophagus. H. pylori-positive individuals had a significantly decreased incidence of aneuploidy and a non-significant trend toward lower incidence of EAC.
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Affiliation(s)
- Alevtina Gall
- Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, Washington, United States of America
- Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - Jutta Fero
- Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - Connor McCoy
- Divisions of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
- Program in Computational Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - Brian C. Claywell
- Divisions of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
- Program in Computational Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - Carissa A. Sanchez
- Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - Patricia L. Blount
- Divisions of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
- Department of Medicine, University of Washington School of Medicine, Seattle, Washington, United States of America
| | - Xiaohong Li
- Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
- Divisions of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - Thomas L. Vaughan
- Divisions of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
- Department of Epidemiology, University of Washington, Seattle, Washington, United States of America
| | - Frederick A. Matsen
- Divisions of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
- Program in Computational Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - Brian J. Reid
- Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
- Divisions of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
- Department of Medicine, University of Washington School of Medicine, Seattle, Washington, United States of America
- Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America
| | - Nina R. Salama
- Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
- Department of Microbiology, University of Washington School of Medicine, Seattle, Washington, United States of America
- * E-mail:
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44
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Kononov AV, Mozgovoĭ SI, Shimanskaia AG, Grishchenko RK, Nazarov AN. [Immunohistochemical detection of biomolecular markers for metaplastic mucosal atrophy in gastric biopsy specimens]. Arkh Patol 2015; 76:44-50. [PMID: 25842925 DOI: 10.17116/patol201476644-50] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
OBJECTIVE To estimate the validity of the signs of metaplastic atrophic gastritis to elaborate a marker principle of its detection. SUBJECTS AND METHODS Two hundred diagnostic cases morphologically diagnosed with chronic gastritis were selected for examination. The validity of the histological and immunohistochemical signs/markers reflecting a gland abnormality (hyperplasia of smooth muscle cells and argyrophilic and elastic fibers) and a cell phenotype change (intestinal and pyloric metaplasia): CDX-2, Shh, villin, CD10, MUC2, and MUC5AC was estimated in gastric biopsy specimens with atrophic gastritis forms verified in accordance with international classifications. The validity of the signs/markers was assessed, by calculating the sensitivity, specificity, prognostic value of positive and negative results, and positive and negative likelihood ratios. RESULTS There were 3 molecules: CDX-2 is a nuclear transcription factor associated with intestinal differentiation; CCD10 is a brush border membrane-bound mycin and MUC2 is an intestinal-type mycin, which showed a high validity like the markers of metaplastic atrophic gastritis. An algorithm that could probably evaluate atrophic gastritis was elaborated for the successive immunohistochemical identification of the above-mentioned marker. CONCLUSION The proposed technical decision to verify atrophic gastritis by the biomarker method may be not an alternative, but complementary technique of identifying the form of atrophic gastritis.
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Affiliation(s)
- A V Kononov
- GBOU VPO "Omskaia gosudarstvennaia meditsinskaia akademiia" Minzdrava Rossii, Rossiĭskaia Federatsiia
| | - S I Mozgovoĭ
- GBOU VPO "Omskaia gosudarstvennaia meditsinskaia akademiia" Minzdrava Rossii, Rossiĭskaia Federatsiia
| | - A G Shimanskaia
- GBOU VPO "Omskaia gosudarstvennaia meditsinskaia akademiia" Minzdrava Rossii, Rossiĭskaia Federatsiia
| | - R K Grishchenko
- GBOU VPO "Omskaia gosudarstvennaia meditsinskaia akademiia" Minzdrava Rossii, Rossiĭskaia Federatsiia
| | - A N Nazarov
- GBOU VPO "Omskaia gosudarstvennaia meditsinskaia akademiia" Minzdrava Rossii, Rossiĭskaia Federatsiia
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Helicobacter pylori: the balance between a role as colonizer and pathogen. Best Pract Res Clin Gastroenterol 2014; 28:1017-29. [PMID: 25439068 DOI: 10.1016/j.bpg.2014.09.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2014] [Revised: 08/25/2014] [Accepted: 09/15/2014] [Indexed: 02/07/2023]
Abstract
The isolation of Helicobacter pylori from the human stomach produced significant changes in how gastroenterologists, immunologists, epidemiologists, pathologists and microbiologists have approached gastro-duodenal diseases in the last half of the XX century. However, research of this organism has progressed greatly in the first decade of this century, evidence suggest that H. pylori is associated with disease only in humans older than 40 years, while, the lack of H. pylori colonization is associated with the emergence of new diseases, particularly in younger individuals. These differing effects of H. pylori colonization have created two contrasting concepts: the 'bad' and the 'good' Helicobacter. Following from renewed interest in the normal human microbiome, we need to reconsider our definitions and perhaps recognize that H. pylori might be a normal member of the human gastric microbiome in ancient humans that gradually, as results of the improvement in our environment, is disappearing.
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Marwaha S, Schumacher MA, Zavros Y, Eghbalnia HR. Crosstalks between cytokines and Sonic Hedgehog in Helicobacter pylori infection: a mathematical model. PLoS One 2014; 9:e111338. [PMID: 25364910 PMCID: PMC4218723 DOI: 10.1371/journal.pone.0111338] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2014] [Accepted: 09/23/2014] [Indexed: 12/13/2022] Open
Abstract
Helicobacter pylori infection of gastric tissue results in an immune response dominated by Th1 cytokines and has also been linked with dysregulation of Sonic Hedgehog (SHH) signaling pathway in gastric tissue. However, since interactions between the cytokines and SHH during H. pylori infection are not well understood, any mechanistic understanding achieved through interpretation of the statistical analysis of experimental results in the context of currently known circuit must be carefully scrutinized. Here, we use mathematical modeling aided by restraints of experimental data to evaluate the consistency between experimental results and temporal behavior of H. pylori activated cytokine circuit model. Statistical analysis of qPCR data from uninfected and H. pylori infected wild-type and parietal cell-specific SHH knockout (PC-SHHKO) mice for day 7 and 180 indicate significant changes that suggest role of SHH in cytokine regulation. The experimentally observed changes are further investigated using a mathematical model that examines dynamic crosstalks among pro-inflammatory (IL1β, IL-12, IFNγ, MIP-2) cytokines, anti-inflammatory (IL-10) cytokines and SHH during H. pylori infection. Response analysis of the resulting model demonstrates that circuitry, as currently known, is inadequate for explaining of the experimental observations; suggesting the need for additional specific regulatory interactions. A key advantage of a computational model is the ability to propose putative circuit models for in-silico experimentation. We use this approach to propose a parsimonious model that incorporates crosstalks between NFĸB, SHH, IL-1β and IL-10, resulting in a feedback loop capable of exhibiting cyclic behavior. Separately, we show that analysis of an independent time-series GEO microarray data for IL-1β, IFNγ and IL-10 in mock and H. pylori infected mice further supports the proposed hypothesis that these cytokines may follow a cyclic trend. Predictions from the in-silico model provide useful insights for generating new hypothesis and design of subsequent experimental studies.
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Affiliation(s)
- Shruti Marwaha
- Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio, United States of America
- * E-mail:
| | - Michael A. Schumacher
- Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio, United States of America
| | - Yana Zavros
- Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio, United States of America
| | - Hamid R. Eghbalnia
- Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio, United States of America
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Shao Y, Sun K, Xu W, Li XL, Shen H, Sun WH. Helicobacter pylori infection, gastrin and cyclooxygenase-2 in gastric carcinogenesis. World J Gastroenterol 2014; 20:12860-12873. [PMID: 25278683 PMCID: PMC4177468 DOI: 10.3748/wjg.v20.i36.12860] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2013] [Revised: 03/12/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is one of the most frequent neoplasms and a main cause of death worldwide, especially in China and Japan. Numerous epidemiological, animal and experimental studies support a positive association between chronic Helicobacter pylori (H. pylori) infection and the development of gastric cancer. However, the exact mechanism whereby H. pylori causes gastric carcinogenesis remains unclear. It has been demonstrated that expression of cyclooxygenase-2 (COX-2) is elevated in gastric carcinomas and in their precursor lesions. In this review, we present the latest clinical and experimental evidence showing the role of gastrin and COX-2 in H. pylori-infected patients and their possible association with gastric cancer risk.
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Tanaka T, Arai M, Minemura S, Oyamada A, Saito K, Jiang X, Tsuboi M, Sazuka S, Maruoka D, Matsumura T, Nakagawa T, Sugaya S, Kanda T, Katsuno T, Kita K, Kishimoto T, Imazeki F, Kaneda A, Yokosuka O. Expression level of sonic hedgehog correlated with the speed of gastric mucosa regeneration in artificial gastric ulcers. J Gastroenterol Hepatol 2014; 29:736-741. [PMID: 24224878 DOI: 10.1111/jgh.12445] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/20/2013] [Indexed: 12/26/2022]
Abstract
BACKGROUND AND AIM Gastric ulcer healing is a complex process involving cell proliferation and tissue remodeling. Sonic hedgehog (Shh) activates the Shh signaling pathway, which plays a key role in processes such as tissue repair. Shh and interleukin 1β (IL1β) have been reported to influence the proliferation of gastric mucosa. We evaluated the relationships between the speed of gastric ulcer healing and the levels of expression of Shh and IL1β. METHODS The study included 45 patients (mean age 71.9 ± 9.0 years; M/F, 30/15) who underwent endoscopic submucosal dissection (ESD) for gastric cancer, followed by standard dose of oral proton-pump inhibitor for 4 weeks. Subsequently, the size of ESD-induced artificial ulcers were measured to determine the speed of gastric ulcer healing, and regenerating mucosa around the ulcers and appropriately matched controls were collected from patients by endoscopic biopsy. Polymerase chain reaction (PCR) array analysis of genes in the Shh signaling pathway was performed, and quantitative reverse transcription (RT)-PCR was used to measure IL1β mRNA. RESULTS The levels of Shh and IL1β mRNA were 3.0 ± 2.7-fold and 2.5 ± 2.5-fold higher, respectively, in regenerating mucosa of artificial ulcers than in appropriately matched controls, with the two being positively correlated (r = 0.9, P < 0.001). Shh (r = 0.8, P < 0.001) and IL1β (r = 0.7, P < 0.005) expression was each positively correlated with the speed of gastric ulcer healing, but multivariate analysis showed that Shh expression was the only significant parameter (P = 0.045). CONCLUSIONS Expression of Shh was correlated with the speed of gastric ulcer healing, promoting the regeneration of gastric mucosa.
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Affiliation(s)
- Takeshi Tanaka
- Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
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Wang DQ, Ding XP, Yin S. Roles of proinflammatory cytokines in precancerous lesions of gastric cancer. Shijie Huaren Xiaohua Zazhi 2014; 22:39-45. [DOI: 10.11569/wcjd.v22.i1.39] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Precancerous lesions of gastric cancer, including intestinal metaplasia and dysplasia, are important stages in the evolution from normal gastric tissue to gastric cancer. Gastric cancer has a very high mortality rate, mainly due to post-metastasis diagnosis. Therefore, diagnosis of precancerous lesions of gastric cancer is of great clinical significance. In recent years, it has been reported that some proinflammatory cytokines such as interleukin 1β (IL-1β), IL-8, IL-11, tumor necrosis factor α (TNF-α) and interferon-gamma (IFN-γ) play important roles in the development of precancerous lesions of gastric cancer. A more detailed understanding of the roles of proinflammatory cytokines may provide new therapeutic targets for precancerous lesions of gastric cancer. Here, we summarize the roles of some proinflammatory cytokines in the progression of precancerous lesions of gastric cancer.
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Yan R, Peng X, Yuan X, Huang D, Chen J, Lu Q, Lv N, Luo S. Suppression of growth and migration by blocking the Hedgehog signaling pathway in gastric cancer cells. Cell Oncol (Dordr) 2013; 36:421-35. [PMID: 24027019 DOI: 10.1007/s13402-013-0149-1] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/27/2013] [Indexed: 12/13/2022] Open
Abstract
PURPOSE Previous studies have indicated that Hedgehog signaling is essential for gastric cancer development, but its precise role is still unclear. The aim of this study was to clarify the role of Hedgehog signaling in gastric cancer development. METHODS The expression of key Hedgehog signaling components in clinical samples of sequential gastric cancer stages was assessed by immunohistochemistry. The roles and regulatory mechanisms of Hedgehog signaling in human gastric cancer cells and normal gastric epithelial cells were investigated using multiple cell biological approaches and cDNA microarray analyses. RESULTS Hedgehog signaling was found to be abnormally activated in a ligand-independent manner during gastric cancer development. Gli1 over-expression and reduced SuFu expression were found to be typical events in gastric cancer tissues. Gli1 over-expression was found to correlate with a poorly differentiated histology, advanced clinical stage, membrane serosa infiltration and lymph node metastasis in patients with gastric cancer. Data obtained from multiple cell biological assays showed that human gastric cancer cells require active Hedgehog signaling for survival, proliferation, migration and colony formation. N-Shh treatment significantly enhanced the migration, invasion and colony formation of gastric cancer cells. Moreover, the results of cDNA microarray analyses indicated that after treatment with cyclopamine or GANT61 (inhibitors of Hedgehog signaling), differentially expressed genes in gastric cancer cells were enriched in the apoptosis and MAPK pathways. Inhibitors of the Hedgehog pathway were found to suppress gastric cancer cell growth via apoptosis induction. CONCLUSIONS Our findings indicate a vital role of the activated Hedgehog signaling pathway in promoting gastric initiation and progression. The Hedgehog signaling pathway may serve as a target for gastric cancer therapy.
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Affiliation(s)
- Runwei Yan
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, No.17 Yongwai street, Donghu district, Nanchang, 330006, China
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