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Spermine oxidase mediates Helicobacter pylori-induced gastric inflammation, DNA damage, and carcinogenic signaling.
Sierra JC, Piazuelo MB, Luis PB, Barry DP, Allaman MM, Asim M, Sebrell TA, Finley JL, Rose KL, Hill S, Holshouser SL, Casero RA, Cleveland JL, Woster PM, Schey KL, Bimczok D, Schneider C, Gobert AP, Wilson KT
(2020) Oncogene 39: 4465-4474
MeSH Terms: Adenocarcinoma, Animals, Cell Transformation, Neoplastic, DNA Damage, Gastritis, Helicobacter Infections, Helicobacter pylori, Mice, Mice, Inbred C57BL, Mice, Knockout, Organoids, Oxidoreductases Acting on CH-NH Group Donors, Proteome, RNA, Messenger, Signal Transduction, Spermidine, Spermine, Stomach Neoplasms, beta Catenin
Show Abstract · Added May 1, 2020
Helicobacter pylori infection is the main risk factor for the development of gastric cancer, the third leading cause of cancer death worldwide. H. pylori colonizes the human gastric mucosa and persists for decades. The inflammatory response is ineffective in clearing the infection, leading to disease progression that may result in gastric adenocarcinoma. We have shown that polyamines are regulators of the host response to H. pylori, and that spermine oxidase (SMOX), which metabolizes the polyamine spermine into spermidine plus HO, is associated with increased human gastric cancer risk. We now used a molecular approach to directly address the role of SMOX, and demonstrate that Smox-deficient mice exhibit significant reductions of gastric spermidine levels and H. pylori-induced inflammation. Proteomic analysis revealed that cancer was the most significantly altered functional pathway in Smox gastric organoids. Moreover, there was also less DNA damage and β-catenin activation in H. pylori-infected Smox mice or gastric organoids, compared to infected wild-type animals or gastroids. The link between SMOX and β-catenin activation was confirmed in human gastric organoids that were treated with a novel SMOX inhibitor. These findings indicate that SMOX promotes H. pylori-induced carcinogenesis by causing inflammation, DNA damage, and activation of β-catenin signaling.
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19 MeSH Terms
Functional Properties of Helicobacter pylori VacA Toxin m1 and m2 Variants.
Caston RR, Sierra JC, Foegeding NJ, Truelock MD, Campbell AM, Frick-Cheng AE, Bimczok D, Wilson KT, McClain MS, Cover TL
(2020) Infect Immun 88:
MeSH Terms: Amino Acid Sequence, Bacterial Proteins, Bacterial Toxins, Gene Expression Regulation, Bacterial, Genetic Variation, Helicobacter Infections, Helicobacter pylori, Humans, Protein Domains, Protein Multimerization, Protein Transport, Vacuoles
Show Abstract · Added April 15, 2020
colonizes the gastric mucosa and secretes a pore-forming toxin (VacA). Two main types of VacA, m1 and m2, can be distinguished by phylogenetic analysis. Type m1 forms of VacA have been extensively studied, but there has been relatively little study of m2 forms. In this study, we generated strains producing chimeric proteins in which VacA m1 segments of a parental strain were replaced by corresponding m2 sequences. In comparison to the parental m1 VacA protein, a chimeric protein (designated m2/m1) containing m2 sequences in the N-terminal portion of the m region was less potent in causing vacuolation of HeLa cells, AGS gastric cells, and AZ-521 duodenal cells and had reduced capacity to cause membrane depolarization or death of AZ-521 cells. Consistent with the observed differences in activity, the chimeric m2/m1 VacA protein bound to cells at reduced levels compared to the binding levels of the parental m1 protein. The presence of two strain-specific insertions or deletions within or adjacent to the m region did not influence toxin activity. Experiments with human gastric organoids grown as monolayers indicated that m1 and m2/m1 forms of VacA had similar cell-vacuolating activities. Interestingly, both forms of VacA bound preferentially to the basolateral surface of organoid monolayers and caused increased cell vacuolation when interacting with the basolateral surface compared to the apical surface. These data provide insights into functional correlates of sequence variation in the VacA midregion (m region).
Copyright © 2020 American Society for Microbiology.
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12 MeSH Terms
Spotlight: Gastric Intestinal Metaplasia.
Shah SC, Gupta S, Li D, Morgan D, Mustafa RA, Gawron AJ
(2020) Gastroenterology 158: 704
MeSH Terms: Algorithms, Biopsy, Endoscopy, Gastrointestinal, Gastric Mucosa, Helicobacter Infections, Helicobacter pylori, Humans, Metaplasia, Population Surveillance, Practice Guidelines as Topic, Precancerous Conditions, Risk Factors, Stomach Neoplasms
Added March 3, 2020
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13 MeSH Terms
AGA Technical Review on Gastric Intestinal Metaplasia-Epidemiology and Risk Factors.
Altayar O, Davitkov P, Shah SC, Gawron AJ, Morgan DR, Turner K, Mustafa RA
(2020) Gastroenterology 158: 732-744.e16
MeSH Terms: Ethnic Groups, European Continental Ancestry Group, Gastric Mucosa, Helicobacter Infections, Helicobacter pylori, Humans, Metaplasia, Precancerous Conditions, Risk Factors, Stomach Neoplasms, United States
Added March 3, 2020
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11 MeSH Terms
AGA Technical Review on Gastric Intestinal Metaplasia-Natural History and Clinical Outcomes.
Gawron AJ, Shah SC, Altayar O, Davitkov P, Morgan D, Turner K, Mustafa RA
(2020) Gastroenterology 158: 705-731.e5
MeSH Terms: Biopsy, Disease Progression, Endoscopy, Gastrointestinal, Gastric Mucosa, Helicobacter Infections, Helicobacter pylori, Humans, Metaplasia, Population Surveillance, Precancerous Conditions, Prevalence, Risk Factors, Stomach Neoplasms, United States
Added March 3, 2020
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14 MeSH Terms
Targeted mobilization of Lrig1 gastric epithelial stem cell populations by a carcinogenic type IV secretion system.
Wroblewski LE, Choi E, Petersen C, Delgado AG, Piazuelo MB, Romero-Gallo J, Lantz TL, Zavros Y, Coffey RJ, Goldenring JR, Zemper AE, Peek RM
(2019) Proc Natl Acad Sci U S A 116: 19652-19658
MeSH Terms: Adenocarcinoma, Animals, Carcinogenesis, Disease Models, Animal, Epithelial Cells, Female, Gastric Mucosa, Gastritis, Helicobacter Infections, Helicobacter pylori, Humans, Male, Membrane Glycoproteins, Mice, Mice, Knockout, Nerve Tissue Proteins, Precancerous Conditions, Primary Cell Culture, Risk Factors, Stem Cells, Stomach, Stomach Neoplasms, Type IV Secretion Systems
Show Abstract · Added September 27, 2019
-induced gastritis is the strongest risk factor for gastric adenocarcinoma, a malignancy preceded by a series of well-defined histological stages, including metaplasia. One microbial constituent that augments cancer risk is the type 4 secretion system (T4SS), which translocates the oncoprotein CagA into host cells. Aberrant stem cell activation is linked to carcinogenesis, and Lrig1 (leucine-rich repeats and Ig-like domains 1) marks a distinct population of progenitor cells. We investigated whether microbial effectors with carcinogenic potential influence Lrig1 progenitor cells ex vivo and via lineage expansion within -infected gastric mucosa. Lineage tracing was induced in (Lrig1/YFP) mice that were uninfected or subsequently infected with or an isogenic mutant (nonfunctional T4SS). In contrast to infection with wild-type (WT) for 2 wk, infection for 8 wk resulted in significantly increased inflammation and proliferation in the corpus and antrum compared with uninfected or mice infected with the mutant. WT -infected mice harbored significantly higher numbers of Lrig1/YFP epithelial cells that coexpressed UEA1 (surface cell marker). The number of cells coexpressing intrinsic factor (chief cell marker), YFP (lineage marker), and GSII lectin (spasmolytic polypeptide-expressing metaplasia marker) were increased only by WT In human samples, Lrig1 expression was significantly increased in lesions with premalignant potential compared with normal mucosa or nonatrophic gastritis. In conclusion, chronic infection stimulates Lrig1-expressing progenitor cells in a -dependent manner, and these reprogrammed cells give rise to a full spectrum of differentiated cells.
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23 MeSH Terms
Preventing Gastric Cancer Development by Inhibiting the Virulence of H. pylori Infection.
Wilson KT
(2019) Oncology (Williston Park) 33: 227-31
MeSH Terms: Antineoplastic Agents, Eflornithine, Helicobacter Infections, Helicobacter pylori, Humans, Stomach Neoplasms, Virulence
Added July 11, 2019
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7 MeSH Terms
Geospatial analyses identify regional hot spots of diffuse gastric cancer in rural Central America.
Dominguez RL, Cherry CB, Estevez-Ordonez D, Mera R, Escamilla V, Pawlita M, Waterboer T, Wilson KT, Peek RM, Tavera G, Williams SM, Gulley ML, Emch M, Morgan DR
(2019) BMC Cancer 19: 545
MeSH Terms: Aged, Case-Control Studies, Central America, Disease Susceptibility, Female, Geography, Helicobacter Infections, Helicobacter pylori, Humans, Male, Middle Aged, Risk Assessment, Risk Factors, Rural Health, Spatial Analysis, Stomach Neoplasms
Show Abstract · Added June 10, 2019
BACKGROUND - Geospatial technology has facilitated the discovery of disease distributions and etiology and helped target prevention programs. Globally, gastric cancer is the leading infection-associated cancer, and third leading cause of cancer mortality worldwide, with marked geographic variation. Central and South America have a significant burden, particularly in the mountainous regions. In the context of an ongoing population-based case-control study in Central America, our aim was to examine the spatial epidemiology of gastric cancer subtypes and H. pylori virulence factors.
METHODS - Patients diagnosed with gastric cancer from 2002 to 2013 in western Honduras were identified in the prospective gastric cancer registry at the principal district hospital. Diagnosis was based on endoscopy and confirmatory histopathology. Geospatial methods were applied using the ArcGIS v10.3.1 and SaTScan v9.4.2 platforms to examine regional distributions of the gastric cancer histologic subtypes (Lauren classification), and the H. pylori CagA virulence factor. Getis-Ord-Gi hot spot and Discrete Poisson SaTScan statistics, respectively, were used to explore spatial clustering at the village level (30-50 rural households), with standardization by each village's population. H. pylori and CagA serologic status was determined using the novel H. pylori multiplex assay (DKFZ, Germany).
RESULTS - Three hundred seventy-eight incident cases met the inclusion criteria (mean age 63.7, male 66.3%). Areas of higher gastric cancer incidence were identified. Significant spatial clustering of diffuse histology adenocarcinoma was revealed both by the Getis-Ord-GI* hot spot analysis (P-value < 0.0015; range 0.00003-0.0014; 99%CI), and by the SaTScan statistic (P-value < 0.006; range 0.0026-0.0054). The intestinal subtype was randomly distributed. H. pylori CagA had significant spatial clustering only in association with the diffuse histology cancer hot spot (Getis-Ord-Gi* P value ≤0.001; range 0.0001-0.0010; SaTScan statistic P value 0.0085). In the diffuse gastric cancer hot spot, the lowest age quartile range was 21-46 years, significantly lower than the intestinal cancers (P = 0.024).
CONCLUSIONS - Geospatial methods have identified a significant cluster of incident diffuse type adenocarcinoma cases in rural Central America, suggest of a germline genetic association. Further genomic and geospatial analyses to identify potential spatial patterns of genetic, bacterial, and environmental risk factors may be informative.
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16 MeSH Terms
Systematic review with meta-analysis: association between Helicobacter pylori CagA seropositivity and odds of inflammatory bowel disease.
Tepler A, Narula N, Peek RM, Patel A, Edelson C, Colombel JF, Shah SC
(2019) Aliment Pharmacol Ther 50: 121-131
MeSH Terms: Adolescent, Adult, Antibodies, Bacterial, Antigens, Bacterial, Bacterial Proteins, Colitis, Ulcerative, Comorbidity, Crohn Disease, Female, Helicobacter Infections, Helicobacter pylori, Humans, Inflammatory Bowel Diseases, Male, Middle Aged, Seroepidemiologic Studies, Young Adult
Show Abstract · Added March 3, 2020
BACKGROUND - Accumulating data support a protective role of Helicobacter pylori against inflammatory bowel diseases (IBD), which might be mediated by strain-specific constituents, specifically cagA expression.
AIM - To perform a systematic review and meta-analysis to more clearly define the association between CagA seropositivity and IBD.
METHODS - We identified comparative studies that included sufficient detail to determine the odds or risk of IBD, Crohn's disease (CD) or ulcerative colitis (UC) amongst individuals with vs without evidence of cagA expression (eg CagA seropositivity). Estimates were pooled using a random effects model.
RESULTS - Three clinical studies met inclusion criteria. cagA expression was represented by CagA seropositivity in all studies. Compared to CagA seronegativity overall, CagA seropositivity was associated with lower odds of IBD (OR 0.31, 95% CI 0.21-0.44) and CD (OR 0.25, 95% CI 0.17-0.38), and statistically nonsignificant lower odds for UC (OR 0.68, 95% CI 0.35-1.32). Similarly, compared to H pylori non-exposed individuals, H pylori exposed, CagA seropositive individuals had lower odds of IBD (OR 0.26, 95% CI 0.16-0.41) and CD (OR 0.23, 95% CI 0.15-0.35), but not UC (OR 0.66, 0.34-1.27). However, there was no significant difference in the odds of IBD, CD or UC between H pylori exposed, CagA seronegative and H pylori non-exposed individuals.
CONCLUSION - We found evidence for a significant association between CagA seropositive H pylori exposure and reduced odds of IBD, particularly CD, but not for CagA seronegative H pylori exposure. Additional studies are needed to confirm these findings and define underlying mechanisms.
© 2019 John Wiley & Sons Ltd.
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17 MeSH Terms
Upper Endoscopy up to 3 Years Prior to a Diagnosis of Gastric Cancer Is Associated With Lower Stage of Disease in a USA Multiethnic Urban Population, a Retrospective Study.
Shah SC, Nakata C, Polydorides AD, Peek RM, Itzkowitz SH
(2019) J Prev Med Public Health 52: 179-187
MeSH Terms: Adult, Aged, Aged, 80 and over, Cross-Sectional Studies, Endoscopy, Female, Helicobacter Infections, Helicobacter pylori, Humans, Male, Mass Screening, Middle Aged, New York City, Retrospective Studies, Stomach Neoplasms, Urban Population
Show Abstract · Added March 3, 2020
OBJECTIVES - In the USA, certain races and ethnicities have a disproportionately higher gastric cancer burden. Selective screening might allow for earlier detection and curative resection. Among a USA-based multiracial and ethnic cohort diagnosed with non-cardia gastric cancer (NCGC), we aimed to identify factors associated with curable stage disease at diagnosis.
METHODS - We retrospectively identified endoscopically diagnosed and histologically confirmed cases of NCGC at Mount Sinai Hospital in New York City. Demographic, clinical, endoscopic and histologic factors, as well as grade/stage of NCGC at diagnosis were documented. The primary outcome was the frequency of curable-stage NCGC (stage 0-1a) at diagnosis in patients with versus without an endoscopy negative for malignancy prior to their index exam diagnosing NCGC. Additional factors associated with curable-stage disease at diagnosis were determined.
RESULTS - A total of 103 racially and ethnically diverse patients were included. Nearly 38% of NCGC were stage 0-Ia, 34% stage Ib-III, and 20.3% stage IV at diagnosis. A significantly higher frequency of NCGC was diagnosed in curable stages among patients who had undergone an endoscopy that was negative for malignancy prior to their index endoscopy that diagnosed NCGC, compared to patients without a negative endoscopy prior to their index exam (69.6% vs. 28.6%, p=0.003). A prior negative endoscopy was associated with 94.0% higher likelihood of diagnosing curable-stage NCGC (p=0.003). No other factors analyzed were associated with curable-stage NCGC at diagnosis.
CONCLUSIONS - Endoscopic screening and surveillance in select high-risk populations might increase diagnoses of curable-stage NCGC. These findings warrant confirmation in larger, prospective studies.
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