Cancers

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17 pages, 2072 KiB

Open AccessArticle

Tailor-Made Detection of Individual Phosphorylated and Non-Phosphorylated EPIYA-Motifs of Helicobacter pylori Oncoprotein CagA

by Suneesh Kumar Pachathundikandi, Andrés Julián Gutiérrez-Escobar and Nicole Tegtmeyer

Cancers 2019, 11(8), 1163; https://doi.org/10.3390/cancers11081163 - 13 Aug 2019

Cited by 8 | Viewed by 3834

Abstract

The gastric pathogen and carcinogen Helicobacter pylori (H. pylori) encodes a type IV secretion system for translocation of the effector protein CagA into host cells. Injected CagA becomes tyrosine-phosphorylated at the five amino acid residue Glutamate-Proline- Isoleucine-Tyrosine-Alanine (EPIYA)-sequence motifs. These phosphorylated EPIYA-sites represent [...] Read more.

The gastric pathogen and carcinogen Helicobacter pylori (H. pylori) encodes a type IV secretion system for translocation of the effector protein CagA into host cells. Injected CagA becomes tyrosine-phosphorylated at the five amino acid residue Glutamate-Proline- Isoleucine-Tyrosine-Alanine (EPIYA)-sequence motifs. These phosphorylated EPIYA-sites represent recognition motifs for binding of multiple host factors, which then manipulate signaling pathways to trigger gastric disease. Thus, efficient detection of single phosphorylated EPIYA-motifs in CagA is required. Detection of phospho-CagA is primarily performed using commercial pan-phosphotyrosine antibodies. However, those antibodies were originally generated to recognize many phosphotyrosines in various mammalian proteins and are not optimized for use in bacteria. To address this important limitation, we synthesized 11-mer phospho- and non-phospho-peptides from EPIYA-motifs A, B, and C, and produced three phospho-specific and three non-phospho-specific rabbit polyclonal CagA antibodies. These antibodies specifically recognized the corresponding phosphorylated and non-phosphorylated EPIYA-motifs, while the EPIYA-C antibodies also recognized the related East-Asian EPIYA-D motif. Otherwise, no cross-reactivity of the antibodies among EPIYAs was observed. Western blotting demonstrated that each EPIYA-motif can be predominantly phosphorylated during H. pylori infection. This represents the first complete set of phospho-specific antibodies for an effector protein in bacteria, providing useful tools to gather information for the categorization of CagA phosphorylation, cancer signaling, and gastric disease progression. Full article

(This article belongs to the Special Issue Helicobacter pylori Associated Cancer)

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16 pages, 2319 KiB

Open AccessArticle

A Novel Role for Helicobacter pylori Gamma-Glutamyltranspeptidase in Regulating Autophagy and Bacterial Internalization in Human Gastric Cells

by Jimena Bravo, Paula Díaz, Alejandro H. Corvalán and Andrew F.G. Quest

Cancers 2019, 11(6), 801; https://doi.org/10.3390/cancers11060801 - 10 Jun 2019

Cited by 13 | Viewed by 4165

Abstract

The risk of developing gastric cancer is strongly linked to Helicobacter pylori (H. pylori) infection. Alternatively, autophagy is a conserved response that is important in cellular homeostasis and provides protection against bacterial infections. Although H. pylori is typically considered an extracellular [...] Read more.

The risk of developing gastric cancer is strongly linked to Helicobacter pylori (H. pylori) infection. Alternatively, autophagy is a conserved response that is important in cellular homeostasis and provides protection against bacterial infections. Although H. pylori is typically considered an extracellular bacterium, several reports indicate that it internalizes, possibly to avoid exposure to antibiotics. Mechanisms by which H. pylori manipulates host cell autophagic processes remain unclear and, importantly, none of the available studies consider a role for the secreted H. pylori virulence factor gamma-glutamyltranspeptidase (HpGGT) in this context. Here, we identify HpGGT as a novel autophagy inhibitor in gastric cells. Our experiments revealed that deletion of HpGGT increased autophagic flux following H. pylori infection of AGS and GES-1 gastric cells. In AGS cells, HpGGT disrupted the late stages of autophagy by preventing degradation in lysosomes without affecting lysosomal acidification. Specifically, HpGGT impaired autophagic flux by disrupting lysosomal membrane integrity, which leads to a decrease in lysosomal cathepsin B activity. Moreover, HpGGT was necessary for efficient internalization of the bacteria into gastric cells. This important role of HpGGT in internalization together with the ability to inhibit autophagy posits HpGGT as a key virulence factor in the development of gastric cancer. Full article

(This article belongs to the Special Issue Helicobacter pylori Associated Cancer)

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14 pages, 2492 KiB

Open AccessArticle

The Helicobacter pylori Urease Virulence Factor Is Required for the Induction of Hypoxia-Induced Factor-1α in Gastric Cells

by Manuel Valenzuela-Valderrama, Paulina Cerda-Opazo, Steffen Backert, María Fernanda González, Nicolás Carrasco-Véliz, Carla Jorquera-Cordero, Sergio Wehinger, Jimena Canales, Denisse Bravo and Andrew F. G. Quest

Cancers 2019, 11(6), 799; https://doi.org/10.3390/cancers11060799 - 10 Jun 2019

Cited by 37 | Viewed by 6348

Abstract

Chronic Helicobacter pylori infection increases the risk of gastric cancer and induction of hypoxia-induced factor (HIF), which is frequently associated with the development and progression of several types of cancer. We recently showed that H. pylori activation of the PI3K-AKT-mTOR pathway in gastric [...] Read more.

Chronic Helicobacter pylori infection increases the risk of gastric cancer and induction of hypoxia-induced factor (HIF), which is frequently associated with the development and progression of several types of cancer. We recently showed that H. pylori activation of the PI3K-AKT-mTOR pathway in gastric cells increased HIF-1α expression. Here, we identified the H. pylori virulence factor responsible for HIF-1α induction. A mutant of the H. pylori 84-183 strain was identified with reduced ability to induce HIF-1α. Coomassie blue staining of extracts from these bacteria separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) revealed poor expression of urease subunits that correlated with reduced urease activity. This finding was confirmed in the 26695 strain, where urease mutants were unable to induce HIF-1α expression. Of note, HIF-1α induction was also observed in the presence of the urease inhibitor acetohydroxamic acid at concentrations (of 20 mM) that abrogated urease activity in bacterial culture supernatants, suggesting that enzymatic activity of the urease is not required for HIF-1α induction. Finally, the pre-incubation of the human gastric adenocarcinoma cell line AGS with blocking antibodies against Toll-like receptor-2 (TLR2), but not TLR4, prevented HIF-1α induction. In summary, these results reveal a hitherto unexpected role for the urease protein in HIF-1α induction via TLR2 activation following H. pylori infection of gastric cells. Full article

(This article belongs to the Special Issue Helicobacter pylori Associated Cancer)

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10 pages, 1430 KiB

Open AccessArticle

Western-Type Helicobacter pylori CagA are the Most Frequent Type in Mongolian Patients

by Tegshee Tserentogtokh, Boldbaatar Gantuya, Phawinee Subsomwong, Khasag Oyuntsetseg, Dashdorj Bolor, Yansan Erdene-Ochir, Dashdorj Azzaya, Duger Davaadorj, Tomohisa Uchida, Takeshi Matsuhisa and Yoshio Yamaoka

Cancers 2019, 11(5), 725; https://doi.org/10.3390/cancers11050725 - 24 May 2019

Cited by 18 | Viewed by 3916

Abstract

Helicobacter pylori infection possessing East-Asian-type CagA is associated with carcinogenesis. Mongolia has the highest mortality rate from gastric cancer. Therefore, we evaluated the CagA status in the Mongolian population. High risk and gastric cancer patients were determined using endoscopy and histological examination. H. [...] Read more.

Helicobacter pylori infection possessing East-Asian-type CagA is associated with carcinogenesis. Mongolia has the highest mortality rate from gastric cancer. Therefore, we evaluated the CagA status in the Mongolian population. High risk and gastric cancer patients were determined using endoscopy and histological examination. H. pylori strains were isolated from different locations in Mongolia. The CagA subtypes (East-Asian-type or Western-type, based on sequencing of Glu-Pro-Ile-Tyr-Ala (EPIYA) segments) and vacA genotypes (s and m regions) were determined using PCR-based sequencing and PCR, respectively. In total, 368 patients were examined (341 gastritis, 10 peptic ulcer, and 17 gastric cancer). Sixty-two (16.8%) strains were cagA-negative and 306 (83.1%) were cagA-positive (293 Western-type, 12 East-Asian-type, and one hybrid type). All cagA-negative strains were isolated from gastritis patients. In the gastritis group, 78.6% (268/341) had Western-type CagA, 2.9% (10/341) had East-Asian-type, and 18.2% (61/341) were cagA-negative. However, all H. pylori from gastric cancer patients possessed Western-type CagA. Histological analyses showed that East-Asian-type CagA was the most virulent strains, followed by Western-type and cagA-negative strains. This finding agreed with the current consensus. CagA-positive strains were the most virulent type. However, the fact that different CagA types can explain the high incidence of gastric cancer might be inapplicable in Mongolia. Full article

(This article belongs to the Special Issue Helicobacter pylori Associated Cancer)

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22 pages, 3176 KiB

Open AccessArticle

Polymorphism in Toll-Like Receptors and Helicobacter Pylori Motility in Autoimmune Atrophic Gastritis and Gastric Cancer

by Valli De Re, Ombretta Repetto, Mariangela De Zorzi, Mariateresa Casarotto, Massimo Tedeschi, Paolo Giuffrida, Marco Vincenzo Lenti, Raffaella Magris, Gianmaria Miolo, Cinzia Mazzon, Giorgio Zanette, Lara Alessandrini, Vincenzo Canzonieri, Laura Caggiari, Stefania Zanussi, Agostino Steffan, Antonio Di Sabatino and Renato Cannizzaro

Cancers 2019, 11(5), 648; https://doi.org/10.3390/cancers11050648 - 10 May 2019

Cited by 23 | Viewed by 4101

Abstract

Autoimmune atrophic gastritis (AAG) is associated with an increased risk of certain types of gastric cancer (GC). Helicobacter pylori (H. pylori) infection may have a role in the induction and/or maintenance of AAG and GC. Toll-like receptors (TLR) are essential for [...] Read more.

Autoimmune atrophic gastritis (AAG) is associated with an increased risk of certain types of gastric cancer (GC). Helicobacter pylori (H. pylori) infection may have a role in the induction and/or maintenance of AAG and GC. Toll-like receptors (TLR) are essential for H. pylori recognition and subsequent innate and adaptive immunity responses. This study therefore aimed to characterize TLR polymorphisms, and features of bacterial flagellin A in samples from patients with AAG (n = 67), GC (n = 114) and healthy donors (HD; n = 97). TLR5 rs5744174 C/C genotype was associated with GC, lower IgG anti H. pylori response and a higher H. pylori flagellin A abundance and motility. In a subset of patients with AAG, H. pylori strains showed a reduction of the flagellin A abundance and a moderate motility compared with strains from GC patients, a prerequisite for active colonization of the deeper layers of the mucosa, host immune response and inflammation. TLR9 rs5743836 T allele showed an association with serum gastrin G17. In conclusion, our study suggests that alterations of flaA protein, moderate motility in H. pylori and two polymorphisms in TLR5 and TLR9 may favor the onset of AAG and GC, at least in a subset of patients. These findings corroborate the function of pathogen–host cell interactions and responses, likely influencing the pathogenetic process. Full article

(This article belongs to the Special Issue Helicobacter pylori Associated Cancer)

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13 pages, 1069 KiB

Open AccessArticle

Gastric Cancer in Northern Canadian Populations: A Focus on Cardia and Non-Cardia Subsites

by Amy Colquhoun, Heather Hannah, André Corriveau, Brendan Hanley, Yan Yuan, Karen J. Goodman and The CANHelp Working Group

Cancers 2019, 11(4), 534; https://doi.org/10.3390/cancers11040534 - 15 Apr 2019

Cited by 13 | Viewed by 4191

Abstract

In northern Canada where there is a high prevalence of Helicobacter pylori infection, there is a paucity of information on gastric cancer by the topographical subsites cardia (CGC) and non-cardia (NCGC). Here we describe the incidence of CGC and NCGC, separately, among northern [...] Read more.

In northern Canada where there is a high prevalence of Helicobacter pylori infection, there is a paucity of information on gastric cancer by the topographical subsites cardia (CGC) and non-cardia (NCGC). Here we describe the incidence of CGC and NCGC, separately, among northern Canadian populations. We used data from the Cancer Incidence in Five Continents Volumes X (CI5X) and XI (CI5XI) to obtain CGC and NCGC incidence for Canada and for Yukon (YT), a northern Canadian territory. Using these data with those provided by the Government of the Northwest Territories (NT), we estimated standardized incidence ratios comparing northern populations to Canada as a whole. We also estimated age-standardized incidence rates to permit comparisons across populations globally. NT and YT populations were disproportionately impacted by gastric cancer, particularly NCGC. This was especially true for Indigenous populations: NCGC incidence rates among NT Indigenous men were 2.7 times the rates among all men in Canada, while rates among NT Indigenous women were 3.1 times the rates among all women in Canada. Similarly, age-standardized rates of NCGC among Indigenous NT residents were comparable to global regions where there is a high burden of NCGC. This study has, for the first time, quantified the incidence of CGC and NCGC for the NT and YT, providing new insights into the burden of these cancers among northern Canadian populations. Full article

(This article belongs to the Special Issue Helicobacter pylori Associated Cancer)

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12 pages, 2105 KiB

Open AccessFeature PaperArticle

Gastric Microbiota in Helicobacter pylori-Negative and -Positive Gastritis Among High Incidence of Gastric Cancer Area

by Boldbaatar Gantuya, Hashem B. El-Serag, Takashi Matsumoto, Nadim J. Ajami, Khasag Oyuntsetseg, Dashdorj Azzaya, Tomohisa Uchida and Yoshio Yamaoka

Cancers 2019, 11(4), 504; https://doi.org/10.3390/cancers11040504 - 10 Apr 2019

Cited by 61 | Viewed by 5964

Abstract

Helicobacter pylori (H. pylori) related chronic gastritis is a well-known major etiological factor for gastric cancer development. However, H. pylori-negative gastritis (HpN) is not well described. We aimed to examine gastric mucosal microbiota in HpN compared to H. pylori-positive [...] Read more.

Helicobacter pylori (H. pylori) related chronic gastritis is a well-known major etiological factor for gastric cancer development. However, H. pylori-negative gastritis (HpN) is not well described. We aimed to examine gastric mucosal microbiota in HpN compared to H. pylori-positive gastritis (HpP) and H. pylori-negative non-gastritis group (control). Here, we studied 11 subjects with HpN, 40 with HpP and 24 controls. We performed endoscopy with six gastric biopsies. Comparison groups were defined based on strict histological criteria for the disease and H. pylori diagnosis. We used 16S rRNA gene amplicon sequencing to profile the gastric microbiota according to comparison groups. These results demonstrate that the HpP group had significantly lower bacterial richness by the operational taxonomic unit (OTU) counts, and Shannon and Simpson indices as compared to HpN or controls. The linear discriminant analysis effect size analysis showed the enrichment of Firmicutes, Fusobacteria, Bacteroidetes and Actinobacteria at phylum level in the HpN group. In the age-adjusted multivariate analysis, Streptococcus sp. and Haemophilus parainfluenzae were at a significantly increased risk for HpN (odds ratio 18.9 and 12.3, respectively) based on abundance. Treponema sp. was uniquely found in HpN based on occurrence. In this paper, we conclude that Streptococcus sp., Haemophilus parainfluenzae and Treponema sp. are candidate pathogenic bacterial species for HpN. These results if confirmed may have important clinical implications. Full article

(This article belongs to the Special Issue Helicobacter pylori Associated Cancer)

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12 pages, 264 KiB

Open AccessArticle

Association between Dietary Salt Intake and Progression in the Gastric Precancerous Process

by Susan Thapa, Lori A. Fischbach, Robert Delongchamp, Mohammed F. Faramawi and Mohammed Orloff

Cancers 2019, 11(4), 467; https://doi.org/10.3390/cancers11040467 - 3 Apr 2019

Cited by 22 | Viewed by 3991

Abstract

Gastric cancer is the third leading cause of cancer mortality worldwide. Studies investigating the effect of salt on gastric cancer have mainly used self-reported measures, which are not as accurate as sodium/creatinine ratios because individuals may not know the amount of salt in [...] Read more.

Gastric cancer is the third leading cause of cancer mortality worldwide. Studies investigating the effect of salt on gastric cancer have mainly used self-reported measures, which are not as accurate as sodium/creatinine ratios because individuals may not know the amount of salt in their food. Using data from a prospective cohort study, we investigated the effect of salt intake on progression to gastric precancerous lesions. Salt intake was estimated by urinary sodium/creatinine ratios, self-reported frequencies of adding salt to food, and total added table salt. We repeated the analyses among groups with and without Helicobacter pylori infection. We did not observe a positive association between salt intake, measured by urinary sodium/creatinine ratio, and overall progression in the gastric precancerous process (adjusted risk ratio (RR): 0.94; 95% confidence interval (CI) 0.76–1.15). We did observe an association between salt intake and increased risk for progression to dysplasia or gastric cancer overall (RR: 1.32; 95% CI: 0.96–1.81), especially among those who continued to have H. pylori infection at the five-month follow-up (adjusted RR: 1.53; 95% CI: 1.12–2.09), and among those who had persistent H. pylori infection over 12 years (adjusted RR: 1.49; 95% CI: 1.09–2.05). Salt intake may increase the risk of gastric dysplasia or gastric cancer in individuals with H. pylori infection. Full article

(This article belongs to the Special Issue Helicobacter pylori Associated Cancer)

13 pages, 4287 KiB

Open AccessArticle

Mutated Rnf43 Aggravates Helicobacter Pylori-Induced Gastric Pathology

by Victoria Neumeyer, Michael Vieth, Markus Gerhard and Raquel Mejías-Luque

Cancers 2019, 11(3), 372; https://doi.org/10.3390/cancers11030372 - 16 Mar 2019

Cited by 13 | Viewed by 4565

Abstract

The E3 ubiquitin ligase ring finger protein 43 (RNF43) is frequently mutated in gastric tumors and loss of RNF43 expression was suggested to be one of the key events during the transition from adenoma to gastric carcinoma. Functional studies on RNF43 have shown [...] Read more.

The E3 ubiquitin ligase ring finger protein 43 (RNF43) is frequently mutated in gastric tumors and loss of RNF43 expression was suggested to be one of the key events during the transition from adenoma to gastric carcinoma. Functional studies on RNF43 have shown that it acts as a tumor suppressor by negatively regulating Wnt signaling. Interestingly, we observed that RNF43^H292R/H295R mice bearing two point mutations in the ring domain displayed thickening of the mucosa at early age but did not develop neoplasia. In this study, we infected these mice for 6 months with Helicobacter pylori, which has been described as one of the major risk factors for gastric cancer. Mice bearing mutant RNF43^H292R/H295R showed higher gastritis scores upon H. pylori infection compared to wild-type mice, accompanied by increased lymphocyte infiltration and Ifng levels. Furthermore, infected Rnf43 mutant mice developed atrophy, hyperplasia and MUC2 expressing metaplasia and displayed higher levels of the gastric stem cell marker CD44 and canonical NF-κB signaling. In summary, our results show that transactivating mutations in the tumor suppressor Rnf43 can worsen H. pylori induced pathology. Full article

(This article belongs to the Special Issue Helicobacter pylori Associated Cancer)

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23 pages, 8507 KiB

Open AccessArticle

In Vitro Activity of 3-Bromopyruvate, an Anticancer Compound, Against Antibiotic-Susceptible and Antibiotic-Resistant Helicobacter pylori Strains

by Paweł Krzyżek, Roman Franiczek, Barbara Krzyżanowska, Łukasz Łaczmański, Paweł Migdał and Grażyna Gościniak

Cancers 2019, 11(2), 229; https://doi.org/10.3390/cancers11020229 - 15 Feb 2019

Cited by 16 | Viewed by 3878

Abstract

Helicobacter pylori (H. pylori) is a bacterium capable of inducing chronic active gastritis, which in some people, develops into gastric cancers. One of the substances that may be useful in the eradication of this microorganism is 3-Bromopyruvate (3-BP), an anticancer compound with antimicrobial [...] Read more.

Helicobacter pylori (H. pylori) is a bacterium capable of inducing chronic active gastritis, which in some people, develops into gastric cancers. One of the substances that may be useful in the eradication of this microorganism is 3-Bromopyruvate (3-BP), an anticancer compound with antimicrobial properties. The aim of this article was to determine the activity of 3-BP against antibiotic-susceptible and antibiotic-resistant H. pylori strains. The antimicrobial activity was determined using a disk-diffusion method, broth microdilution method, time-killing assay, and checkerboard assay. The research was extended by observations using light, fluorescence, and scanning electron microscopy. The growth inhibition zones produced by 2 mg/disk with 3-BP counted for 16–32.5 mm. The minimal inhibitory concentrations (MICs) ranged from 32 to 128 μg/mL, while the minimal bactericidal concentrations (MBCs) for all tested strains had values of 128 μg/mL. The time-killing assay demonstrated the concentration-dependent and time-dependent bactericidal activity of 3-BP. The decrease in culturability below the detection threshold (<100 CFU/mL) was demonstrated after 6 h, 4 h, and 2 h of incubation for MIC, 2× MIC, and 4× MIC, respectively. Bacteria treated with 3-BP had a several times reduced mean green/red fluorescence ratio compared to the control samples, suggesting bactericidal activity, which was independent from an induction of coccoid forms. The checkerboard assay showed the existence of a synergistic/additive interaction of 3-BP with amoxicillin, tetracycline, and clarithromycin. Based on the presented results, it is suggested that 3-BP may be an interesting anti-H. pylori compound. Full article

(This article belongs to the Special Issue Helicobacter pylori Associated Cancer)

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Graphical abstract

8 pages, 687 KiB

Open AccessArticle

Vonoprazan-Based Third-Line Therapy Has a Higher Eradication Rate against Sitafloxacin-Resistant Helicobacter pylori

by Yoshimasa Saito, Kaho Konno, Moeka Sato, Masaru Nakano, Yukako Kato, Hidetsugu Saito and Hiroshi Serizawa

Cancers 2019, 11(1), 116; https://doi.org/10.3390/cancers11010116 - 19 Jan 2019

Cited by 29 | Viewed by 5501

Abstract

Eradication of Helicobacter pylori (H. pylori) is an effective strategy for preventing various gastrointestinal diseases such as gastric cancer and mucosa-associated lymphoid tissue (MALT) lymphoma. However, the eradication success rate is decreasing because of a recent increase in drug-resistant strains of [...] Read more.

Eradication of Helicobacter pylori (H. pylori) is an effective strategy for preventing various gastrointestinal diseases such as gastric cancer and mucosa-associated lymphoid tissue (MALT) lymphoma. However, the eradication success rate is decreasing because of a recent increase in drug-resistant strains of H. pylori. Here, we evaluated the success rate of eradication therapy with vonoprazan (VPZ), a new potassium-competitive acid blocker, against drug-resistant H. pylori. In total, 793 patients who received H. pylori eradication therapy were investigated retrospectively. All underwent esomeprazole (EPZ)-based triple therapy (n = 386) or VPZ-based triple therapy (n = 407) for first-, second- and third-line H. pylori eradication for 7 days. The overall success rates of first- and third-line H. pylori eradication were significantly higher for VPZ-based triple therapy (88.4% and 93.0%, respectively, per protocol (PP)) than for EPZ-based triple therapy (69.5% and 56.5%, respectively, PP). Moreover, the success rates of first- and third-line eradication of clarithromycin (CLR)- and sitafloxacin (STFX)-resistant H. pylori were significantly higher for VPZ-based triple therapy (72.0% and 91.7%, PP) than for EPZ-based triple therapy (38.5% and 20.0%, PP). In addition, patient age did not affect the eradication rate of VPZ-based first-line therapy, whereas the success rate of EPZ-based therapy was lower in patients under 65 years of age. Our results clearly demonstrated that VPZ-based therapy achieved a higher eradication rate even against CLR- and STFX-resistant H. pylori, and that patient age did not affect the eradication rate of VPZ-based therapy. These findings suggest that dual therapy using VPZ and amoxicillin may be sufficient for standard H. pylori eradication, and may thus also be beneficial for avoiding antibiotic misuse. Full article

(This article belongs to the Special Issue Helicobacter pylori Associated Cancer)

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16 pages, 3207 KiB

Open AccessArticle

Helicobacter pylori Infection-Induced Hepatoma-Derived Growth Factor Regulates the Differentiation of Human Mesenchymal Stem Cells to Myofibroblast-Like Cells

by Chung-Jung Liu, Yao-Kuang Wang, Fu-Chen Kuo, Wen-Hung Hsu, Fang-Jung Yu, Shuchen Hsieh, Ming-Hong Tai, Deng-Chyang Wu and Chao-Hung Kuo

Cancers 2018, 10(12), 479; https://doi.org/10.3390/cancers10120479 - 30 Nov 2018

Cited by 21 | Viewed by 3887

Abstract

Hepatoma-derived growth factor (HDGF) plays a critical role in tumor cell proliferation, anti-apoptosis, VEGF expression, lymph node metastasis and poor prognosis in human gastric cancer. Gastric cancer, as one of the most prevalent cancers worldwide, is the second leading cause of cancer-related mortality [...] Read more.

Hepatoma-derived growth factor (HDGF) plays a critical role in tumor cell proliferation, anti-apoptosis, VEGF expression, lymph node metastasis and poor prognosis in human gastric cancer. Gastric cancer, as one of the most prevalent cancers worldwide, is the second leading cause of cancer-related mortality in the world for the prognosis of gastric cancer is generally poor, especially in patients with advanced stage. Helicobacter pylori (H. pylori) infection causes the chronic inflammation of stomach as well as the development of gastric cancer, with a three to six-fold increased risk of gastric cancer. Carcinoma-associated fibroblasts (CAFs) are myofibroblasts in tumor microenvironment, which possess various abilities to promote the progression of cancer by stimulating neoangiogenesis, proliferation, migration, invasion and therapy resistance of tumor cell. Mesenchymal stem cells (MSCs) are reported to promote tumor malignance through differentiation of MSCs toward CAFs. In the present study, we demonstrated that H. pylori infection promotes HDGF expression in human gastric cancer cells. HBMMSCs treated with HDGF assume properties of CAF-like myofibroblastic phenotypes, including expression of myofibroblast markers (α-smooth muscle actin (α-SMA), procollagen α1, tropomyoson I, desmin, fibroblast activation protein (FAP)), and fibroblast markers (prolyl-4-hydroxylase A1 (PHA1) and fibroblast specific protein-1 (FSP-1)/S100A4). HDGF recruits HBMMSCs, and then HBMMSCs further contributes to cell survival and invasive motility in human gastric cancer cells. Treatment of HDGF neutralizing antibody (HDGF-NAb) and serum significantly inhibit HDGF-regulated differentiation and recruitment of HBMMSCs. These findings suggest that HDGF might play a critical role in gastric cancer progress through stimulation of HBMMSCs differentiation to myofibroblast-like cells. Full article

(This article belongs to the Special Issue Helicobacter pylori Associated Cancer)

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18 pages, 917 KiB

Open AccessArticle

Physical Activity and Gastric Cancer Risk in Patients with and without Helicobacter pylori Infection in A Korean Population: A Hospital-Based Case-Control Study

by Madhawa Neranjan Gunathilake, Jeonghee Lee, Aelee Jang, Il Ju Choi, Young-Il Kim and Jeongseon Kim

Cancers 2018, 10(10), 369; https://doi.org/10.3390/cancers10100369 - 2 Oct 2018

Cited by 14 | Viewed by 4719

Abstract

Although physical activity (PA) is beneficial for prolonging lifespan, evidence for the protective role of PA against the development of gastric cancer (GC) is not yet well established. This study assessed the association between PA and GC risk in patients with and without [...] Read more.

Although physical activity (PA) is beneficial for prolonging lifespan, evidence for the protective role of PA against the development of gastric cancer (GC) is not yet well established. This study assessed the association between PA and GC risk in patients with and without Helicobacter pylori (H. pylori) infection in a Korean population. In total, 415 GC patients and 830 controls were enrolled at the National Cancer Center, Korea. The International Physical Activity Questionnaire-Short Form was used to collect PA data. The odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression models. In the H. pylori-positive group, subjects who engaged in regular exercise showed a significantly reduced risk of GC in the entire population (OR = 0.52, 95% CI = 0.38–0.70) and in females (OR = 0.60, 95% CI = 0.21–0.64). Subjects who engaged in a high level of total PA showed a significantly reduced risk of GC relative to subjects in the lowest tertile in the fully adjusted model (OR = 0.46, 95% CI = 0.32–0.65, p-trend < 0.001). There was an inverse association between PA and GC risk in the entire population, and in the H. pylori-positive subgroup. Our data indicate the need for the promotion of all domains of PA, especially for Korean populations. Full article

(This article belongs to the Special Issue Helicobacter pylori Associated Cancer)

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Review

Jump to: Research, Other

16 pages, 1804 KiB

Open AccessReview

Efficacy and Long-Term Safety of H. pylori Eradication for Gastric Cancer Prevention

by Jyh-Ming Liou, Yi-Chia Lee, Emad M. El-Omar and Ming-Shiang Wu

Cancers 2019, 11(5), 593; https://doi.org/10.3390/cancers11050593 - 28 Apr 2019

Cited by 39 | Viewed by 9308

Abstract

Helicobacter pylori (H. pylori) has been shown to be a causal factor of gastric cancer in cohort studies and animal models. Meta-analysis of case-control studies nested within prospective cohorts showed that H. pylori infection was associated with a 5.9-fold increased risk of non-cardia [...] Read more.

Helicobacter pylori (H. pylori) has been shown to be a causal factor of gastric cancer in cohort studies and animal models. Meta-analysis of case-control studies nested within prospective cohorts showed that H. pylori infection was associated with a 5.9-fold increased risk of non-cardia gastric cancer. Prospective cohort studies showed that gastric cancer developed in 1–4% of H. pylori-infected subjects. Gastric cancer was successfully induced in Mongolian gerbils and insulin-gastrin (INS-GAS) transgenic mice after inoculation of H. pylori. Meta-analysis of randomized control trials also showed that eradication of H. pylori may reduce the risk of gastric cancer. However, there are several concerns regarding the widespread use of antibiotics to prevent gastric cancer, including the emergence of antibiotic resistance and the perturbation of gut microbiota after H. pylori eradication. Recent studies showed that eradication of H. pylori resulted in an increase in the bacterial diversity and restoration of the relative abundance of other bacteria to levels similar to H. pylori non-infected subjects in the gastric microbiota. The administration of antibiotics may also alter the composition of intestinal microbiota. The α-diversity and β-diversity of fecal microbiota are significantly altered immediately after H. pylori eradication but are gradually restored to levels similar to those before therapy. Yet, the rate of recovery varies with regimens. The diversity was restored at week 8 after triple therapy but was not yet fully recovered at 1 year after concomitant and quadruple therapies. Some studies showed that supplementation of probiotics may reduce the dysbiosis during H. pylori eradication therapy. Although some earlier studies showed high levels of macrolide resistance after triple therapy, recent studies showed that the increased antibiotic resistance rate may be restored 2–12 months after eradication therapy. These results collectively provide evidence of the long-term safety of H. pylori eradication. Yet, more prospective cohort studies and randomized trials are warranted to assess the efficacy and long-term safety of H. pylori eradication for gastric cancer prevention. Full article

(This article belongs to the Special Issue Helicobacter pylori Associated Cancer)

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20 pages, 1091 KiB

Open AccessReview

Novel Insights of Lymphomagenesis of Helicobacter pylori-Dependent Gastric Mucosa-Associated Lymphoid Tissue Lymphoma

by Sung-Hsin Kuo, Ming-Shiang Wu, Kun-Huei Yeh, Chung-Wu Lin, Ping-Ning Hsu, Li-Tzong Chen and Ann-Lii Cheng

Cancers 2019, 11(4), 547; https://doi.org/10.3390/cancers11040547 - 17 Apr 2019

Cited by 31 | Viewed by 5959

Abstract

Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is the most common subtype of gastric lymphoma. Most gastric MALT lymphomas are characterized by their association with the Helicobacter pylori (HP) infection and are cured by first-line HP eradication therapy (HPE). Several studies have been conducted [...] Read more.

Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is the most common subtype of gastric lymphoma. Most gastric MALT lymphomas are characterized by their association with the Helicobacter pylori (HP) infection and are cured by first-line HP eradication therapy (HPE). Several studies have been conducted to investigate why most gastric MALT lymphomas remain localized, are dependent on HP infection, and show HP-specific intratumoral T-cells (e.g., CD40-mediated signaling, T-helper-2 (Th2)-type cytokines, chemokines, costimulatory molecules, and FOXP3+ regulatory T-cells) and their communication with B-cells. Furthermore, the reason why the antigen stimuli of these intratumoral T-cells with tonic B-cell receptor signaling promote lymphomagenesis of gastric MALT lymphoma has also been investigated. In addition to the aforementioned mechanisms, it has been demonstrated that the translocated HP cytotoxin-associated gene A (CagA) can promote B-cell proliferation through the activation of Src homology-2 domain-containing phosphatase (SHP-2) phosphorylation-dependent signaling, extracellular-signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK), B-cell lymphoma (Bcl)-2, and Bcl-xL. Furthermore, the expression of CagA and these CagA-signaling molecules is closely associated with the HP-dependence of gastric MALT lymphomas (completely respond to first-line HPE). In this article, we summarize evidence of the classical theory of HP-reactive T-cells and the new paradigm of direct interaction between HP and B-cells that contributes to the HP-dependent lymphomagenesis of gastric MALT lymphomas. Although the role of first-line HPE in the treatment of HP-negative gastric MALT lymphoma remains uncertain, several case series suggest that a proportion of HP-negative gastric MALT lymphomas remains antibiotic-responsive and is cured by HPE. Considering the complicated interaction between microbiomes and the genome/epigenome, further studies on the precise mechanisms of HP- and other bacteria-directed lymphomagenesis in antibiotic-responsive gastric MALT lymphomas are warranted. Full article

(This article belongs to the Special Issue Helicobacter pylori Associated Cancer)

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The Association between Salt and Potential Mediators of the Gastric Precancerous Process

by Susan Thapa, Lori A. Fischbach, Robert Delongchamp, Mohammed F. Faramawi and Mohammed Orloff

Cancers 2019, 11(4), 535; https://doi.org/10.3390/cancers11040535 - 15 Apr 2019

Cited by 11 | Viewed by 3833

Abstract

Background: The process by which salt affects the gastric precancerous process has not been adequately studied in humans. Methods: We investigated the effects of salt on gastric inflammation, epithelial damage, the density of Helicobacter pylori infection, and gastric epithelial cell proliferation, all of [...] Read more.

Background: The process by which salt affects the gastric precancerous process has not been adequately studied in humans. Methods: We investigated the effects of salt on gastric inflammation, epithelial damage, the density of Helicobacter pylori infection, and gastric epithelial cell proliferation, all of which may be mediators between salt and gastric precancerous/cancerous lesions. These potential mediators were measured using gastric biopsies as: (a) the density of polymorphonuclear and mononuclear cells (gastric inflammation), (b) mucus depletion (gastric epithelial damage), and (c) the severity of H. pylori infection. Salt intake was measured with spot urine samples (using urinary sodium/creatinine ratios), self-reported frequency of adding salt to food, and as total added salt. Results: The average sodium/creatinine ratio (at baseline and post-treatment at five months) was associated with increased epithelial damage over the 12-year follow-up period among those with a greater severity of chronic inflammation and among those with continued H. pylori infection after treatment at five months. This association was stronger when both severe gastric inflammation and H. pylori infection were present at five months (ß: 1.112, 95% CI: 0.377, 1.848). Conclusion: In humans, salt was associated with an increase in epithelial damage in stomachs with more severe previous H. pylori-induced chronic inflammation. Full article

(This article belongs to the Special Issue Helicobacter pylori Associated Cancer)

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