• Title, Summary, Keyword: cagA

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Helicobacter pylori cag Pathogenicity Island cagL and orf17 Genotypes Predict Risk of Peptic Ulcerations but not Gastric Cancer in Iran

  • Raei, Negin;Latifi-Navid, Saeid;Zahri, Saber
    • Asian Pacific Journal of Cancer Prevention
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    • v.16 no.15
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    • pp.6645-6650
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    • 2015
  • Background: Gastric cancer (GC) is the third most common cancer regarding mortality in the world. The cag pathogenicity island (PAI) of Helicobacter pylori which contains genes associated with a more aggressive phenotype may involve in the pathogenesis of gastrointestinal disease. We here aimed to examine the associations of cagH, cagL, orf17, and cagG genotypes of H. pylori cag PAI with severe gastrointestinal disease. Materials and Methods: A total of 242 H. pylori strains were genotyped. Histopathological examination and classification of subjects were performed. Results: The frequencies of the cagH, cagL, cagG, and orf17 genotypes were 40/54 (74.1%), 53/54 (98.1%), 38/54 (70.4%), and 43/54 (79.6%), respectively, in patients with peptidic ulceration (PU),while in the control group, the frequencies were 87/147 (59.6%) for cagH, 121/146 (82.9%) for cagL, 109/146 (74.7%) for cagG, and 89/146 (61.0%) for orf17. The results of simple logistic regression analysis showed that the cagL and orf17 genotypes were significantly associated with an increased risk of PU not GC; the ORs (95% CI) were 10.950 (1.446-82.935), and 2.504 (1.193-5.253), respectively. No significant association was found between the cagH and cagG genotypes and the risk of both the PU and the GC in Iran (P>0.05). Finally, multiple logistic regression analysis showed that the cagL genotype was independently and significantly associated with the age-and sex-adjusted risk for PU; the OR (95% CI) was 9.557 (1.219-17.185). Conclusions: We conclude that the orf17 and especially cagL genotypes of H. pylori cag PAI could be factors for risk prediction of PU, but not GC in Iran.

Overview on Molecular Toxicological Aspects of Helicobacter pylori Virulence Factor, Cytotoxin-associated Antigen A (CagA) (헬리코박터 파이로리의 병원성 단백질, CagA에 대한 분자 독성학적 측면에서의 고찰)

  • Kim Byung J.;Jung Hwa Jin;Hwang Jee Na;Kang Seok Ha;Oh Se-Jin;Seo Young Rok
    • Toxicological Research
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    • v.20 no.3
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    • pp.179-185
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    • 2004
  • Helicobacter pylori (H. pylori) infects more than half of the people in the world as a major microbe to cause most of gastric diseases. Recently, cytotoxin associated-antigen A (CagA) is believed as one of the most important virulence factors of H. pylori. Molecular toxicological pathway of CagA is necessary to investigate for understanding the pathological and toxicological aspects of H. pylori, since this virulence protein harasses intercellular processes of host cells to get profit for the survival of H. pylori. CagA is coded from cag pathogenicity island (cag PAI) and translocated into host cells by Type 4 secretion system (TFSS). Tyrosine phosphorylation of CagA targets Src homology 2-containing phosphotyrosine phosphatase (SHP-2) to form a CagA-SHP-2 complex. This complex depends on the similarity of sequence between EPIYA motif and Src homology 2 domain (SH2 domain) of CagA. The generation of growth factors is an essential role of CagA in protecting and healing gastric mucosa for the survival of H. pylori. On the other hand, the activation of IL-8 by CagA induces neutrophils generating inflammation and free radicals. Indeed, free radicals are well known carcinogen to induce DNA damage. In addition, the transduction of mitogen-activation signal by CagA is one of the interesting features to understand how to cause cancer. The relationship between cancer and inflammation with CagA was mainly discussed in this review.

Association of Helicobacter pylori cagA Gene with Gastric Cancer and Peptic Ulcer in Saudi Patients

  • Saber, Taisir;Ghonaim, Mabrouk M.;Yousef, Amany R.;Khalifa, Amany;Qurashi, Hesham Al;Shaqhan, Mohammad;Samaha, Mohammad
    • Journal of Microbiology and Biotechnology
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    • v.25 no.7
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    • pp.1146-1153
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    • 2015
  • This study was conducted to assess the relationship between occurrence of gastric cancer and peptic ulcer, and the presence of H. pylori cagA gene and anti-CagA IgG, and to estimate the value of these antibodies in detecting infection by cagA gene-positive H. pylori strains in Saudi patients. The study included 180 patients who were subjected to upper gastrointestinal endoscopy in Taif province and Western region of Saudi Arabia (60 gastric cancer, 60 peptic ulcer, and 60 with non-ulcer dyspepsia). Gastric biopsy specimens were obtained and tested for H. pylori infection by rapid urease test and culture. PCR was performed on the isolated strains and biopsy specimens for detection of the cagA gene. Blood samples were collected and tested for CagA IgG by ELISA. H. pylori infection was detected among 72.8% of patients. The cagA gene and anti-CagA IgG were found in 63.4% and 61.8% of H. pylori-infected patients, respectively. They were significantly (p < 0.01) higher in patients with gastric cancer and peptic ulcer compared with those with non-ulcer dyspepsia. Detection of the CagA IgG was 91.6% sensitive, 89.6% specific, and 90.8% accurate compared with detection of the cagA gene. Its positive and negative predictive values were 93.8% and 86%, respectively. The study showed a significant association between the presence of the cagA gene and gastric cancer and peptic ulcer disease, and between anti-CagA IgG and the cagA gene in Saudi patients. However, a further larger study is required to confirm this finding.

A Potential Efficacy of Rebamipide as Anti-gastric Cancer Drug (위암치료제로서 rebamipide의 잠재적 효능)

  • Min, Do Sik
    • Journal of Life Science
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    • v.26 no.10
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    • pp.1214-1217
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    • 2016
  • Rebamipide is a mucosal-protective antiulcer drug, but its mechanism of action in gastric cancer remains elusive. CagA, a major virulence factor of Helicobacter pylori (H. pylori), is associated with the risk of gastric cancer. CagA protein is injected into gastric epithelial cells and deregulates a variety of cellular signaling molecules. CagA from H. pylori induces phospholipase D1 (PLD1) expression through NFκB activation in gastric epithelial cells, followed by invasion and proliferation of gastric epithelial cancer cells. Infection with cagA-positive H. pylori and expression of CagA enhances the binding of NFκB to the PLD1 promoter. Rebamipide abolishes H. pylori cagA-induced PLD1 expression via inhibition of binding of NFκB to the PLD1 promoter and also inhibits PLD activity. Moreover, rebamipide abolishes H. pylori CagA-induced β-catenin and the expression of a target cancer stem cell (CSC) marker gene via upregulation of miRNA-320a and -4496, followed by attenuation of self-renewal capacity of H. pylori CagA-infected gastric CSCs. In addition, rebamipide increases the chemosensitivity of CagA-expressed gastric CSCs and suppresses gastric carcinogenesis. Thus, it is speculated that rebamipide might show a potent efficacy as chemotherapeutic drug against gastric cancer cells. In this review, we summarizes recent results regarding the novel insights for the efficacy of rebamipide in gastric cancer cells.

Helicobacter Pylori CagA and Gastric Carcinogenesis

  • Zheng, Ri-Nan;Li, Shu-Rong;Masahiro, Asaka
    • Asian Pacific Journal of Cancer Prevention
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    • v.13 no.12
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    • pp.6305-6310
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    • 2012
  • Objectives: This study aimed to demonstrate the tyrosine phosphorylation motif (TPM) and 3' region structure of the Helicobacter pylori CagA gene as well as its SHP-2 binding activity in AGS cells and relation to gastric carcinogenesis. Methods: Sixteen clinical isolate H. pylori strains from eight duodenal ulcer and eight gastric adenocarcinoma patients were studied for CagA repeat sequence EPIYA motifs, C-terminal structure, and western blot analysis of CagA protein expression, translocation, and SHP-2 binding in AGS cells. Results: Except for strain 547, all strains from the gastric adenocarcinoma patients were positive for CagA by PCR and had three EPIYA copy motifs. Western blotting showed that all strains were positive for CagA protein expression (100%), CagA protein translocation (100%), and SHP-2 binding (100%). CagA protein expression was significantly higher in the gastric adenocarcinoma patients than in the duodenal ulcer patients (P=0.0023). CagA protein translocation and SHP-2 binding in the gastric adenocarcinoma patients were higher than those in the duodenal ulcer patients, but no significant differences were found between the two groups (P=0.59, P=0.21, respectively). Conclusions: The TPMs and 3' region structures of the H. pylori CagA gene in the duodenal ulcer and gastric adenocarcinoma patients have no significant differences.

Helicobacter pylori babA2 Positivity Predicts Risk of Gastric Cancer in Ardabil, a Very High-Risk Area in Iran

  • Abdi, Esmat;Latifi-Navid, Saeid;Yazdanbod, Abbas;Zahri, Saber
    • Asian Pacific Journal of Cancer Prevention
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    • v.17 no.2
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    • pp.733-738
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    • 2016
  • Background: Ardabil, a Northwestern province of Iran, was found to have the highest rate of gastric cancer (GC) in the country (ASRs = 51.8/100,000 for males and 24.9/100,000 for females) and one of the highest gastric cardia cancer rates in the world. The aim of the present study was to assess the associations of the cagA and babA2 status of Helicobacter pylori with GC in the Ardabil population. Materials and Methods: A total of 103 patients with non-atrophic gastritis (56) and GC (47), who underwent endoscopy at the Imam Khomeini Hospital in Ardabil, were assessed. The status of 16S rDNA, cagA and babA2 genes was determined using PCR and histopathological assessment was performed. Results: The following genotypic frequency was observed: cagA+ (50.6%), cagA-(49.4%), babA2+ (26.5%), babA2- (73.5%) cagA+/babA2+ (19.3%), cagA-/babA2+ (7.2%), cagA+/babA2-(31.3%), cagA-/babA2-(42.2%). Although the frequency of the cagA+, cagA+/babA2+ and cagA-/babA2+ genotypes in patients with GC (55.6%, 25.9%, and 14.8%, respectively) was higher than in those with NAG (48.2%, 16.1%, and 3.6%, respectively), the difference did not reach significance. In contrast, the presence of the babA2 gene (40.7% vs 19.6%) significantly increased the risk of GC; the age-sex-adjusted odds ratio (95% confidence interval) was 5.068 (1.506-17.058; P=0.009), by multiple logistic regression. Conclusions: It is proposed that the H. pylori babA2 positivity might be considered as an important determinant of GC risk in Ardabil.

Helicobacter pylori Chaperone-Like Protein CagT Plays an Essential Role in the Translocation of CagA into Host Cells

  • Ding, Honglei;Zeng, Hao;Huang, Linping;Dong, Yandong;Duan, Yijun;Mao, Xuhu;Guo, Gang;Zou, Quanming
    • Journal of Microbiology and Biotechnology
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    • v.22 no.10
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    • pp.1343-1349
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    • 2012
  • Most of the Helicobacter pylori strains containing the cag pathogenicity island (PAI) have been associated with more severe gastric disease in infected humans. The cag PAI is composed of 27 proteins, and some of the components are required for CagA translocation into host cells as well as induction of proinflammatory cytokines, such as interleukin-8 (IL-8); however, the exact function of most of the components remains unknown or poorly characterized. In this study, we demonstrated that CagT (HP0532), which is an essential structural component of the cag PAI apparatus, plays an important role in the translocation of CagA into host epithelial cells. In addition to being located on the bacterial surface, CagT is also partially localized in the inner membrane, where it acts as a chaperone-like protein and promotes CagA translocation. However, CagT secretion was not detected by immunoprecipitation analysis of cell culture supernatants. Meanwhile, CagT was related to the introduction of IL-8 of the host cell. These results suggest that CagT is expressed on both the inner and outer bacterial membranes, where it serves as a unique type IV secretion system component that is involved in CagA secretion and cag PAI apparatus assembly.

Investigation of Helicobacter pylori cagE Locus Diversity on Interleukin-8 Induction in AGS Cell-line (Helicobacter pylori cagE 유전자 다형성이 위상피세포주에서 Interleukin-8 유도능에 미치는 영향)

  • Lee Su-Min;Lee Hak-Sung;Lee In-Suk;Co Yu-Kyung;Han Hae-Won;Oh Jung-Hwan;Park Jae-Myung;Choi Myung-Gyu;Chung In-Sik
    • Journal of Life Science
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    • v.14 no.6
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    • pp.906-912
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    • 2004
  • Helicobacter pylori infection is highly prevalent, as high as 2/3 of whole population infected, in Korea. H. pylori infection initiates inflammation by induction of interleukin-8 through type IV secretion of CagA. It was recently suggested that induction failure of IL-8 is not associated with defect in cag PAI but associated with cagE locus diversity. This study was designed to investigate ability of 11-8 in-duction according to sequence variation within the cagE gene, cagA TP motifs and vacA m-types in vitro study using AGS cell-line, and to evaluate its association with different clinical outcome. Seventy-four H. pylori stains were isolated from 23 patients with gastric cancer (Ca), 24 subjects with gastritis (G) and 27 patients with duodenal ulcer (Du) in Kangnam St. Mary's Hospital, Seoul, Korea. cagE gene diversity was confirmed by the PCR-RFLP methods with MboI/NlaIII and tyrosine phosphate motifs (TPMs) of cagA was determined TPM-A and C by using DdeI/Tsp5091 restriction enzyme and TPM-B was determend by Real time PCR the method of Owen et al. and IL-8 was measured by ELISA assay. IL-8 activity was positively detected in 59 among 74 strains $(79.7\%)$. IL-8 secretion was significantly increased in MboI A and MboI B type compared to MboI C type and in MboI/NlaIII A-C and B-C type than C-C type. 1L-8 activity was not associated with either the number or composition of cagA tyrosine phosphorylation motifs and vacA m-type. There was no significant difference in IL-8 activity among patient groups. cagE gene diversity is thought to be mainly associated with the induction of IL-8 in H. pylori infection.

Association between Genotypes and Gastric Mucosal Lymphocytes in Helicobacter pylori-infected Children (Helicobacter pylori 감염 소아에서 유전형과 위점막 림프구)

  • Yom, Hye-Won;Cho, Min-Sun;Lee, Mi-Ae;Seo, Jeong-Wan
    • Pediatric Gastroenterology, Hepatology & Nutrition
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    • v.12 no.2
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    • pp.140-149
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    • 2009
  • Purpose: Helicobacter pylori infection is probably acquired in childhood and persists as an asymptomatic infection for decades in most individuals. It is unclear why only a minority of those infected develop a clinical manifestation, even in childhood, such as peptic ulcer disease. H. pylori infection activates local immune responses and causes lymphocyte infiltration in the gastric mucosa. We have previously reported that both T and B cells in the lamina propria play important roles in the local immune response of H. pylori-infected children. The aim of this study was to investigate the association between H. pylori genotypes and gastric mucosal lymphocytes. Methods: Twenty-five H. pylori-infected children (10 with peptic ulcer disease and 15 with gastritis) were enrolled in this study. We investigated the genotypes (cagA, cagE, vacA, and babA2) and evaluated the association with clinical manifestations, histopathology, and gastric mucosal lymphocytes. Results: The prevalence of cagA, cagE, vacA s1m1, and babA2 was 80%, 60%, 84%, and 88%, respectively. The most prevalent (68%) combination of cagA, vacA, and babA2 genotypes was cagA+/vacA s1m1+/babA2+. H. pylori genotypes were not associated with clinical manifestations, histopathology, or gastric mucosal lymphocytes. Conclusion: There was no association between the cagA, cagE, vacA, or babA2 status and gastric mucosal lymphocytes. The role of the host immune response in relation to H. pylori genotypes and disease potential in children needs further studies.

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Effect of Recombinant CagL Immunization on the Gastric Diseases Induced by Helicobacter pylori in Mongolian gerbils (CagL 재조합 단백질 접종후에 Mongolian gerbil에서 나타나는 Helicobacter pylori 감염에 대한 반응)

  • Bak, Eun-Jung;Jang, Sung-Il;Choi, Yun-Hui;Kim, Jin-Moon;Kim, Ae-Ryun;Kim, Ji-Hye;Woo, Gye-Hyeong;Yoo, Yun-Jung;Lee, Sung-Haeng;Cha, Jeong-Heon
    • Korean Journal of Microbiology
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    • v.48 no.2
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    • pp.109-115
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    • 2012
  • Helicobacter pylori is an important factor of chronic gastritis, digestive ulcer, and stomach cancer. CagL, a virulence factor of H. pylori, is well-known as a pilus protein which acts as adhesion to host cell and a component of Type 4 secretion system. In this study, we evaluated the protective response of recombinant CagL protein (rCagL) using Mongolian gerbil animal model for H. pylori infection. The cagL gene was cloned from 26695 H. pylori followed by over-expression and purification of the protein in E. coli. Mongolian gerbils were immunized with rCagL protein mixed with aluminum adjuvant via intramuscular injections once a week during 4 weeks. At a week after the last immunization, the Mongolian gerbils were administrated with H. pylori 7.13 strain into the stomach and sacrificed to measure antibody titer on rCagL by ELISA and bacterial colonization in the stomach, and to examine the histopathological changes and cytokine expression at 6 week after challenge. Antibody titers on recombinant protein were significantly increased from a week after the first immunization. There was no significant change of the number of bacterial colony between control group and immunized group. The relative stomach weight was significantly decreased in immunized group, but the significant change of histopathological assessment was not observed in the stomach. Cytokine expression such as IL-$1{\beta}$ and KC also was not significantly different between control and immunized groups. These results indicate that rCagL could effectively induce the formation of the specific IgG antibodies. However, bacterial colonization and histopathological lesions could not be inhibited by the immunization in the stomach, indicating not enough protection against H. pylori infection. We consider that along with CagL other adequate antigens could be needed stimulating immune response and inducing protective effects against gastric disease, and also a better adjuvant could be considered.