CagA and VacA Helicobacter pylori antibodies in gastric cancer.

BACKGROUND: Infection with different genotypes of virulent Helicobacter pylori strains (cytotoxin-associated gene A [CagA]- and/or vacuolating cytotoxin A [VacA]-positive) can play a role in the development of atrophic gastritis, duodenal ulcer (DU) and gastric cancer (GC). OBJECTIVE: To determine whether patients with GC and H pylori-negative histological staining had previously been infected with H pylori CagA- and/or VacA-positive virulent strains. METHODS: Twenty-three GC patients with a mean (+/- SD) age of 68.14+/-9.8 years who tested H pylori-negative on histological staining took part in the study. Three control groups were included. The first group comprised 19 patients with past H pylori infection and DUs eradicated 10 years earlier, with a mean age of 58+/-18.2 years. H pylori-negative status for this group was determined every year with Giemsa staining, and follow-up testing occured 120+/-32 months (mean +/- SD) after therapy. The subsequent control groups included 20 asymptomatic children, with a mean age of 7+/-4.47 years, and with H pylori-negative fecal tests; the final group contained 30 patients without clinical symptoms of H pylori infection, with a mean age of 68+/-11.6 years, who tested H pylori-negative by histological staining. RESULTS: Prevalence of CagA and VacA seropositivity, respectively was 82.6% and 73.91% in GC patients; 84.2% and 84.2% in H pylori-negative DU patients; 25% and 5% in H pylori-negative children; and 36.6% and 16.6% in the patients without clinical symptoms on histological staining. CagA and VacA antibody positivity was not significantly different between GC patients and patients with DUs that had been eradicated 10 years earlier. Significant positivity was found between the children's group and the H pylori-negative (with past DUs) group (P<0.001). A statistically significant difference was found in age between groups (P<0.03). CONCLUSIONS: Patients with GC, even when H pylori-negative at the time of the present study, may have been infected by H pylori before the onset of the disease, as confirmed by CagA and VacA seropositivity. These data reinforce the hypothesis that H pylori may be a direct carcinogenic agent of GC.     

Seropositivity against Helicobacter pylori CagA in Turkish gastric cancer patients

BACKGROUND: Increased prevalence of CagA in gastric cancer has been reported; yet, other reports suggest that the cagA gene is not associated with gastric cancer. GOALS: To evaluate the frequency of CagA seropositivity in Turkish patients with gastric cancer. STUDY: Thirty-two patients with gastric adenocarcinoma and 46 patients with nonulcer dyspepsia were examined for Helicobacter pylori status and for antibodies against CagA. RESULTS: H. pylori was positive in 56.3% of patients and in 71.7% of controls. CagA was positive in all patients in the study group, regardless of H. pylori positivity, and in 56.5% of the control group. CagA positivity in H. pylori -positive patients was significantly more frequent in patients with gastric cancer than in those with nonulcer dyspepsia ( p < 0.001). As for H. pylori -negative patients in both groups, CagA positivity was also more frequent in gastric cancer patients ( p < 0.001). CONCLUSION: Testing for H. pylori antibodies without testing for antibodies against CagA will miss patients with either recent or previous infection, which may be a cause of missing the relationship between H. pylori and gastric cancer. The authors think that testing for CagA in patients with dyspepsia can reveal which patients should be followed up for the risk of developing gastric cancer.     

Relationship between Helicobacter pylori CagA status and colorectal cancer

OBJECTIVES: Infection with Helicobacter pylori, particularly with strains positive for CagA protein, increases the risk of gastric adenocarcinoma. Few studies have explored the possible association between H. pylori infection and colorectal cancer. This study evaluated whether the seroprevalence of CagA in H. pylori-infected patients affected risk for colorectal cancer independently of H. pylori status. METHODS: In this study, we tested serum IgG antibodies against H. pylori (ELISA) and CagA protein (Western blot assay) in 67 patients with colorectal adenocarcinoma, 36 with gastric adenocarcinoma, 47 with other malignancies (cancer controls), and 45 hospitalized for transesophageal echocardiography (TEE controls). Colonic cancer and gastric cancer patients with H. pylori infection were compared to each control group and to the pooled controls using simple and adjusted analyses. RESULTS: H. pylori infection was noted in 50 colon cancer patients, 31 gastric cancer patients, 31 cancer controls, and 32 TEE controls. In all, 41 (82%), 29 (94%), 11 (35%), and 13 (41%), respectively, of these H. pylori-positive sera expressed CagA reactivity (p < 0.001 for all pairwise comparisons between cases and controls). In the adjusted analysis, infection with H. pylori CagA+ compared to H. pylori CagA- was associated with increased risk for colorectal adenocarcinoma (odds ratio = 10.6; 95% CI = 2.7-41.3; p = 0.001) and gastric adenocarcinoma (odds ratio = 88.1; 95% CI = 6.3-1229.2; p = 0.001). CONCLUSIONS: Among patients infected with H. pylori, CagA+ seropositivity is associated with increased risk for both gastric and colonic cancer. This finding should stimulate additional research into the role of cagA+ H. pylori infection in the development of colorectal cancer.     

Differential functions of the two Src homology 2 domains in protein tyrosine phosphatase SH-PTP1.

SH-PTP1 (also known as PTP1C, HCP, and SHP) is a non-transmembrane protein tyrosine phosphatase (PTPase) containing two tandem Src homology 2 (SH2) domains. We show here that the two SH2 (N-SH2 and C-SH2) domains in SH-PTP1 have different functions in regulation of the PTPase domain and thereby signal transduction. While the N-terminal SH2 domain is both necessary and sufficient for autoinhibition through an intramolecular association with the PTPase domain, truncation of the C-SH2 domain [SH-PTP1 (delta CSH2) construct] has little effect on SH-PTP1 activity. A synthetic phosphotyrosine residue (pY) peptide derived from the erythropoietin receptor (EpoR pY429) binds to the N-SH2 domain and activates both wild-type SH-PTP1 and SH-PTP1 (delta CSH2) 60- to 80-fold. Another pY peptide corresponding to a phosphorylation site on the IgG Fc receptor (Fc gamma RIIB1 pY309) associates with both the C-SH2 domain (Kd = 2.8 microM and the N-SH2 domain (Kd = 15.0 microM) and also activates SH-PTP1 12-fold. By analysis of the effect of the Fc gamma RIIB1 pY309 peptide on SH-PTP1 (delta CSH2), SH-PTP1 (R30K/R33E), SH-PTP1 (R30K/R136K), and SH-PTP1 (R136K) mutants in which the function of either the N- or C-SH2 domain has been impaired, we have determined that both synthetic pY peptides stimulate SH-PTP1 by binding to its N-SH2 domain; binding of pY ligand to the C-SH2 domain has no effect on SH-PTP1 activity. We propose that the N-terminal SH2 domain serves both as a regulatory domain and as a recruiting unit, whereas the C-terminal SH2 domain acts merely as a recruiting unit.     

Increased expression of tyrosine phosphatase SHP-2 in Helicobacter pylori-infected gastric cancer

AIM:To explore the alteration of tyrosine phosphatase SHP-2 protein expression in gastric cancer and to assess its prognostic values.METHODS:Three hundred and five consecutive cases of gastric cancer were enrolled into this study.SHP-2 expression was carried out in 305 gastric cancer specimens,of which 83 were paired adjacent normal gastric mucus samples,using a tissue microarray immunohistochemical method.Correlations were analyzed between expression levels of SHP-2 protein and tumor parameters or clinical outcomes.Serum anti-Helicobacter pylori(H.pylori) immunoglobulin G was detected with enzyme-linked immunosorbent assay.Cox proportional hazards model was used to evaluate prognostic values by compassion of the expression levels of SHP-2 and disease-specific survivals in patients.RESULTS:SHP-2 staining was found diffuse mainly in the cytoplasm and the weak staining was also observed in the nucleus in gastric mucosa cells.Thirty-two point five percent of normal epithelial specimen and 62.6% of gastric cancer specimen were identified to stain with SHP-2 antibody positively(P < 0.001).Though SHP-2 staining intensities were stronger in the H.pylori(+) group than in the H.pylori(-) group,no statistically significant difference was found in the expression levels of SHP-2 between H.pylori(+) and H.pylori(-) gastric cancer(P = 0.40).The SHP-2 expression in gastric cancer was not significantly associated with cancer stages,lymph node metastases,and distant metastasis of the tumors(P = 0.34,P = 0.17,P = 0.52).Multivariate analysis demonstrated no correlation between SHP-2 expression and disease-free survival(P = 0.86).CONCLUSION:Increased expression of SHP-2 protein in gastric cancer specimen suggesting the aberrant upregulation of SHP-2 protein might play an important role in the gastric carcinogenesis.     

Impact of Helicobacter pylori CagA diversity on gastric mucosal damage: an immunohistochemical study of East-Asian-type CagA

Background and Aims: Recently, we successfully produced an anti‐East‐Asian‐type CagA‐specific antibody called α‐EAS Ab, which is specifically immunoreactive only with East‐Asian‐type CagA but not Western‐type CagA. In this study, the correlations between Helicobacter pylori CagA protein diversity and gastric mucosal condition was investigated using immunohistochemical staining with α‐EAS Ab in Japan. Methods: There were 254 H. pylori‐positive patients enrolled in this study. α‐EAS Ab was used to determine the CagA phenotype instead of cagA sequencing, and, moreover, the histological findings and endoscopic gastric mucosal condition were evaluated according to the updated Sydney System and the Kimura–Takemoto classification system, respectively. Results: A total of 224 (88.2%) of the patients were immunoreactive for α‐EAS Ab. The remaining 30 (11.8%) were negative for α‐EAS Ab, suggesting that they were infected with either Western‐type CagA or CagA‐negative strains (i.e. non‐East‐Asian‐type CagA strains). The grades of activity of gastritis, mucosal atrophy and intestinal metaplasia according to the updated Sydney System were significantly higher in patients infected with East‐Asian‐type CagA strains than those infected with non‐East‐Asian‐type CagA strains. The grade of endoscopic gastric mucosal atrophy evaluated using the Kimura–Takemoto classification system was similar. All 28 strains isolated from patients with gastric cancer possessed the East‐Asian‐type CagA. Conclusions: Infection with East‐Asian‐type CagA H. pylori was more closely associated with gastric mucosal atrophy and gastric cancer than infection with non‐East‐Asian‐type CagA H. pylori. The efficiency of immunohistochemical analysis for CagA should be equivalent to that of cagA sequencing.     

Risk for gastric cancer in people with CagA positive or CagA negative Helicobacter pylori infection.

BACKGROUND AND AIMS: It is not known why some people with Helicobacter pylori infection develop gastric cancer whereas others do not. Whether the CagA phenotype of H pylori infection affected risk for cancer independently of other posited risk factors was evaluated. SUBJECTS: 242 persons who participated in a previous nested case-control study of gastric cancer. 179 (90 cases and 89 controls) were infected with H pylori as determined by enzyme linked immunosorbent assay (ELISA) in serum and 63 (13 cases and 50 controls) were uninfected. METHODS: Serum samples from cases and controls, obtained a mean of 14.2 years before diagnosis of cancer in the cases, were tested by ELISA for IgG antibodies against the CagA gene product of H pylori. They had previously been tested for pepsinogen I. Using logistic regression analysis, risk for cancer was compared among infected persons with CagA antibodies, infected persons without CagA antibodies, and uninfected persons. RESULTS: Subjects infected with H pylori who had CagA antibodies were 5.8-fold more likely than uninfected subjects to develop gastric cancer (95% confidence interval (95% CI) = 2.6-13.0). This was true for both intestinal (odds ratio (OR) 5.1, 95% CI = 2.1-12.2) and diffuse type (OR 10.1, 95% CI = 2.2-47.4) cancers. By contrast, H pylori infected subjects without CagA antibodies were only slightly, and not significantly, at increased risk for cancer (OR 2.2, 95% CI = 0.9-5.4) and any possible association was restricted to diffuse type carcinoma (OR 9.0, 95% CI = 1.2-65.8). Pepsinogen 1 < 50 ng/ml significantly increased risk for both cancer types in H pylori infected persons and lessened the magnitude of association between CagA and cancer. Educational attainment, cigarette smoking, and ABO blood group were not associated with malignancy. CONCLUSIONS: When compared with uninfected subjects, persons infected with CagA positive H pylori are at considerably increased risk of gastric cancer. CagA negative H pylori are less strongly linked to malignancy and may only be associated with diffuse type disease.     

Runx3在不同类型胃息肉与胃癌中的蛋白表达及与幽门螺杆菌感染的相关性

目的:检测不同病理类型胃息肉和胃癌中Runx3蛋白的表达和幽门螺杆菌(H.pylori)的感染率,探讨其在胃息肉与胃癌中的相关性.方法:对炎性胃息肉组25例、增生性胃息肉组25例、腺瘤性息肉组25例、胃癌组30例采用SP染色法检测Runx3的表达水平,HE染色、甲苯胺蓝染色和Warthin-Starry(W-S)银染法检测H.pyloti的感染情况.结果:胃癌组Runx3蛋白的阳性表达率明显低于正常胃黏膜组、炎性胃息肉组和增生性胃息肉组,差异有统计学意义(X2=8.967、5.632、4.289,均P<0.05);腺瘤性息肉组明显低于正常胃黏膜组、炎性胃息肉组和增生性胃息肉组,差异有统计学意义(P<0.05).胃癌组低于腺瘤性息肉组,但差异无统计学意义.H.pylori的感染率在胃癌组与正常胃黏膜组相比H.pylori感染率有统计学意义(P<0.05).胃息肉组和胃癌组中H.pylori、Runx3的表达率之间存在着负性相关.结论:Runx3蛋白表达下调与H.pylori感染可能在胃癌的发生过程中起着协同作用.     

Association between Helicobacter pylori status and metachronous gastric cancer after endoscopic resection

AIM To investigate the effect of Helicobacter pylori(H. pylori) status test and H. pylori eradication on the occurrence of metachronous gastric cancer(MGC) after endoscopic submucosal dissection(ESD) of early gastric cancer(EGC) and risk factors of MGC. METHODS The authors retrospectively reviewed the medical records of 433 patients(441 lesions) who underwent ESD for EGC from January 2005 to January 2015 in Yeungnam University Hospital. Patients were categorized into two groups; the H. pylori tested group(n = 257) and the H. pylori non-tested group(n = 176) based on performance of H. pylori status test after ESD of EGC. The H. pylori tested group was further categorized into three subgroups based on H. pylori status; the H. pylori-eradicated subgroup(n = 120), the H. pylori-persistent subgroup(n = 42), and the H. pylori-negative subgroup(n = 95). Incidences of MGC and risk factors of MGC were identified.RESULTS Median follow-up duration after ESD was 30.00 mo(range, 6-107 mo). Total 15 patients developed MGC during follow-up. MGC developed in 11 patients of the H. pylori tested group(7 in the H. pylori-negative subgroup, 3 in the H. pylori-eradicated subgroup, and 1 in the H. pylori-persistent subgroup) and 4 patients of the H. pylori non-tested group(P 0.05). The risk factors of MGC were endoscopic mucosal atrophy in the H. pylori tested group and intestinal metaplasia in all patients. CONCLUSION H. pylori eradication and H. pylori status test seems to have no preventive effect on the development of MGC after ESD for EGC. The risk factors of MGC development were endoscopic mucosal atrophy in the H. pylori tested group alone and intestinal metaplasia in all patients.     

Association of polymorphism of PTPN 11 encoding SHP-2 with gastric atrophy but not gastric cancer in Helicobacter pylori seropositive Chinese population

ABSTRACT: BACKGROUND: The interaction between Src homology 2 domain-containing protein tyrosine phosphatase (SHP-2) of gastric epithelial cells and cagA from H.pylori plays a crucial role in developments of gastric atrophy and gastric cancer. This study aimed to investigate the association of haplotype tagging SNPs (htSNPs) in the PTPN11 gene encoding SHP-2 with gastric atrophy and gastric cancer in Chinese population. METHODS: The subjects comprised 414 patients with gastric cancer, 109 individuals with gastric atrophy and 923 healthy controls. Blood was collected from October 2008 to October 2010. Five htSNPs rs2301756, rs12423190, rs12229892, rs7958372 and rs4767860 from the PTPN11 gene were selected and genotyped by Taqman assay. Serum Ig G antibodies to H.pylori were detected by ELISA. Gastric atrophy was screened by the levels of serum pepsinogenIandII,and confirmed by endoscopy and histopatholgical examinations. Odds ratio (ORs) and 95% confidence intervals (CIs) were calculated by a multivariate logistic regression. RESULTS: Among H.pylori seropositive subjects, age and gender-adjusted OR of gastric atrophy was 2.47 (95%CI 1.13-4.55, P = 0.02) for CC genotype compared with CT/TT genotypes, suggesting a recessive model of genetic risk for rs12423190. The prevalence of H.pylori seropositivity were significantly higher in groups of gastric cancer and gastric atrophy compared to the control group (70.3% vs.75.2% vs.49.7%, P <0.001). However, the distributions of genotypes and haplotypes in patients with gastric cancer were not significantly different from healthy controls. CONCLUSIONS: Our study provides the first evidence that rs12423190 polymorphism of the PTPN11 gene is significantly associated with an increased risk of gastric atrophy in H.pylori infected Chinese Han population, suggesting that rs12423190 polymorphism could be used as a useful marker of genetic susceptibility to gastric atrophy among H.pylori infected subjects. The biological roles of this polymorphism require a further investigation.     

Profiling the global tyrosine phosphorylation state by Src homology 2 domain binding.

Reversible tyrosine phosphorylation plays a crucial role in signal transduction, regulating many biological functions including proliferation, differentiation, and motility. The comprehensive characterization of the tyrosine phosphorylation state of a cell is of great interest for understanding the mechanisms that underlie signaling; however, current methods for analyzing tyrosine-phosphorylated proteins in crude protein extracts provide limited information, or are laborious and require relatively large amounts of protein. We have developed a simple, rapid, and flexible competitive binding assay based on the far-Western blot technique, in which a battery of Src homology 2 domain probes is used to detect patterns of specific tyrosine-phosphorylated sites. We demonstrate that distinct profiles of tyrosine phosphorylation can be detected with high sensitivity and specificity and low background. This proteomic approach can be used to rapidly profile the global tyrosine phosphorylation state of any cell of interest and has obvious applications as a molecular diagnostic tool, for example in the classification of tumors. The general strategy we describe here is not limited to Src homology 2 domains and could be used to profile the binding sites for any class of protein interaction domain.     

幽门螺杆菌致胃癌机理的研究进展

Hp感染增加了胃癌危险性，但其确切的致癌机制目前尚不清楚，故近来这方面的研究较多，亦取得了一定的进展。Hp感染可导致慢性活动性胃炎，而炎性细胞浸润首先累及腺颈部，腺颈部细胞属组织干细胞，为细胞增生、增殖、肠化的起始点，在长期的Hp感染所导致的慢性活动性炎症过程中。     

Association of Helicobacter pylori babA2 with peptic ulcer disease and gastric cancer

AIM: To investigate the association between babA2 gene and peptic ulcer disease (PUD) and gastric cancer (GC) in Helicobacter pylori -infected populations. METHODS: We evaluated the relationship between babA2 and clinical outcomes (PUD and GC) using a meta-analysis. A literature search was performed using the PubMed and Web of Science databases for relevant case-control studies that met the defined inclusion criteria. The ORs and 95%CIs were calculated to estimate the association between babA2 genotype and clinical outcomes. A fixed-effect or random-effect model was performed depending on the absence or presence of significant heterogeneity. RESULTS: A total of 25 articles with 38 studies met the inclusion criteria and were finally included in this metaanalysis. The results showed that the babA2 genotype was significantly associated with an increased risk of PUD (OR = 2.069, 95%CI: 1.530-2.794, P < 0.001) and especially in the subgroup of duodenal ulcer (OR = 1.588, 95%CI: 1.141-2.209, P = 0.006). Moreover, a significant association between babA2 gene and PUD and duodenal ulcer (OR = 2.739, 95%CI: 1.860-4.032, P < 0.001; OR = 2.239, 95%CI: 1.468-3.415, P < 0.001, respectively) was observed in western countries but not in Asian countries. CONCLUSION: We demonstrated that the presence of babA2 may be associated with increased risks for PUD, especially duodenal ulcer, in western countries.