Role of Helicobacter pylori virulence factor cytotoxin-associated gene A in gastric mucosa-associated lymphoid tissue lymphoma

Helicobacter pylori(H.pylori)infection might initiate and contribute to the progression of lymphoma from gastric mucosa-associated lymphoid tissue(MALT).Increasing evidence shows that eradication of H.pylori with antibiotic therapy can lead to regression of gastric MALT lymphoma and can result in a 10-year sustained remission.The eradication of H.pylori is the standard care for patients with gastric MALT lymphoma.Cytotoxin-associated gene A(CagA)protein,one of the most extensively studied H.pylori virulence factors,is strongly associated with the gastric MALT lymphoma.CagA possesses polymorphisms according to its C-terminal structure and displays different functions among areas and races.After being translocated into B lymphocytes via typeⅣsecretion system,CagA deregulates intracellular signaling pathways in both tyrosine phosphorylation-dependent and-independent manners and/or some other pathways,and thereby promotes lymphomagenesis.A variety of proteins including p53and protein tyrosine phosphatases-2 are involved in the malignant transformation induced by CagA.Mucosal inflammation is the foundational mechanism underlying the occurrence and development of gastric MALT lymphoma.

海南省39株幽门螺杆菌的耐药性及毒力基因特征

目的了解海南省幽门螺杆菌(Hp)耐药性及其毒力基因vacA、cagA和iceA基因型特征。方法对146例上消化道症状疾病患者进行胃镜检查,取胃黏膜组织进行Hp的分离和培养,对Hp进行药敏检测;通过聚合酶链式反应(PCR)对毒力基因cagA、vacA和iceA进行检测和分型,cagA测序进行聚类分析、并构建系统进化树;使用Fisher确切概率法分析各型毒力基因和患者疾病发生的相关性。结果共培养出39株Hp,对阿莫西林和克拉霉素的耐药率分别为2.6%和48.7%;39株均为vacA^(+)菌株,iceA 1型26株、2型13株;33株为cagA^(+)菌株,其中5株为西方型(EPIYA-ABC型),28株为东亚型(EPIYA-ABD型);cagA^(+)和vacA^(+)菌株与胃和十二指肠疾病有显著的相关性(P<0.05),iceA则无显著性差异(P>0.05)。结论海南省胃和十二指肠Hp患者中Hp毒力基因多样化,vacA s1am2/cagA^(+)基因型在消化性溃疡患者中占优势,不同毒力基因型对胃和十二指肠疾病的发生具有明显的差别,阿莫西林可作为该地区根除Hp首选抗生素。

Impact of Helicobacter pylori virulence markers on clinical outcomes in adult populations

BACKGROUND In recent years,associations between specific virulence markers of Helicobacter pylori(H.pylori)and gastrointestinal disorders have been suggested.AIM To investigate the presence of virulence factors including vacuolating cytotoxin A genotypes(s1m1,s1m2,s2m1,and s2m2),cytotoxin-associated gene A(CagA),and urease activity in H.pylori strains isolated from Arab and Jewish populations in northern Israel and to assess associations between these factors and patients’demographics and clinical outcomes.METHODS Patients(n=108)who underwent gastroscopy at the Baruch Padeh Medical Center,Poriya due to symptomatic gastroduodenal pathologies as part of H.pylori diagnosis were enrolled in the study.Gastric biopsy specimens were collected from the antrum of the stomach.Clinical condition was assessed by clinical pathology tests.Bacteria were isolated on modified BD Helicobacter Agar(BD Diagnostics,Sparks,MD,United States).Bacterial DNA was extracted,and PCR was performed to detect CagA and vacuolating cytotoxin A genes.Urease activity was assessed using a rapid urease test.RESULTS A significant correlation was found between disease severity and patient ethnicity(P=0.002).A significant correlation was found between CagA presence and the s1m1 genotype(P=0.02),which is considered the most virulent genotype.Further,a higher level of urease activity was associated with isolates originating from the Jewish population.Moreover,higher urease activity levels were measured among CagA-/s1m1 and CagA-/s2m2 isolates.CONCLUSION Our study highlights the importance of incorporating molecular methods for detection of virulence markers of H.pylori in order to tailor optimal treatments for each patient.Further investigation should be performed regarding associations between H.pylori virulence factors and ethnicity.

Amino acid deletions at positions 893 and 894 of cytotoxinassociated gene A protein affect Helicobacter pylori gastric epithelial cell interactions

BACKGROUND Helicobacter pylori(H.pylori)persistently colonizes the human gastric mucosa in more than 50%of the global population,leading to various gastroduodenal diseases ranging from chronic gastritis to gastric carcinoma.Cytotoxin-associated gene A(CagA)protein,an important oncoprotein,has highly polymorphic Glu-Pro-Ile-Tyr-Ala segments at the carboxyl terminus,which play crucial roles in pathogenesis.Our previous study revealed a significant association between amino acid deletions at positions 893 and 894 and gastric cancer.AIM To investigate the impact of amino acid deletions at positions 893 and 894 on CagA function.METHODS We selected a representative HZT strain from a gastric cancer patient with amino acid deletions at positions 893 and 894.The cagA gene was amplified and mutated into cagA-NT and cagA-NE(sequence characteristics of strains from nongastric cancer patients),cloned and inserted into pAdtrack-CMV,and then transfected into AGS cells.The expression of cagA and its mutants was examined using realtime polymerase chain reaction and Western blotting,cell elongation via cell counting,F-actin cytoskeleton visualization using fluorescence staining,and interleukin-8(IL-8)secretion via enzyme-linked immunosorbent assay.RESULTS The results revealed that pAdtrack/cagA induced a more pronounced hummingbird phenotype than pAdtrack/cagA-NT and pAdtrack/cagA-NE(40.88±3.10 vs 32.50±3.17,P<0.001 and 40.88±3.10 vs 32.17±3.00,P<0.001)at 12 hours after transfection.At 24 hours,pAdtrack/cagA-NE induced significantly fewer hummingbird phenotypes than pAdtrack/cagA and pAdtrack/cagA-NT(46.02±2.12 vs 53.90±2.10,P<0.001 and 46.02±2.12 vs 51.15±3.74,P<0.001).The total amount of F-actin caused by pAdtrack/cagA was significantly lower than that caused by pAdtrack/cagA-NT and pAdtrack/cagA-NE(27.54±17.37 vs 41.51±11.90,P<0.001 and 27.54±17.37 vs 41.39±14.22,P<0.001)at 12 hours after transfection.Additionally,pAdtrack/cagA induced higher IL-8 secretion than pAdtrack/cagA-NT and pAdtrack/cagA-NE at different times after transfection.CONCLUSION Amino acid deletions at positions 893 and 894 enhance CagA pathogenicity,which is crucial for revealing the pathogenic mechanism of CagA and identifying biomarkers of highly pathogenic H.pylori.

Interactions between CagA and smoking in gastric cancer

AIM: To examine the interactions between cytotoxinassociated gene (CagA) positive Helicobacter pylori infection and smoking in non-cardiac gastric cancer.METHODS: A case-control study (257 cases and 514 frequency-matched controls) was conducted from September 2008 to July 2010 in Xi’an,China.Cases were newly diagnosed,histologically confirmed non-cardiac cancer.Controls were randomly selected from similar communities to the cases and were further matched by sex and age (± 5 years).A face-to-face interview was performed by the investigators for each participant.Data were obtained using a standardized questionnaire that included questions regarding known or suspected lifestyle and environmental risk factors of gastric cancer.A 5 mL sample of fasting venous blood was taken.CagA infection was serologically detected by enzymelinked immunosorbent assays.RESULTS: Smoking and CagA infection were statistically significant risk factors of non-cardiac cancer.CagA was categorized in tertiles,and the odds ratio (OR) was 12.4 (95% CI: 6.1-20.3,P = 0.003) for CagA after being adjusted for confounding factors when the highexposure category was compared with the low-exposure category.Smokers had an OR of 5.4 compared with subjects who never smoked (95% CI: 2.3-9.0,P = 0.002).The OR of non-cardiac cancer was 3.5 (95% CI: 1.8-5.3) for non-smokers with CagA infection,3.5 (95% CI: 1.9-5.1) for smokers without CagA infection,and 8.7 (95% CI: 5.1-11.9) for smokers with CagA infection compared with subjects without these risk factors.After adjusting for confounding factors,the corresponding ORs of non-cardiac cancer were 3.2 (95% CI: 1.5-6.8),2.7 (95% CI: 1.3-4.9) and 19.5 (95% CI: 10.3-42.2),respectively.There was a multiplicative interaction between smoking and CagA,with a synergistic factor of 2.257 (Z = 2.315,P = 0.021).CONCLUSION: These findings support a meaningful interaction between CagA and smoking for the risk of gastric cancer which may have implications for its early detection.

Helicobacter pylori and gastric cardia cancer:What do we know about their relationship?

The incidence of gastric cardia cancer is increasing around the world.Since the discovery of Helicobacter pylori(H.pylori),numerous studies have proved that it is a causative factor for many kinds of digestive system tumors.Although the literature on gastric cardia cancer and H.pylori is not scarce,there are still many controversies on the relationship between gastric cardia cancer and H.pylori.Many Western research results showed that there was a negative or no correlation between H.pylori infection and gastric cardia cancer,but in several studies in Asian countries,such as China,H.pylori was demonstrated to be a risk factor for gastric cardia cancer.Therefore,we intended to analyze the related studies to find out the relationship between H.pylori and gastric cardia cancer and find out the causes of the above controversies.We also conducted a metaanalysis of the relationship between cagA positive expression of H.pylori and gastric cardia cancer,to find out whether there is an effect between those two.The primary purpose of this paper was to explore the relationship between gastric cardia cancer and H.pylori.Through analysis,the study showed the reasons for the controversies mentioned above:(1)Geographical factors could affect the relationship between H.pylori and gastric cardia cancer;(2)The definition of gastric cardia cancer in various studies is inconsistent.The result of a meta-analysis about the relationship between H.pylori virulence factor cagA and gastric cardia cancer showed that there was no relationship between these two.