Regulation of Gastric Carcinogenesis by Helicobacter pylori Virulence Factors

Abstract

Helicobacter pylori is the strongest known risk factor for gastric adenocarcinoma, and strains that possess the cag secretion system, which translocates the bacterial effector CagA into host cells, augment cancer risk. H. pylori strains that express the vacuolating cytotoxin or the outer membrane protein OipA are similarly associated with severe pathologic outcomes. We previously reported that an in vivo adapted H. pylori strain, 7.13, induces gastric adenocarcinoma in rodent models of gastritis. In the current study, we used carcinogenic strain 7.13 as a prototype to define the role of virulence constituents in H. pylori-mediated carcinogenesis. Mongolian gerbils were infected with wild-type strain 7.13 or cagA À , vacA À , or oipA À mutants for 12 to 52 weeks. All infected gerbils developed gastritis; however, inflammation was significantly attenuated in animals infected with the cagA À but not the vacA À or oipA À strains. Gastric dysplasia and cancer developed in >50% of gerbils infected with either the wild-type or vacA À strain but in none of the animals infected with the cagA À strain. Inactivation of oipA decreased B-catenin nuclear localization in vitro and reduced the incidence of cancer in gerbils. OipA expression was detected significantly more frequently among H. pylori strains isolated from human subjects with gastric cancer precursor lesions versus persons with gastritis alone. These results indicate that loss of CagA prevents the development of cancer in this model. Inactivation of oipA attenuates B-catenin nuclear translocation and also decreases the incidence of carcinoma. In addition to defining factors that mediate H. pylori-induced cancer, these results provide insight into mechanisms that may regulate the development of other malignancies arising within the context of inflammatory states. [Cancer Res 2008;68(2):379-87]

Alteration in Methylation Pattern of Retinoblastoma 1 Gene Promotor Region in Intestinal Metaplasia with or without Helicobacter pylori and Gastric Cancer Patients

“…Abnormal methylations in promoter regions of several genes are induced by H. pylori in gastric mucosa including cell growth-related genes p16(INK4a), p14(ARF), and APC; DNArepair genes, hMLH1, BRCA1, and MGMT; the cell adherence gene E-cadherin; as well as LOX, FLNC, HRASLS, HAND1, THBD, and p41ARC, which are known to be methylated in GC patients [22][23][24]. Individuals with H. pylori infection have increased level of gene methylations, which decrease in the absence of the bacteria, consistent with the notion that methylations are induced by the bacterial infection [4,22,24,25].…”

“…pylori are known to be a major risk factor for GC progression. It causes chronic active inflammation in the gastric mucosa and has the capacity to colonize human stomach persistently [4,5]. Abnormal methylations in promoter regions of several genes are induced by H. pylori in gastric mucosa including cell growth-related genes p16(INK4a), p14(ARF), and APC; DNArepair genes, hMLH1, BRCA1, and MGMT; the cell adherence gene E-cadherin; as well as LOX, FLNC, HRASLS, HAND1, THBD, and p41ARC, which are known to be methylated in GC patients [22][23][24].…”

“…tic factors can be held responsible for gastric carcinogenesis in addition to H. pylori infection [4,5].…”

Helicobacter pylori γ-glutamyl transpeptidase and vacuolating cytotoxin promote gastric persistence and immune tolerance

“…Because PMSS1 harbors the nontoxic s2/m2 variant of VacA, our studies do not allow us to draw conclusions with respect to the role of cytotoxic VacA in gastric pathology. Despite a clear association of toxigenic forms of VacA with an increased risk of peptic ulceration and gastric cancer in humans (30), other experimental studies in rodents have not detected a role for VacA in gastritis (17) or gastric dysplasia and cancer (31,32).…”

Role of Helicobacter pylori infection in cancer‐associated fibroblast‐induced epithelial‐mesenchymal transition in vitro

“…H. pylori colonizes mainly gastric epithelium but may also penetrate the mucus layer reaching pits of gastric glands 9. We have previously shown that fibroblasts may constitute a direct target for H. pylori 10 next to epithelial cells 11, 12…”