Regulation of gastric carcinogenesis by Helicobacter pylori virulence factors.
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(-), vacA(-), or oipA(-) mutants for 12 to 52 weeks. All infected gerbils developed gastritis; however, inflammation was significantly attenuated in animals infected with the cagA(-) but not the vacA(-) or oipA(-) strains. Gastric dysplasia and cancer developed in >50% of gerbils infected with either the wild-type or vacA(-) strain but in none of the animals infected with the cagA(-) strain. Inactivation of oipA decreased beta-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 beta-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.
Franco
Aime T
AT
Division of Gastroenterology, Department of Medicine, Vanderbilt University, Nashville, TN 37232-2279, USA.
Johnston
Elizabeth
E
Krishna
Uma
U
Yamaoka
Yoshio
Y
Israel
Dawn A
DA
Nagy
Toni A
TA
Wroblewski
Lydia E
LE
Piazuelo
Maria Blanca
MB
Correa
Pelayo
P
Peek
Richard M
RM
D000230:Adenocarcinoma / Q000209:etiology* / Q000382:microbiology; D018829:Adhesins, Bacterial / Q000235:genetics / Q000502:physiology; D000328:Adult; D000818:Animals; D000942:Antigens, Bacterial / Q000235:genetics / Q000502:physiology; D001422:Bacterial Adhesion / Q000235:genetics; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics / Q000502:physiology; D001426:Bacterial Proteins / Q000235:genetics / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D005756:Gastritis / Q000235:genetics / Q000382:microbiology; D015964:Gene Expression Regulation, Bacterial; D005849:Gerbillinae; D016480:Helicobacter pylori / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D050505:Mutant Proteins / Q000235:genetics; D013274:Stomach Neoplasms / Q000209:etiology* / Q000382:microbiology; D037521:Virulence Factors / Q000235:genetics / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism
D018829:Adhesins, Bacterial; D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins; D050505:Mutant Proteins; C526444:OipA protein, Helicobacter pylori; C074689:VacA protein, Helicobacter pylori; D037521:Virulence Factors; D051176:beta Catenin; C080866:cagA protein, Helicobacter pylori