Persistent gastritis induced by Helicobacter pylori is the strongest known risk factor for adenocarcinoma of the distal stomach, yet only a fraction of colonized persons ever develop gastric cancer. The H. pylori cytotoxin-associated gene (cag) pathogenicity island encodes a type IV secretion system that delivers the bacterial effector CagA into host cells after bacterial attachment, and cag ؉ strains augment gastric cancer risk. A host effector that is aberrantly activated in gastric cancer precursor lesions is ␤-catenin, and activation of ␤-catenin leads to targeted transcriptional up-regulation of genes implicated in carcinogenesis. We report that in vivo adaptation endowed an H. pylori strain with the ability to rapidly and reproducibly induce gastric dysplasia and adenocarcinoma in a rodent model of gastritis. Compared with its parental noncarcinogenic isolate, the oncogenic H. pylori strain selectively activates ␤-catenin in model gastric epithelia, which is dependent on translocation of CagA into host epithelial cells. ␤-Catenin nuclear accumulation is increased in gastric epithelium harvested from gerbils infected with the H. pylori carcinogenic strain as well as from persons carrying cag ؉ vs. cag ؊ strains or uninfected persons. These results indicate that H. pylori-induced dysregulation of ␤-catenindependent pathways may explain in part the augmentation in the risk of gastric cancer conferred by this pathogen.bacteria ͉ cancer ͉ inflammation

Helicobacter pylori is the strongest known risk factor for gastric adenocarcinoma, yet only a fraction of infected persons develop cancer. One H. pylori constituent that augments disease risk is the cytotoxin-associated gene (cag) pathogenicity island, which encodes a secretion system that translocates bacterial effector molecules into host cells. Matrix metalloproteinase (MMP)-7, a member of a family of enzymes with tumor-initiating properties, is overexpressed in premalignant and malignant gastric lesions, and H. pylori cag ؉ strains selectively increase MMP-7 protein levels in gastric epithelial cells in vitro and in vivo. We now report that H. pylori-mediated mmp-7 induction is transcriptionally regulated via aberrant activation of p120-catenin (p120), a component of adherens junctions. H. pylori increases mmp-7 mRNA levels in a cagand p120-dependent manner and induces translocation of p120 to the nucleus in vitro and in a novel ex vivo gastric gland culture system. Nuclear translocation of p120 in response to H. pylori relieves Kaiso-mediated transcriptional repression of mmp-7, which is implicated in tumorigenesis. These results indicate that selective and coordinated induction of mmp-7 expression by H. pylori cag ؉ isolates may explain in part the augmentation in gastric cancer risk associated with these strains. INTRODUCTIONHelicobacter pylori induces an inflammatory response in the stomach that persists for decades, and biological costs incurred by this pathogen include an increased risk for gastric adenocarcinoma and non-Hodgkins lymphoma of the stomach (Nomura et al., 1991;Parsonnet et al., 1991;Peterson, 1991;Hansson et al., 1993;Correa, 1996;Uemura et al., 2001;Peek and Blaser, 2002;Moss and Sood, 2003). However, only a fraction of colonized persons ever develop neoplasia, and enhanced cancer risk is related to strain-specific differences, aberrant host responses, and/or specific interactions between microbial and host determinants.H. pylori strains that possess the cytotoxin-associated gene (cag) pathogenicity island increase the risk for cancer compared with strains that lack this genetic locus (Peek and Blaser, 2002). The cag island encodes proteins, such as CagE, that form a type IV secretion system that translocates components of bacterial peptidoglycan and CagA, the product of the terminal gene of the island, into host cells (Asahi et al., 2000;Backert et al., 2000;Odenbreit et al., 2000;Stein et al., 2000;Selbach et al., 2002;Viala et al., 2004). After translocation, peptidoglycan initiates innate immune signaling via activation of the intracellular pattern recognition receptor, Nod-1, and the transcriptional activator nuclear factor-B (NF-B) (Viala et al., 2004). Intracellular CagA undergoes Src-dependent tyrosine phosphorylation and activates a eukaryotic phosphatase, leading to dephosphorylation of host cell proteins and cellular morphological changes (Backert et al., 2000;Higashi et al., 2002;Selbach et al., 2002;Stein et al., 2002). Recently, CagA has been shown to activate ␤-catenin and...