Helicobacter pylori is the strongest identified risk factor for gastric cancer and contact between this microbial pathogen and epithelial cells activates signaling pathways that drive oncogenesis. Our long-term objective is to define targetable pathways induced by carcinogenic H. pylori strains that lead to oncogenic epithelial responses. One H. pylori strain-specific determinant that augments cancer risk is the cag type IV secretion system (TFSS), which translocates an oncoprotein (CagA) into epithelial cells following bacterial attachment. A host molecule that influences gastric cancer in conjunction with H. pylori is the transcription co- regulator -catenin. Expression of -catenin is increased in human gastric adenocarcinoma specimens and nuclear accumulation of -catenin is enhanced within gastric adenomas and dysplasia; thus, aberrant activation of -catenin precedes the development of gastric cancer. Importantly, we have demonstrated that the H. pylori cag TFSS can activate -catenin in vitro and in vivo. A key regulator of -catenin is the nodal kinase AKT, and genes within the AKT pathway are the most frequently altered in human cancers. Pertinent to this application, human Akt polymorphisms are significantly associated with the development of gastric pre-malignant and malignant lesions. In exciting new studies, we have demonstrated for the first time that H. pylori activates AKT and -catenin in a novel model, human gastroids, via cag-dependent CagA translocation. These results directly informed provocative new translational studies examining H. pylori isolates and gastric samples harvested from a unique human population in Colombia in which individuals reside in either a high- or low-risk region of gastric cancer. These data indicate that H. pylori-infected gastric tissues harbor increased expression levels of -catenin target genes, which has focused our current studies on defining the role of - catenin as a mediator of H. pylori-induced carcinogenesis. Our hypothesis is that selective activation of AKT-mediated -catenin-dependent pathways contributes to the augmentation in carcinogenic risk conferred by H. pylori cag+ strains. We will test this hypothesis via the following Aims: 1. Utilize gastroid systems derived from genetic mouse models and human samples to define the role of AKT in regulating -catenin dependent oncogenic responses to H. pylori wild-type and isogenic mutant strains. 2. Define the effects of AKT deficiency and inhibition on gastric carcinogenesis using rodent models of H. pylori-induced inflammation and cancer. 3. Validate findings in unique human populations that reside in high or low gastric cancer risk regions and use these results to inform mechanistic studies focused on AKT and -catenin within the context of H. pylori. These studies will help to identify people who are at greatest risk for H. pylori-induced stomach cancer, which will greatly improve the diagnosis and therapy of this disease.
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