Delineation of signaling pathways induced by Helicobacter pylori that regulate host cell survival

Abstract

Gastric adenocarcinoma is strongly associated with the presence of H. pylori. Microbial factors of H. pylori and host responses induced by the interactions of H. pylori with gastric epithelial cells play important roles in the development of disease. PI3K and β-catenin/p120 are multifunctional host proteins that coordinate carcinogenic epithelial responses when aberrantly activated, such as in malignant gastric lesions. We demonstrate that H. pylori infection results in upregulation of PI3K-AKT signaling, through stimulation of EGFR. Activation of this pathway reduces rates of epithelial cell death induced by H. pylori and promotes resistance to apoptosis. We also demonstrate that H. pylori infection induces additional host signaling pathways to potentiate a proliferative response in gastric epithelial cells. Specifically, PPARδ, a target of β-catenin transcriptional activation, contributes to increased rates of gastric epithelial cell proliferation in response to H. pylori infection. Based on these findings we hypothesize that an anti-apoptotic response in the presence of increased proliferation increases the risk of retaining mutagenized gastric epithelial cells in the presence of H. pylori induced gastritis. Taken together, these studies have identified effectors that directly mediate host responses related to carcinogenesis. Molecular delineation of such pathways activated by host-microbial interactions will improve our understanding of H. pylori-induced carcinogenesis, allowing for targeted therapies to high-risk individuals, as well as provide insight into other malignancies that arise within the context of pathogen-induced inflammation.