title: Role of Raf kinase inhibitor protein in Helicobacter pylori-mediated signaling in gastric cancer.
abstract: Helicobacter pylori is a helical bacterium that colonizes the stomach in over half of the world's population. Infection with this bacterium has been linked to peptic ulcer disease and gastric cancer. The bacterium has been shown to affect regulatory pathways in its host cells through specific virulence factors that control gene expression. Infection with H. pylori increases levels of phosphorylation of Raf kinase inhibitor protein (pRKIP) in gastric adenocarcinoma (AGS) cells in vitro and in vivo. We investigated the role of H. pylori in the phosphorylation of RKIP as a possible mechanism to downregulate pro-survival signals in gastric adenocarcinoma. pRKIP induces RKIP transcriptional activity, which serves to induce apoptosis of damaged cells to prevent further tumorigenesis. Infection of wild type and RKIP knockout mice with H. pylori for 2 months further confirmed roles of RKIP and pRKIP in the prevention of gastric cancer progression. Loss of RKIP in AGS cells results in increased expression of the Cag A virulence factor after H. pylori infection and RKIP overexpression inhibits H. pylori-mediated STAT3 phosphorylation and STAT3 and NF-κB transcriptional activity. We examined the role of mTOR (mammalian target of rapamycin) after H. pylori infection on the phosphorylation of RKIP. Cells treated with rapamycin, an inhibitor of mTOR, displayed less expression of pRKIP after H. pylori infection. Microarray antibody analysis was conducted on wild-type and RKIP-knockdown AGS cells and showed that in the absence of RKIP, there was increased expression of pro-tumorigenic proteins such as EGFR, Raf-1, and MAPKs. Although further work is needed to confirm the interaction of RKIP and mTOR in AGS cells as a result of H. pylori infection, we hypothesize that H. pylori-mediated induction of pro-survival signaling in gastric epithelial cells induces a feedback response through the activation of RKIP. The phosphorylated, or active, form of RKIP is important in protecting gastric epithelial cells from tumorigenesis after H. pylori infection.
authors.affiliation: Department of Medicine, Rhode Island Hospital and The Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Liana
authors.initials: L
authors.lastname: Nisimova
authors.affiliation: Department of Medicine, Rhode Island Hospital and The Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Sicheng
authors.initials: S
authors.lastname: Wen
authors.affiliation: Department of Medicine, Rhode Island Hospital and The Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Sam
authors.initials: S
authors.lastname: Cross-Knorr
authors.affiliation: Cummings School of Veterinary Medicine, Tufts University, North Grafton, Massachusetts.
authors.forename: Arlin B
authors.initials: AB
authors.lastname: Rogers
authors.affiliation: Department of Medicine, Rhode Island Hospital and The Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Steven F
authors.initials: SF
authors.lastname: Moss
authors.affiliation: Department of Medicine, Rhode Island Hospital and The Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Devasis
authors.initials: D
authors.lastname: Chatterjee
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics; D016481:Helicobacter Infections / Q000150:complications* / Q000235:genetics; D016480:Helicobacter pylori / Q000502:physiology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D049488:Phosphatidylethanolamine Binding Protein / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics* / Q000382:microbiology*
chemical_list: D049488:Phosphatidylethanolamine Binding Protein; C539308:Raf kinase inhibitory protein, mouse