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Critical Reviews™ in Oncogenesis
SJR: 0.631 SNIP: 0.503 CiteScore™: 2.2

ISSN Druckformat: 0893-9675
ISSN Online: 2162-6448

Critical Reviews™ in Oncogenesis

DOI: 10.1615/CritRevOncog.2014012044
pages 469-481

Role of Raf Kinase Inhibitor Protein in Helicobacter pylori-Mediated Signaling in Gastric Cancer

Liana Nisimova
Department of Medicine, Rhode Island Hospital and The Alpert Medical School of Brown University, Providence, Rhode Island
Sicheng Wen
Department of Medicine, Rhode Island Hospital and The Alpert Medical School of Brown University, Providence, Rhode Island
Sam Cross-Knorr
Department of Medicine, Rhode Island Hospital and The Alpert Medical School of Brown University, Providence, Rhode Island
Arlin B. Rogers
Cummings School of Veterinary Medicine, Tufts University, North Grafton, Massachusetts
Steven F. Moss
Department of Medicine, Rhode Island Hospital and The Alpert Medical School of Brown University, Providence, Rhode Island
Devasis Chatterjee
Rhode Island Hospital and The Alpert Medical School of Brown University, Providence, Rhode Island

ABSTRAKT

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.

SCHLÜSSELWÖRTER: Cag A, gastric cancer, H. pylori, RKIP, STAT3

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