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.