Helicobacter pylori

H. pylori, which adheres to the luminal surface of gastric epithelial cells, is the causative agent of gastritis and possesses a number of virulence factors that modulate its interaction with the host [10, 11]. These virulence factors include the secreted cytotoxin VacA and the gene products of the pathogenicity island cagPAl. The cagPAl encodes a type IV secretion system that facilitates the injection of bacterial proteins into host cells [10, 11]. One of these proteins, CagA, undergoes tyrosine phosphorylation within epithelial cells and deregulates SHP-2 [12], and mediates alteration of the actin cytoskeleton [13].

Several analyses of the interaction of Helicobacter with epithelial cells and the role of the cagPAl for modulation of gene expression were performed. Cox et al. [14] infected Kato 3 gastric epithelial cells with a wildtype cagPAl+ or an isogenic cagPAl- H. pylori mutant strain and analyzed host gene expression by cDNA arrays. Exposure of cells to the various H. pylori strains revealed 106 genes which were at least 1.3-fold differentially expressed upon infection with cagPAl+ or cagPAl- strains. ln line with previous findings [15], several NF-jB regulated genes were found to be differentially expressed upon CagPAl+ infection. Moreover, several genes involved in regulation of cell cycle (e.g., cyclin D1) and apoptosis (e.g., Bclx) were more highly expressed upon infection with a cagPAl+ strain, confirming that cagPAl+ strains are associated with reduced apoptosis and higher gastric epithelial cell proliferation [16].

lnfection with cagPAl+ strain was associated with early decreased expression of genes coding for cellular regulation such as elongin B. Elongin B is part of the multifunctional regulatory elongin BC complex, which is thought to play an important role in negative regulation of hypoxia-inducible proteins by promoting degradation of HlF1-a [17]. Several genes were found in gastric biopsies from patients undergoing routine upper gastrointestinal endoscopy [14]. The mRNA expression of amphiregulin, a member of the epidermal growth factor family which has mitogenic effects on epithelial cells, was confirmed and is cagPAl-inde-pendently regulated. Four genes of the ADAMs family of membrane metallopro-teinases which may have important functions in the release of cell surface molecules, cell-cell and cell-extracellular matrix interaction were changed upon H. pylori infection. ADAM10, which is expressed in hematological malignancies [18], has collagenase type lV activity [19], and cleaves proTNF-a to the soluble forms [20], is expressed more frequently in patients infected with cagPAl strains. Further studies have to show how these findings are linked to H. pylori-induced gastric pathology.

Guillemin et al. [21] infected gastric epithelial AGS cells with H. pylori G27 and isogenic deletion mutants for cagA, vacA, cagE, cagN, or the entire cagPAl. A total of 206 genes were designated as a canonical H. pylori response. The most abundant functional groups were genes encoding proteins involved in either innate immune response or the regulation of cell shape and adhesion, consistent with the characterized cytokine secretion by and cell elongation of gastric epithelial

AGS cells upon H. pylori infection. Moreover, genes involved in NF-jB signaling were found to be upregulated upon H. pylori infection. A large number of genes involved in cytoskeleton function were found to be upregulated, such as Cdc42 effector protein 2 (CEP2), genes associated with the actin cytoskeleton (arinteg-rin) and intermediate filaments (keratin 17), as well as genes encoding components of cell junctions (claudin 1 and 4).

In addition, gene repression was also found. Twenty percent of these repressed genes were signal transduction molecules such as the wingless (Wnt) signaling pathway members frizzled 7 and dickkopf, the antagonist of tyrosine kinase signaling DAB2, and the mitoattractant CTGF. Deletion of the entire cagPAI abolishes most of the gene modulation by H. pylori, indicating that the major response of AGS cells to H. pylori is mediated through the cagPAI. CagA- infection differed from wildtype infection in a subset of 18 genes including genes involved in cell shape changes such as pleckstrin homologue domain 1, RhoB, CEP2, claudin 4, and enigma. Since cagA requires cagE to be translocated into host cells the cagA-dependent genes represent a subset of cagE-dependent genes. In contrast to cagA- mutant, cagE mutant no longer modulates gene expression involved in inflammation such as NF-jB and TNF signaling, which may indicate that other factors of the cagPAI are crucial to elicit these responses. The identification of cagA-mediated gene expression may help to shed new light on the cagA-modulated host responses such as CagA signal transduction and small GTPAse regulation of the cytoskeleton.

Environmental and genetic factors are important in gastric carcinogenesis. Chronic gastritis caused by H. pylori infection is associated with gastric cancer, and infection with H. pylori is an almost invariant feature of chronic gastritis in patients with gastric cancer [22]. Boussioutas et al. [23] used more than one hundred tumor and adjacent mucosa samples from Australian and Chinese patients displaying different gastric tumor types as well as mucosa which showed chronic gastritis or intestinal metaplasia in order to perform gene expression profiling using a spotted cDNA array containing 9381 nonredundant gene elements. Each nonneoplastic sample and each gastric cancer subtype could be defined by a distinct gene expression profile [23]. Unsupervised clustering of the data led to a highly structured partitioning of samples into the recognized histological subgroups. Comparison of Chinese and Australian patients showed no clear segregation of gastric cancer samples based on ethnicity.

Chronic gastritis was characterized by expression patterns of groups of genes sharing similar biological functions, including metallothionein or elongation factor gene cluster. In particular, a large number of nuclear genes encoding mito-chondrial proteins was found. For vacA it was shown that the p34 fragment of vacA localizes specifically to mitochondria [24], causing release of cytochrome c and apoptosis [25, 26]. Furthermore, VacA induces mitochondrial damage when applied to the gastric epithelial cell line AZ521 [26]. Therefore the finding presented above may be consistent with the loss or damage of mitochondria which may lead to a high level of mitochondrial biogenesis in chronic gastritis. Interestingly, the above-mentioned in vitro studies using gastric epithelial cell lines for

H. pylori infection did not describe any changes in mitochondrial genes, which may be due to the different microarrays used or to the cell line used. Taken together, this study and others [27] may help to introduce a gene-expression-based classification of gastric carcinoma and may contribute to creating novel hypotheses to explore the pathogenesis of gastritis and the development of gastric cancer at the molecular level.

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