幽門桿菌 CagL, CagI 及基質金屬蛋白酵素多型性於胃癌致病機制之角色

Abstract

Helicobacter pylori infection has been well-recognized to closely associate with a spectrum of pathologies, ranging from mild gastritis to peptic ulcer and even gastric malignancy in humans. The cagA and vacA are the two major virulence factors of H. pylori that have been associated with disease induction. However, in Taiwan, the cagA-genopositive or vacA genopositive H. pylori infection was nearly to 100% and thus showed poor correlation to explain the different outcomes. Integrin α5β1 has been well recognized as a receptor for the delivery of CagA protein. Moreover, the CagL protein of H. pylori is an integrin-specific adhesion, and the CagL-integrin interaction by itself activates an integrin-associated kinase cascade for CagA phosphorylation. We tested whether cagL genopositivity or amino acid sequence polymorphisms of H. pylori correlated with the more adverse clinical-pathological outcomes, such as gastric cancer, and whether CagL interact with host gastric integrin α5β1 expressions, and correlate with the clinicohistological outcomes. We found that nearly 100% of the H. pylori isolates had cagL-positive genotype and with RGD motif. H. pylori CagL amino acid polymorphisms as Y58/E59 has a 4.6-fold risk of gastric cancers, and exerted with a corpus shift-up of gastric integrin α5β1 to mediate more severe corpus gastritis. The gastric epithelial cell AGS infected with CagL-Y58/E59 H. pylori had higher integrin β1 activation and clustering, more CagA phosphorylation to have more CagA translocation into cells, higher IL-8 secretion, and apoptosis rate. As low acid secretion happen in gastric cancer patients to correlate with gastric cancer progression. We therefore tested whether pH condition affect CagA phosphorylation or integrin expression, and found that higher level of CagA phosphorylation and integrin expression were mediated by H. pylori in higher pH condition. Besides to CagL, CagI and CagY also interact with integrin α5β1. We examined whether cagI and cagY genopositive or amino acid sequence polymorphisms of H. pylori correlated with clinical outcomes. We found the prevalence rates of cagI and cagY are nearly 100%. H. pylori CagI amino acid polymorphism as N125 correlates with a 4.5-fold risk of gastric cancers. In in vitro study, the AGS infected with CagI-N125 H. pylori could exert with higher integrin β1 activation, rather than affect the ability of CagA translocation into cells. H. pylori CagY amino acid polymorphisms have no correlation to gastric cancers, but H. pylori CagY-I1725 infection correlates with a 3.7-fold risk of gastric ulcers. Matrix metalloproteinases (MMPs) are a family of enzymes that degrade most extracellular matrix and participate in the processes of tissue repairing, growth, development and remodeling. However, when the expressions and activities of MMPs lose control, MMPs may be associated with some diseases. Recent studied indicated that MMPs play important roles in many inflammatory diseases processes, and some studies reported that several MMPs can be induced during H. pylori infection. We therefore examined whether the serum levels or single nucleotide polymorphisms (SNPs) of MMPs may correlate with the clinical outcomes. Among the H. pylori-infected subjects, the gastric cancer patients had higher serum levels of MMP-3 and MMP-7 than those with duodenal ulcer and gastritis. Moreover, the concomitant elevations of MMP-3 and MMP-7 serum levels in the H. pylori-infected gastric cancer patients correlate to a poor survival. Our SNP analysis revealed that the MMP-3 6A6A genotype were more common in the patients with duodenal ulcers than in those with gastritis in H. pylori-infected females. Combining the MMP-3/TIMP-1 genotypes as 6A6A/CC, the risk of duodenal ulcer may increase up to 3.6 folds in the H. pylori-infected females. So the MMP-3 promoter polymorphism may correlate to duodenal ulcer formation after H. pylori infection in the Taiwanese females.