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H. pylori CagL-Y58/E59 prime higher integrin α5β1 in adverse pH condition to enhance hypochlorhydria vicious cycle for gastric carcinogenesis.

Yeh YC, Cheng HC, Yang HB, Chang WL, Sheu BS - PLoS ONE (2013)

Bottom Line: H. pylori CagL amino acid polymorphisms such as Y58/E59 can increase integrin α5β1 expression and gastric cancer risk.Differences in the pepsinogen I/II ratio (indirectly indicating gastric acidity) and gastric integrin α5β1 expression were compared among the 172 H. pylori-infected patients with different cancer risks.In the H. pylori-infected patients, the gastric integrin α5β1 expressions were higher in those with pepsinogen I/II ratio <6 than in those without (p<0.05).

View Article: PubMed Central - PubMed

Affiliation: Institute of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

ABSTRACT

Background/aims: H. pylori CagL amino acid polymorphisms such as Y58/E59 can increase integrin α5β1 expression and gastric cancer risk. Hypochlorhydria during chronic H. pylori infection promotes gastric carcinogenesis. The study test whether CagL-Y58/E59 isolates may regulate integrin α5β1 to translocate CagA via the type IV secretory system even under adverse pH conditions, and whether the integrin α5β1 expression primed by H. pylori is a pH-dependent process involving hypochlorhydria in a vicious cycle to promote gastric carcinogenesis.

Methods: The expressions of integrin α5 and β1, CagA phosphorylation, IL-8, FAK, EGFR, and AKT activation of AGS cells exposed to CagL-Y58/E59 H. pylori, isogenic mutants, and different H. pylori CagL amino acid replacement mutants under different pH values were determined. Differences in the pepsinogen I/II ratio (indirectly indicating gastric acidity) and gastric integrin α5β1 expression were compared among the 172 H. pylori-infected patients with different cancer risks.

Results: Even under adversely low pH condition, H. pylori CagL-Y58/E59 still keep active integrin β1 with stronger binding affinity, CagA translocation, IL-8, FAK, EGFR, and AKT activation than the other mutants (p<0.05). The in vitro assay revealed higher priming of integrin α5β1 by H. pylori under elevated pH as hypochlorhydria (p<0.05). In the H. pylori-infected patients, the gastric integrin α5β1 expressions were higher in those with pepsinogen I/II ratio <6 than in those without (p<0.05).

Conclusions: H. pylori CagL-Y58/E59 prime higher integrin under adverse pH and may involve to enhance hypochlorhydria vicious cycle for gastric carcinogenesis, and thus require an early eradication.

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Related in: MedlinePlus

The immunohistochemical stains for integrin α5β1 in the gastric superficial epithelial cells (40X) in the duodenal ulcer group, gastritis group, intestinal metaplasia group, and gastric cancer group, respectively.The integrin α5β1 was stained on the basolateral membrane of the gastric superficial epithelial cells in the duodenal ulcer group (arrows in A) and gastritis group (arrows in B), but stained on supranuclear or apical surfaces in the intestinal metaplasia group (arrows in C) and gastric cancer group (arrows in D).
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pone-0072735-g004: The immunohistochemical stains for integrin α5β1 in the gastric superficial epithelial cells (40X) in the duodenal ulcer group, gastritis group, intestinal metaplasia group, and gastric cancer group, respectively.The integrin α5β1 was stained on the basolateral membrane of the gastric superficial epithelial cells in the duodenal ulcer group (arrows in A) and gastritis group (arrows in B), but stained on supranuclear or apical surfaces in the intestinal metaplasia group (arrows in C) and gastric cancer group (arrows in D).

Mentions: As evidenced from the in vitro assays, the decrease of gastric acidity with a higher pH value may up-regulate the integrin α5β1. We further validated that such a finding could be translated to the clinical patients. The integrin α5β1 was in general stained on the basolateral membrane of the gastric epithelial cells in the duodenal ulcer group (Figure 4A) and gastritis group (Figure 4B), but could be stained on the supranuclear or apical surfaces in the intestinal metaplasia group (Figure 4C) and gastric cancer group (Figure 4D). In Table 1, it can be seen that the rates of patients with PG I/II ratio <6.0 increased in order in the following ranking: duodenal ulcer (8.3%), gastritis (19.2%), intestinal metaplasia (19.6%), and gastric cancer group (39.5%) (p = 0.01 by linear-by-linear association). The rates of supranuclear or apical integrin α5β1 expression on the gastric epithelium also increased in the same order for patients with duodenal ulcer, gastritis, intestinal metaplasia, and gastric cancer group (respectively for antrum: 22.2%, 34.6%, 56.5%, and 63.2%, p = 0.001; respectively for corpus: 16.7%, 28.8%, 34.8%, and 50%, p = 0.02).


H. pylori CagL-Y58/E59 prime higher integrin α5β1 in adverse pH condition to enhance hypochlorhydria vicious cycle for gastric carcinogenesis.

Yeh YC, Cheng HC, Yang HB, Chang WL, Sheu BS - PLoS ONE (2013)

The immunohistochemical stains for integrin α5β1 in the gastric superficial epithelial cells (40X) in the duodenal ulcer group, gastritis group, intestinal metaplasia group, and gastric cancer group, respectively.The integrin α5β1 was stained on the basolateral membrane of the gastric superficial epithelial cells in the duodenal ulcer group (arrows in A) and gastritis group (arrows in B), but stained on supranuclear or apical surfaces in the intestinal metaplasia group (arrows in C) and gastric cancer group (arrows in D).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3757014&req=5

pone-0072735-g004: The immunohistochemical stains for integrin α5β1 in the gastric superficial epithelial cells (40X) in the duodenal ulcer group, gastritis group, intestinal metaplasia group, and gastric cancer group, respectively.The integrin α5β1 was stained on the basolateral membrane of the gastric superficial epithelial cells in the duodenal ulcer group (arrows in A) and gastritis group (arrows in B), but stained on supranuclear or apical surfaces in the intestinal metaplasia group (arrows in C) and gastric cancer group (arrows in D).
Mentions: As evidenced from the in vitro assays, the decrease of gastric acidity with a higher pH value may up-regulate the integrin α5β1. We further validated that such a finding could be translated to the clinical patients. The integrin α5β1 was in general stained on the basolateral membrane of the gastric epithelial cells in the duodenal ulcer group (Figure 4A) and gastritis group (Figure 4B), but could be stained on the supranuclear or apical surfaces in the intestinal metaplasia group (Figure 4C) and gastric cancer group (Figure 4D). In Table 1, it can be seen that the rates of patients with PG I/II ratio <6.0 increased in order in the following ranking: duodenal ulcer (8.3%), gastritis (19.2%), intestinal metaplasia (19.6%), and gastric cancer group (39.5%) (p = 0.01 by linear-by-linear association). The rates of supranuclear or apical integrin α5β1 expression on the gastric epithelium also increased in the same order for patients with duodenal ulcer, gastritis, intestinal metaplasia, and gastric cancer group (respectively for antrum: 22.2%, 34.6%, 56.5%, and 63.2%, p = 0.001; respectively for corpus: 16.7%, 28.8%, 34.8%, and 50%, p = 0.02).

Bottom Line: H. pylori CagL amino acid polymorphisms such as Y58/E59 can increase integrin α5β1 expression and gastric cancer risk.Differences in the pepsinogen I/II ratio (indirectly indicating gastric acidity) and gastric integrin α5β1 expression were compared among the 172 H. pylori-infected patients with different cancer risks.In the H. pylori-infected patients, the gastric integrin α5β1 expressions were higher in those with pepsinogen I/II ratio <6 than in those without (p<0.05).

View Article: PubMed Central - PubMed

Affiliation: Institute of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

ABSTRACT

Background/aims: H. pylori CagL amino acid polymorphisms such as Y58/E59 can increase integrin α5β1 expression and gastric cancer risk. Hypochlorhydria during chronic H. pylori infection promotes gastric carcinogenesis. The study test whether CagL-Y58/E59 isolates may regulate integrin α5β1 to translocate CagA via the type IV secretory system even under adverse pH conditions, and whether the integrin α5β1 expression primed by H. pylori is a pH-dependent process involving hypochlorhydria in a vicious cycle to promote gastric carcinogenesis.

Methods: The expressions of integrin α5 and β1, CagA phosphorylation, IL-8, FAK, EGFR, and AKT activation of AGS cells exposed to CagL-Y58/E59 H. pylori, isogenic mutants, and different H. pylori CagL amino acid replacement mutants under different pH values were determined. Differences in the pepsinogen I/II ratio (indirectly indicating gastric acidity) and gastric integrin α5β1 expression were compared among the 172 H. pylori-infected patients with different cancer risks.

Results: Even under adversely low pH condition, H. pylori CagL-Y58/E59 still keep active integrin β1 with stronger binding affinity, CagA translocation, IL-8, FAK, EGFR, and AKT activation than the other mutants (p<0.05). The in vitro assay revealed higher priming of integrin α5β1 by H. pylori under elevated pH as hypochlorhydria (p<0.05). In the H. pylori-infected patients, the gastric integrin α5β1 expressions were higher in those with pepsinogen I/II ratio <6 than in those without (p<0.05).

Conclusions: H. pylori CagL-Y58/E59 prime higher integrin under adverse pH and may involve to enhance hypochlorhydria vicious cycle for gastric carcinogenesis, and thus require an early eradication.

Show MeSH
Related in: MedlinePlus