Abstract
Chronic Helicobacter pylori infection increases the risk of gastric cancer and induction of hypoxia-induced factor (HIF), which is frequently associated with the development and progression of several types of cancer. We recently showed that H. pylori activation of the PI3K-AKT-mTOR pathway in gastric cells increased HIF-1α expression. Here, we identified the H. pylori virulence factor responsible for HIF-1α induction. A mutant of the H. pylori 84-183 strain was identified with reduced ability to induce HIF-1α. Coomassie blue staining of extracts from these bacteria separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) revealed poor expression of urease subunits that correlated with reduced urease activity. This finding was confirmed in the 26695 strain, where urease mutants were unable to induce HIF-1α expression. Of note, HIF-1α induction was also observed in the presence of the urease inhibitor acetohydroxamic acid at concentrations (of 20 mM) that abrogated urease activity in bacterial culture supernatants, suggesting that enzymatic activity of the urease is not required for HIF-1α induction. Finally, the pre-incubation of the human gastric adenocarcinoma cell line AGS with blocking antibodies against Toll-like receptor-2 (TLR2), but not TLR4, prevented HIF-1α induction. In summary, these results reveal a hitherto unexpected role for the urease protein in HIF-1α induction via TLR2 activation following H. pylori infection of gastric cells.
Highlights
Helicobacter pylori (H. pylori) colonizes the human gastric mucosa of approximately half of the human population worldwide [1]
We present evidence showing that the H. pylori urease is responsible for hypoxia-induced factor (HIF)-1α induction in gastric cells
Our results indicated that enzymatic urease activity was not essential for HIF-1α induction
Summary
Helicobacter pylori (H. pylori) colonizes the human gastric mucosa of approximately half of the human population worldwide [1] These bacteria are often acquired during childhood and can persist asymptomatically over a lifetime in most cases; in some individuals, chronic infection can promote a more exacerbated inflammatory response, which triggers a loss of gastric epithelial cells by apoptosis and an accumulation of epigenetic changes that lead to alterations in signaling pathways, affecting epithelial cell turnover, cell differentiation, and gastric epithelial homeostasis [2,3]. H. pylori infection is widely considered to increase the risk of developing gastric cancer and is held responsible for approximately 90% of cases of intestinal-type gastric carcinoma [4] This disease is characterized by a cascade well-defined histological changes in the gastric mucosa, beginning with chronic gastritis, followed by atrophy and intestinal metaplasia, which may lead to dysplasia and gastric cancer [5,6]. The bacterial adhesins BabA, SabA or HopQ permit binding of the bacteria to the gastric epithelium, thereby preventing elimination with gastric emptying
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