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The Helicobacter pylori Urease Virulence Factor Is Required for the Induction of Hypoxia-Induced Factor-1α in Gastric Cells

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 gastr...

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Autores principales: Valenzuela-Valderrama, Manuel, Cerda-Opazo, Paulina, Backert, Steffen, González, María Fernanda, Carrasco-Véliz, Nicolás, Jorquera-Cordero, Carla, Wehinger, Sergio, Canales, Jimena, Bravo, Denisse, Quest, Andrew F. G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627347/
https://www.ncbi.nlm.nih.gov/pubmed/31185594
http://dx.doi.org/10.3390/cancers11060799
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author Valenzuela-Valderrama, Manuel
Cerda-Opazo, Paulina
Backert, Steffen
González, María Fernanda
Carrasco-Véliz, Nicolás
Jorquera-Cordero, Carla
Wehinger, Sergio
Canales, Jimena
Bravo, Denisse
Quest, Andrew F. G.
author_facet Valenzuela-Valderrama, Manuel
Cerda-Opazo, Paulina
Backert, Steffen
González, María Fernanda
Carrasco-Véliz, Nicolás
Jorquera-Cordero, Carla
Wehinger, Sergio
Canales, Jimena
Bravo, Denisse
Quest, Andrew F. G.
author_sort Valenzuela-Valderrama, Manuel
collection PubMed
description 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.
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spelling pubmed-66273472019-07-23 The Helicobacter pylori Urease Virulence Factor Is Required for the Induction of Hypoxia-Induced Factor-1α in Gastric Cells Valenzuela-Valderrama, Manuel Cerda-Opazo, Paulina Backert, Steffen González, María Fernanda Carrasco-Véliz, Nicolás Jorquera-Cordero, Carla Wehinger, Sergio Canales, Jimena Bravo, Denisse Quest, Andrew F. G. Cancers (Basel) Article 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. MDPI 2019-06-10 /pmc/articles/PMC6627347/ /pubmed/31185594 http://dx.doi.org/10.3390/cancers11060799 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Valenzuela-Valderrama, Manuel
Cerda-Opazo, Paulina
Backert, Steffen
González, María Fernanda
Carrasco-Véliz, Nicolás
Jorquera-Cordero, Carla
Wehinger, Sergio
Canales, Jimena
Bravo, Denisse
Quest, Andrew F. G.
The Helicobacter pylori Urease Virulence Factor Is Required for the Induction of Hypoxia-Induced Factor-1α in Gastric Cells
title The Helicobacter pylori Urease Virulence Factor Is Required for the Induction of Hypoxia-Induced Factor-1α in Gastric Cells
title_full The Helicobacter pylori Urease Virulence Factor Is Required for the Induction of Hypoxia-Induced Factor-1α in Gastric Cells
title_fullStr The Helicobacter pylori Urease Virulence Factor Is Required for the Induction of Hypoxia-Induced Factor-1α in Gastric Cells
title_full_unstemmed The Helicobacter pylori Urease Virulence Factor Is Required for the Induction of Hypoxia-Induced Factor-1α in Gastric Cells
title_short The Helicobacter pylori Urease Virulence Factor Is Required for the Induction of Hypoxia-Induced Factor-1α in Gastric Cells
title_sort helicobacter pylori urease virulence factor is required for the induction of hypoxia-induced factor-1α in gastric cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627347/
https://www.ncbi.nlm.nih.gov/pubmed/31185594
http://dx.doi.org/10.3390/cancers11060799
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