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Open AccessArticle

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

1
Laboratorio de Microbiología Celular, Instituto de Innovación e Investigación en Salud, Facultad de Ciencias de la Salud, Universidad Central de Chile, Santiago 8320000, Chile
2
Centro de Estudios Avanzados en Enfermedades Crónicas (ACCDiS), Independencia, Santiago 8380000, Chile
3
Laboratorio de Comunicaciones Celulares, Centro de estudios en Ejercicio, Metabolismo y Cáncer (CEMC), Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Independencia, Santiago 8380000, Chile
4
Department of Biology, Division of Microbiology, University of Erlangen-Nuremberg, 91054 Erlangen, Germany
5
Thrombosis Research Center, Medical Technology School, Department of Clinical Biochemistry and Immunohaematology, Faculty of Health Sciences, Interdisciplinary Excellence Research Program on Healthy Aging (PIEI-ES), Universidad de Talca, Talca 3460000, Chile
6
Laboratorio de Microbiología Oral, Departamento de Patología y Medicina Oral, Facultad de Odontología, Universidad de Chile, Independencia, Santiago 8380000, Chile
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(6), 799; https://doi.org/10.3390/cancers11060799
Received: 21 January 2019 / Revised: 24 April 2019 / Accepted: 27 April 2019 / Published: 10 June 2019
(This article belongs to the Special Issue Helicobacter pylori Associated Cancer)
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. View Full-Text
Keywords: Helicobacter pylori; urease; HIF-1α; Toll-like receptor 2 (TLR2) Helicobacter pylori; urease; HIF-1α; Toll-like receptor 2 (TLR2)
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Valenzuela-Valderrama, M.; Cerda-Opazo, P.; Backert, S.; González, M.F.; Carrasco-Véliz, N.; Jorquera-Cordero, C.; Wehinger, S.; Canales, J.; Bravo, D.; Quest, A.F.G. The Helicobacter pylori Urease Virulence Factor Is Required for the Induction of Hypoxia-Induced Factor-1α in Gastric Cells. Cancers 2019, 11, 799.

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