Oncotarget

Research Papers:

Deletion of IQGAP1 promotes Helicobacter pylori-induced gastric dysplasia in mice and acquisition of cancer stem cell properties in vitro

Emilie Bessède _, Silvia Molina, Luis Acuña Amador, Pierre Dubus, Cathy Staedel, Lucie Chambonnier, Alice Buissonnière, Elodie Sifré, Alban Giese, Lucie Buissonnière, Benoît Rousseau, Pierre Costet, David B. Sacks, Francis Mégraud, Christine Varon

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Oncotarget. 2016; 7:80688-80699. https://doi.org/10.18632/oncotarget.12486

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Abstract

Emilie Bessède1,2, Silvia Molina1,2, Luis Acuña Amador1,2, Pierre Dubus3, Cathy Staedel4,5, Lucie Chambonnier1,2, Alice Buissonnière1,2, Elodie Sifré1,2, Alban Giese3,9, Lucie Bénéjat1,2, Benoît Rousseau6, Pierre Costet7, David B. Sacks8, Francis Mégraud1,2, Christine Varon1,2

1Bacteriology Laboratory, University of Bordeaux, Bordeaux, France

2INSERM, U853, Bordeaux, France

3EA2406 Histologie et pathologie moléculaire des tumeurs, University of Bordeaux, Bordeaux, France

4‘RNA: Natural and Artificial Regulation’ (ARNA) Laboratory, University of Bordeaux, Bordeaux, France

5INSERM, U869, Bordeaux, France

6Service Commun des Animaleries, Animalerie A2, University of Bordeaux, Bordeaux, France

7Service Commun des Animaleries, Animalerie Transgénique, University of Bordeaux, Bordeaux, France

8Department of Laboratory Medicine, National Institutes of Health, Bethesda, MD, USA

9Experimental Pathology Platform, SIRIC BRIO, University of Bordeaux, Bordeaux, France

Correspondence to:

Emilie Bessède, email: ebessede@gmail.com

Keywords: EMT, gastric cancer, CD44, E-cadherin, Zeb

Received: January 12, 2016     Accepted: July 18, 2016     Published: October 06, 2016

ABSTRACT

Helicobacter pylori infection is responsible for gastric carcinogenesis but host factors are also implicated. IQGAP1, a scaffolding protein of the adherens junctions interacting with E-cadherin, regulates cellular plasticity and proliferation. In mice, IQGAP1 deficiency leads to gastric hyperplasia. The aim of this study was to elucidate the consequences of IQGAP1 deletion on H. pylori-induced gastric carcinogenesis.

Transgenic mice deleted for iqgap1 and WT littermates were infected with Helicobacter sp., and histopathological analyses of the gastric mucosa were performed. IQGAP1 and E-cadherin expression was evaluated in gastric tissues and in gastric epithelial cell lines in response to H. pylori infection. The consequences of IQGAP1 deletion on gastric epithelial cell behaviour and on the acquisition of cancer stem cell (CSC)-like properties were evaluated. After one year of infection, iqgap1+/- mice developed more preneoplastic lesions and up to 8 times more gastro-intestinal neoplasia (GIN) than WT littermates. H. pylori infection induced IQGAP1 and E-cadherin delocalization from cell-cell junctions. In vitro, knock-down of IQGAP1 favoured the acquisition of a mesenchymal phenotype and CSC-like properties induced by H. pylori infection.

Our results indicate that alterations in IQGAP1 signalling promote the emergence of CSCs and gastric adenocarcinoma development in the context of an H. pylori infection.


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