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

• Published in: Oncotarget Vol. 7; no. 49; pp. 80688 - 80699
• Main Authors: Bessède, Emilie, Molina, Silvia, Acuña-Amador, Luis, Dubus, Pierre, Staedel, Cathy, Chambonnier, Lucie, Buissonnière, Alice, Sifré, Elodie, Giese, Alban, Bénéjat, Lucie, Rousseau, Benoît, Costet, Pierre, Sacks, David B, Mégraud, Francis, Varon, Christine
• Format: Journal Article
• Language: English
• Published: United States Impact journals 06-12-2016; Impact Journals LLC
• Subjects: Adenocarcinoma - genetics; Adenocarcinoma - metabolism; Adenocarcinoma - microbiology; Adenocarcinoma - pathology; Animals; Cadherins - metabolism; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Disease Models, Animal; Epithelial-Mesenchymal Transition; Female; Gastric Mucosa - metabolism; Gastric Mucosa - microbiology; Gastric Mucosa - pathology; Genetic Predisposition to Disease; Helicobacter Infections - genetics; Helicobacter Infections - metabolism; Helicobacter Infections - microbiology; Helicobacter Infections - pathology; Helicobacter pylori - pathogenicity; Host-Pathogen Interactions; Hyaluronan Receptors - metabolism; Hyperplasia; Life Sciences; Mice, 129 Strain; Mice, Knockout; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - microbiology; Neoplastic Stem Cells - pathology; Phenotype; Precancerous Conditions - genetics; Precancerous Conditions - metabolism; Precancerous Conditions - microbiology; Precancerous Conditions - pathology; ras GTPase-Activating Proteins - deficiency; ras GTPase-Activating Proteins - genetics; Research Paper; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism; Stomach Neoplasms - microbiology; Stomach Neoplasms - pathology; Time Factors; gastric cancer; E-cadherin; EMT; Zeb; CD44
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.12486

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.