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
Bacteriology Laboratory, University of Bordeaux, Bordeaux, France.
INSERM, U853, Bordeaux, France.
Oncotarget. 2016 Dec 6;7(49):80688-80699. 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.
幽门螺杆菌感染是胃癌发生的原因，但宿主因素也与之相关。IQGAP1是一种与E-钙黏蛋白相互作用的黏附连接支架蛋白，可调节细胞可塑性和增殖。在小鼠中，IQGAP1缺陷会导致胃增生。本研究的目的是阐明IQGAP1缺失对幽门螺杆菌诱导的胃癌发生的影响。对缺失iqgap1的转基因小鼠和野生型同窝小鼠感染幽门螺杆菌，并对胃黏膜进行组织病理学分析。评估了幽门螺杆菌感染后胃组织和胃上皮细胞系中IQGAP1和E-钙黏蛋白的表达。评估了IQGAP1缺失对胃上皮细胞行为和癌症干细胞（CSC）样特性获得的影响。感染一年后，与野生型同窝小鼠相比，iqgap1+/-小鼠出现更多的癌前病变，胃肠道肿瘤（GIN）多达8倍。幽门螺杆菌感染导致IQGAP1和E-钙黏蛋白从细胞间连接部位移位。在体外，敲低IQGAP1有利于获得由幽门螺杆菌感染诱导的间充质表型和CSC样特性。我们的结果表明，在幽门螺杆菌感染的情况下，IQGAP1信号改变促进了CSC的出现和胃腺癌的发展。
