Deletion of IQGAP1 promotes Helicobacter pylori-induced gastric dysplasia in mice and acquisition of cancer stem cell properties in vitro
Deletion of IQGAP1 promotes Helicobacter pylori-induced gastric dysplasia in mice and acquisition of cancer stem cell properties in vitro
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DOI：
10.18632/oncotarget.12486
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发表时间：
2016-12-06
期刊：
影响因子：
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通讯作者：
Varon, Christine
中科院分区：
文献类型：
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作者：
Bessede, Emilie;Molina, Silvia;Varon, Christine
幽门螺杆菌感染是胃癌发生的原因，但宿主因素也参与其中。 IQGAP1 是一种与 E-钙粘蛋白相互作用的粘附连接的支架蛋白，调节细胞可塑性和增殖。在小鼠中，IQGAP1 缺乏会导致胃增生。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。将iqgap1缺失的转基因小鼠和WT同窝小鼠感染螺杆菌，并对胃粘膜进行组织病理学分析。评估了胃组织和胃上皮细胞系对幽门螺杆菌感染的反应中的 IQGAP1 和 E-钙粘蛋白表达。评估了 IQGAP1 缺失对胃上皮细胞行为和获得癌症干细胞 (CSC) 样特性的影响。感染一年后，iqgap1+/- 小鼠出现更多肿瘤前病变，胃肠道肿瘤 (GIN) 比 WT 同窝小鼠多 8 倍。幽门螺杆菌感染诱导 IQGAP1 和 E-钙粘蛋白从细胞-细胞连接处离域。在体外，敲低 IQGAP1 有利于获得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，IQGAP1 信号的改变促进幽门螺杆菌感染背景下 CSC 的出现和胃腺癌的发展。
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 gastrointestinal 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.