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.
Highlights
Gastric adenocarcinoma remains the third most common cause of cancer-related mortality worldwide [1]
In order to determine the role of IQGAP1 in the development of lesions in the gastric mucosa in response to Helicobacter infection, infection experiments were carried out on female 129/Bl/6 mice deleted for one allele of iqgap1 [19] and on their wild type (WT) littermates
We previously reported that the epithelial to mesenchymal transition (EMT)-like changes induced during H. pylori infection are associated with the emergence of CD44+ cells possessing cancer stem cell (CSC)-like properties [5, 6]
Summary
Gastric adenocarcinoma remains the third most common cause of cancer-related mortality worldwide [1]. The CagA protein produced by certain H. pylori strains is the main www.impactjournals.com/oncotarget pathogenic factor implicated in gastric adenocarcinoma. IQGAP1 is a scaffold protein interacting with numerous partners which modulates the actin cytoskeleton via Rac and Cdc, cell/cell adhesions via E-cadherin, plasticity and proliferation via the Wnt/ß-catenin proteins, β-catenin and APC, and MEK and Erk [11]. It appears that IQGAP1, as well as E-cadherin, could play a role in gastric carcinogenesis. The role of IQGAP1 has been studied in different models. Cai et al, using a murine model, showed that a Helicobacter sp. infection leads to a progressive shift of IQGAP1 from cytoplasmic expression to cell surface expression [20]
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