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

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.

The Hippo Kinase LATS2 Controls Helicobacter pylori-Induced Epithelial-Mesenchymal Transition and Intestinal Metaplasia in Gastric Mucosa

“…The Correa cascade can be reproduced in a C57BL/6 mouse model force-fed with Helicobacter felis or with certain proinflammatory strains of H pylori such as the cytotoxin-associated gene A-pathogenicity island (cagPAI)and cagA-positive H pylori HPARE strain ( Figure 1C), as previously described. 9,19,20 The exception in these mouse models is that they do not develop a true intestinal metaplasia with goblet cells as in human beings, but a spasmolytic polypeptide expressing metaplasia composed of mucous-producing cells, replacing parietal and chief cells, and that can evolve after 1 year into pseudointestinal metaplasia composed of enterocyte-like cells characterized by an absorptive intestinal cell morphology in the upper portion of metaplastic glands. 9,19,20 In noninfected mouse stomachs, both LATS2-and YAP1-nuclear positive cells were restricted to the isthmus areas, as in human beings.…”

Gastric Cancer: A Stem Cell Disease?

“…E-cadherin expression is lost in most difuse-type gastric carcinomas, but E-cadherin loss alone is not suicient to initiate difuse-type gastric cancer in mice [40]. Loss of the tight junction protein IQGAP1 is also insuicient to induce difuse-type gastric carcinoma in transgenic mice after challenge with Helicobacter infection, as it indeed promotes intestinal-type carcinogenesis [41]. To try to reproduce the difuse-type gastric cancer, some authors infected Mist1;CreERT2;Cdh1 lox/lox mice with H. felis to induce chronic inlammation.…”

“…In vivo, the expansion of the compartment of CD44 + stem cells at the isthmus in the corpus and at the base of the glands in the antro-pyloric region is associated with the expression of mesenchymal markers in the context of H. pylori-associated gastritis, metaplasia, and dysplasia, in humans and in wild-type mice [23,36,41]. We recently showed that invalidation of iqgap1, a partner of E-cadherin at the cell/cell junctions, increased EMT both in vitro and in vivo, promoted H. felis-and H. pylori-induced regenerative hyperplasia expressing CD44 and mesenchymal markers, and accelerated and worsened metaplasia and dysplasia development, reinforcing the causal link between EMT and emergence of CSC-like cells [41].…”

Deletion and overexpression of the scaffolding protein IQGAP1 promotes HCC

“…Furthermore, in vivo studies demonstrate that increased IQGAP1 expression can promote tumor growth, indicating that IQGAP1 could be an effective molecular target for HCC [15][16][17]. Yet, other studies revealed that deletion of IQGAP1 in cancer cells and/or stromal cells can also enhance tumorigenesis by modulating transforming growth factor (TGF) signaling [18,19] and adherens junction stability [20].…”