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

Gastric carcinoma is related mostly to CagA+-Helicobacter pylori infection, which disrupts the gastric mucosa turnover and elicits an epithelial-mesenchymal transition (EMT) and preneoplastic transdifferentiation. The tumor suppressor Hippo pathway controls stem cell homeostasis; its core, constituted by the large tumor suppressor 2 (LATS2) kinase and its substrate Yes-associated protein 1 (YAP1), was investigated in this context. Hippo, EMT, and intestinal metaplasia marker expression were investigated by transcriptomic and immunostaining analyses in human gastric AGS and MKN74 and nongastric immortalized RPE1 and HMLE epithelial cell lines challenged by H pylori, and on gastric tissues of infected patients and mice. LATS2 and YAP1 were silenced using small interfering RNAs. A transcriptional enhanced associated domain (TEAD) reporter assay was used. Cell proliferation and invasion were evaluated. LATS2 and YAP1 appear co-overexpressed in the infected mucosa, especially in gastritis and intestinal metaplasia. H pylori via CagA stimulates LATS2 and YAP1 in a coordinated biphasic pattern, characterized by an early transient YAP1 nuclear accumulation and stimulated YAP1/TEAD transcription, followed by nuclear LATS2 up-regulation leading to YAP1 phosphorylation and targeting for degradation. LATS2 and YAP1 reciprocally positively regulate each other's expression. Loss-of-function experiments showed that LATS2 restricts H pylori-induced EMT marker expression, invasion, and intestinal metaplasia, supporting a role of LATS2 in maintaining the epithelial phenotype of gastric cells and constraining H pylori-induced preneoplastic changes. H pylori infection engages a number of signaling cascades that alienate mucosa homeostasis, including the Hippo LATS2/YAP1/TEAD pathway. In the host-pathogen conflict, which generates an inflammatory environment and perturbations of the epithelial turnover and differentiation, Hippo signaling appears as a protective pathway, limiting the loss of gastric epithelial cell identity that precedes gastric carcinoma development.

Molina-Castro SE ，Tiffon C ，Giraud J ，Boeuf H ，Sifre E ，Giese A ，Belleannée G ，Lehours P ，Bessède E ，Mégraud F ，Dubus P ，Staedel C ，Varon C ... -  《Cellular and Molecular Gastroenterology and Hepatology》

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

Bessède E ，Molina S ，Acuña-Amador L ，Dubus P ，Staedel C ，Chambonnier L ，Buissonnière A ，Sifré E ，Giese A ，Bénéjat L ，Rousseau B ，Costet P ，Sacks DB ，Mégraud F ，Varon C ... -  《Oncotarget》

TAZ Controls Helicobacter pylori-Induced Epithelial-Mesenchymal Transition and Cancer Stem Cell-Like Invasive and Tumorigenic Properties.

Tiffon C ，Giraud J ，Molina-Castro SE ，Peru S ，Seeneevassen L ，Sifré E ，Staedel C ，Bessède E ，Dubus P ，Mégraud F ，Lehours P ，Martin OCB ，Varon C ... -  《Cells》

Effects of the hippo signaling pathway in human gastric cancer.

Zhou GX ，Li XY ，Zhang Q ，Zhao K ，Zhang CP ，Xue CH ，Yang K ，Tian ZB ... -  《-》

Cyclooxigenase-2 and osteopontin in gastric pre-neoplastic lesions in relation to H-pylori infection and grade of inflammation.

The association between Helicobacter-pylori-induced inflammation and gastric adenocarcinoma is well documented and it has been suggested that the pro-mitotic and apoptotic effect of Cyclooxygenase-2 and Osteopontin on the epithelial cells of the gastric mucosa may have a role in carcinogenesis of the gastric mucosa. The aim of this study was to determine the expression of Cyclooxygenase-2 and Osteopontin in normal gastric mucosa, mucosa with gastritis and gastric mucosa with intestinal metaplasia, in relation to Helicobacter-pylori infection and grade of inflammation. Immunohistochemistry was performed on 108 gastric biopsies in order to detect Cyclooxygenase-2 and Osteopontin expression. The intensity and percentage of staining were evaluated using the H-Score, and its association with grade of inflammation, Helicobacter pylori infection and intestinal metaplasia was determined. Expression of Cyclooxygenase-2 and Osteopontin was higher in gastric biopsies (values shown respectively) with Helicobacter-pylori infection (179.9/142.3), intestinal metaplasia (208.8/179.3) or higher grades of inflammation (190/135.7) in comparison to normal gastric mucosa (100.7/80) or mild grade of inflammation (128.4/128.4), (p<0.05).There is an overexpression of Cyclooxygenase-2 and Osteopontin in gastric mucosa with H. pylori infection, intestinal metaplasia and high grades of inflammation, suggesting a constant up-regulation of protein expression in response to the inflammatory process generated by a Helicobacter-pylori infection, leading to the development of intestinal metaplasia.

Benedetti I ，Hoyos J ，Barrios L 《-》