The Hippo Kinase LATS2 Controls Helicobacter pylori-Induced Epithelial-Mesenchymal Transition and Intestinal Metaplasia in Gastric Mucosa
| Autor: | Silvia Molina-Castro, Alban Giese, Christine Varon, Philippe Lehours, Pierre Dubus, Julie Giraud, Camille Tiffon, Francis Mégraud, Emilie Bessède, Hélène Boeuf, Elodie Sifré, Geneviève Belleannée, Cathy Staedel |
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| Přispěvatelé: | Varon, Christine, Bordeaux Research In Translational Oncology [Bordeaux] (BaRITOn), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Bioingénierie tissulaire (BIOTIS), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Acides Nucléiques : Régulations Naturelle et Artificielle (ARNA), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS) |
| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine [SDV]Life Sciences [q-bio] Cell Cycle Proteins Mice CDX2 caudal-type homeobox protein 2 0302 clinical medicine KRT7 keratin 7 RT-qPCR reverse-transcription quantitative polymerase chain reaction IAP intestinal alkaline phosphatase Original Research Aged 80 and over VGLL4 vestigial-like family member 4 YAP1 Transdifferentiation Gastroenterology siControl small interference RNA Control Intestinal metaplasia mRNA messenger RNA 3. Good health Gene Expression Regulation Neoplastic CagA [SDV] Life Sciences [q-bio] Editorial medicine.anatomical_structure Hippo signaling Host-Pathogen Interactions LATS2 large tumor suppressor 2 Long-Acting Thyroid Stimulator Female ZEB1 Zinc finger E-box-binding homeobox 1 030211 gastroenterology & hepatology Signal Transduction Epithelial-Mesenchymal Transition cagPAI cytotoxin-associated gene A-Pathogenicity Island NF-κB nuclear factor-κB Protein Serine-Threonine Kinases Adenocarcinoma Biology Helicobacter Infections HPI Helicobacter pylori infection CTGF conective tissue growth factor Viral Proteins 03 medical and health sciences BMP1 bone morphogenic protein-1 HMLE human mammary epithelial cells Stomach Neoplasms Epithelial-to-Mesenchymal Transition medicine Gastric mucosa Animals Humans Hippo Signaling Pathway GC gastric adenocarcinoma Epithelial–mesenchymal transition Dancing lcsh:RC799-869 Aged Adaptor Proteins Signal Transducing Metaplasia Hippo signaling pathway TEAD transcriptional enhanced associated domain Helicobacter pylori Hepatology Tumor Suppressor Proteins Membrane Proteins YAP-Signaling Proteins MMP9 matrix metalloproteinase 9 Protective Factors MST1/2 Mammalian Ste20-like kinases 1/2 medicine.disease WT wild-type MUC2 mucin 2 030104 developmental biology Gastric Mucosa Cancer research lcsh:Diseases of the digestive system. Gastroenterology RPE1 retinal pigment epithelial cells Precancerous Conditions Ca-Mg 1 mmol/L CaCl2 and 1 mmol/L MgCl2 EMT epithelial-to-mesenchymal transition Transcription Factors |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology Cellular and Molecular Gastroenterology and Hepatology, 2020, 9 (2), pp.257-276. ⟨10.1016/j.jcmgh.2019.10.007⟩ Cellular and Molecular Gastroenterology and Hepatology 9(2) Kérwá Universidad de Costa Rica instacron:UCR Cellular and Molecular Gastroenterology and Hepatology, Philadelphia, PA : American Gastroenterological Association, [2015]-, 2020, 9 (2), pp.257-276. ⟨10.1016/j.jcmgh.2019.10.007⟩ Cellular and Molecular Gastroenterology and Hepatology, Vol 9, Iss 2, Pp 257-276 (2020) |
| ISSN: | 2352-345X |
| Popis: | Background & Aims 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. Methods 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. Results 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. Conclusions 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. Graphical abstract |
| Databáze: | OpenAIRE |
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