1. The Hippo Kinase LATS2 Controls Helicobacter pylori-Induced Epithelial-Mesenchymal Transition and Intestinal Metaplasia in Gastric Mucosa
- Author
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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, 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), and 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)
- Subjects
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 - Abstract
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
- Published
- 2020
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