1. La déficience de USF1 favorise la dégradation de p53 au cours de l'infection par Helicobacter pylori et accélère la cancérogenèse gastrique
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Nicolas Mouchet, Margarita Camorlinga, Hilde De Reuse, Valérie Michel, Javier Torres, Julien Fernandes, Marie-Dominique Galibert, Lionel Costa, David Da Silva Barreira, Mario Milco D'Elios, Krysten Le Luel, Eliette Touati, Laurence Fiette, Sébastien Corre, Anne Danckaert, Grégory Jouvion, Jason Ziveri, Pathogenèse de Helicobacter - Helicobacter Pathogenesis, Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre de Ressources et de Recherche Technologique - Center for Technological Resources and Research (C2RT), Institut Pasteur [Paris], Pathogénie des infections systémiques (Inserm U1002), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neuropathologie expérimentale - Experimental neuropathology, Institut Pasteur [Paris]-Université Paris Descartes - Paris 5 (UPD5), AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Instituto Mexicano del Seguro Social [Mexico City, Mexico] (IMSS), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Institut Mutualiste de Montsouris (IMM), CHU Pontchaillou [Rennes], Université Paris Diderot, Ligue Contre le Cancer, Odyssey Reinsurance Company, FIS/IMSS/PROT/PRIO/13/027), Fondo de Investigacion en salud, IMSS, Mexico, West committee Ligue Nationale Contre le Cancer, UMS Biosit, We thank Sophie Vaulont (Institut Cochin, Paris, France) for Usf1-/- mice, Timothy C Wang (Columbia University, NY, USA) for providing us couples of INS-GAS mice and Joana Gomes and Celso Reis (I3S-IPATIMUP, Porto, Portugal) for MKN45 cells. We also thank Laurence Bernard-Touami and the Animal Housing ARCHE (UMS Biosit, https://biosit.univ-rennes1.fr, University of Rennes, France), and David Hardy and Magalie Tichit (Unit of Experimental Neuropathology, Institut Pasteur, Paris, France) for her technical help on the histology part and the UtechS Photonic BioImaging (Imagopole), C2RT, Institut Pasteur, supported by the French National Research Agency (France BioImaging, ANR-10–INSB–04, Investments for the Future), both as a part of the FranceBioImaging infrastructure., and ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010)
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0301 basic medicine ,Proteasome Endopeptidase Complex ,Carcinogenesis ,oncogenes ,DNA damage ,[SDV]Life Sciences [q-bio] ,Cell ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Context (language use) ,medicine.disease_cause ,Genomic Instability ,Helicobacter Infections ,Cell Line ,gastric cancer ,genetic instability ,helicobacter pylori infection ,Animals ,DNA Damage ,Humans ,Mice ,Tumor Suppressor Protein p53 ,Ubiquitination ,Upstream Stimulatory Factors ,Gastric Mucosa ,Helicobacter pylori ,Stomach Neoplasms ,03 medical and health sciences ,0302 clinical medicine ,In vivo ,medicine ,Chemistry ,Stomach ,Gastroenterology ,[SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology ,In vitro ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,Cytoplasm ,030220 oncology & carcinogenesis ,Cancer research ,Camptothecin ,medicine.drug - Abstract
ObjectiveHelicobacter pylori (Hp) is a major risk factor for gastric cancer (GC). Hp promotes DNA damage and proteasomal degradation of p53, the guardian of genome stability. Hp reduces the expression of the transcription factor USF1 shown to stabilise p53 in response to genotoxic stress. We investigated whether Hp-mediated USF1 deregulation impacts p53-response and consequently genetic instability. We also explored in vivo the role of USF1 in gastric carcinogenesis.DesignHuman gastric epithelial cell lines were infected with Hp7.13, exposed or not to a DNA-damaging agent camptothecin (CPT), to mimic a genetic instability context. We quantified the expression of USF1, p53 and their target genes, we determined their subcellular localisation by immunofluorescence and examined USF1/p53 interaction. Usf1-/- and INS-GAS mice were used to strengthen the findings in vivo and patient data examined for clinical relevance.ResultsIn vivo we revealed the dominant role of USF1 in protecting gastric cells against Hp-induced carcinogenesis and its impact on p53 levels. In vitro, Hp delocalises USF1 into foci close to cell membranes. Hp prevents USF1/p53 nuclear built up and relocates these complexes in the cytoplasm, thereby impairing their transcriptional function. Hp also inhibits CPT-induced USF1/p53 nuclear complexes, exacerbating CPT-dependent DNA damaging effects.ConclusionOur data reveal that the depletion of USF1 and its de-localisation in the vicinity of cell membranes are essential events associated to the genotoxic activity of Hp infection, thus promoting gastric carcinogenesis. These findings are also of clinical relevance, supporting USF1 expression as a potential marker of GC susceptibility.
- Published
- 2019
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