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Mécanismes De Régulation Post-Transcriptionnelle De L'expression Des Mucines Par La Galectine-3

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Mécanismes De Régulation Post-Transcriptionnelle De L'expression Des Mucines Par La Galectine-3 UNIVERSITE DU DROIT ET DE LA SANTE – LILLE II THESE DE DOCTORAT D’UNIVERSITE Pour l’obtention du titre de DOCTEUR DE L’UNIVERSITE DU DROIT ET DE LA SANTE – LILLE II Discipline : Sciences de la Vie et de la Santé Présentée par Lucie COPPIN ___________________________________________________________________ Mécanismes de régulation post-transcriptionnelle de l’expression des mucines par la galectine-3 ___________________________________________________________________ Thèse dirigée par Monsieur le Professeur Pascal PIGNY Soutenue le 12 juin 2017 Membres du jury : Président Madame le Professeur Nicole PORCHET Rapporteurs Madame le Docteur Stéfania MILLEVOI Monsieur le Professeur Pascal REBOUL Examinateurs Madame le Docteur Delphine DELACOUR Monsieur le Professeur Hervé PUY Directeur de Thèse Monsieur le Professeur Pascal PIGNY Ce travail de thèse a été effectué au sein de l’équipe « Mucines, différenciation et cancérogenèse épithéliales » de l’UMR-S 1172 Inserm - Université Lille - CHRU de Lille Directrice d’équipe : Madame le Docteur Isabelle Van Seuningen sous la direction scientifique de Monsieur le Professeur Pascal Pigny Remerciements Je remercie Madame le Professeur Nicole Porchet pour l’honneur qu’elle me fait de présider ce jury ; Je tiens à remercier Madame le Docteur Stéfania Millevoi et Monsieur le Professeur Pascal Reboul d’avoir accepté d’être rapporteurs de cette thèse ; J’exprime également toute ma reconnaissance à Madame le Docteur Delphine Delacour, à Monsieur le Professeur Hervé Puy et à Monsieur le Professeur Pascal Pigny pour avoir accepté de juger ce travail. Remerciements Je tiens à remercier : Monsieur le Docteur Luc Buée, directeur de l'UMR-S 1172 et Monsieur le Professeur Pierre Formstecher, ancien directeur du Centre (ex UMR n°837) pour m'avoir accueillie au sein du Centre de Recherche Jean-Pierre Aubert où j'ai effectué mon Master 2 Recherche puis ma thèse d’Université ; Madame le Docteur Isabelle Van Seuningen qui m'a accueillie au sein de son équipe ; Monsieur le Professeur Pascal Pigny pour m'avoir encadrée pendant cette thèse ; Madame le Professeur Nicole Porchet pour son soutien, son aide et ses précieux conseils ; Madame le Professeur Marie-Pierre Buisine pour son accueil dans le secteur d’oncologie au centre de Biologie-Pathologie-Génétique du CHRU de Lille ; Mesdames les Docteurs Audrey Vincent, Florence Renaud et Julie Leclerc pour leur aide et leurs conseils scientifiques ; Messieurs les Docteurs Nicolas Jonckheere et Mickael Perrais ainsi que Mesdames les Docteurs Bernadette Neve et Guillemette Huet pour les remarques pertinentes sur le sujet ; Madame le Professeur Emmanuelle Leteurtre pour son expertise d’anatomopathologiste sur le sujet ; Madame Céline Schulz pour ses conseils, sa présence et son amitié ; Madame Marie-Paule Ducourouble pour ses conseils techniques et son soutien tout au long de ses années ; Mesdames Belinda Dûchene et Brigitte Hémon pour leur aide technique ; L’ensemble des collaborateurs extérieurs, les bioinformaticiens et ingénieurs du centre de Biologie Pathologie qui ont participé à ce travail ; Les membres de l’équipe d’oncologie moléculaire du centre de Biologie-Pathologie- Génétique ainsi que Madame le Docteur Marie-Françoise Odou pour leur accueil au centre de Biologie Pathologie, leur gentillesse et leur aide ; L’ensemble des membres actuels et anciens membres de l’équipe IVS que j’ai rencontré au cours de ces 7 années : Nicolas, Johann, Emilie, Audrey, Romain, Matthieu, François, Remerciements Fatima, Mehdi, Marjolaine, Nihad, Solange, Kelly, Mouloud et tous les autres pour les moments agréables partagés avec eux ; Ma famille et plus spécialement mes parents pour leur soutien et confiance tout au long de ces années ; Johan pour son soutien sans faille surtout ces derniers mois et ma petite Margaux pour ses jolis sourires. Remerciements Je remercie : Le Centre Hospitalier Régional Universitaire de Lille, La Région Hauts de France, Le SIRIC ONCOLille, La Ligue Nationale Contre le Cancer, L’Université de Lille 2, Pour leur soutien financier qui a permis la réalisation de ces travaux. Valorisation des travaux Les travaux exposés dans ce mémoire et auxquels j’ai participé ont fait l’objet des publications et communications suivantes : Articles scientifiques publiés “Galectin-3 is a non-classic RNA binding protein that stabilizes the mucin MUC4 mRNA in the cytoplasm of cancer cells” Coppin L, Vincent A, Frénois F, Duchêne B, Lahdaoui F, Stechly L, Renaud F, Villenet C, van Seuningen I, Leteurtre E, Dion J, Grandjean C, Poirier F, Figeac M, Delacour D, Porchet N, Pigny P. Sci Rep. 2017;7:43927. doi: 10.1038/srep43927 “CA-125, but not galectin-3, complements CA 19-9 for discriminating ductal adenocarcinoma versus non-malignant pancreatic diseases” Coppin L, Benomar K, Corfiotti F, Cattan S, Renaud F, Lapere C, Leteurtre E, Vantyghem MC, Truant S, Pigny P. Pancreatology. 2016; 16:115-20 Articles scientifiques issus de collaborations pendant la thèse “The serrated neoplasia pathway of colorectal tumors: Identification of MUC5AC hypomethylation as an early marker of polyps with malignant potential” Renaud F, Mariette C, Vincent A, Wacrenier A, Maunoury V, Leclerc J, Coppin L, Crépin M, Van Seuningen I, Leteurtre E, Buisine MP. Int J Cancer. 2016; 138:1472-81 “MUC1 expression in papillary thyroid carcinoma is associated with BRAF mutation and lymph node metastasis; the latter is the most important risk factor of relapse” Renaud F, Gnemmi V, Devos P, Aubert S, Crepin M, Coppin L, Ramdane N, Bouchindhomme B, Boidein M, Van Seuningen I, Do Cao C, Pattou F, Carnaille B, Pigny P, Wemeau JL, Leteurtre E. Thyroid. 2014; 24: 1375-84 Valorisation des travaux Communications orales “Galectin-3 interacts with large exon mucin transcripts and prevents MUC4 mRNA decay in pancreatic cancer cells” Lucie Coppin, Fredéric Frénois, Fatima Lahdaoui, Laurence Stechly, Florence Renaud, Evelyne Crème, Claudine Grutzmacher, Emmanuelle Leteurtre, Isabelle Van Seuningen, Martin Figeac, Nicole Porchet & Pascal Pigny Journée des doctorants, Inserm, Lille, janvier 2015 “Post-transcriptionnal regulation of mucins expression by galectin-3 in cancer” Lucie Coppin, Frédéric Frénois, Fatima Lahdaoui, Laurence Stechly, Florence Renaud, Evelyne Crème, Claudine Grutzmacher, Emmanuelle Leteurtre, Isabelle Van seuningen, Martin Figeac, Nicole Porchet & Pascal Pigny Journée lilloise des doctorants en cancérologie, Lille, Juin 2014 Communications par affiche “Identification of a new function for galectin-3 : control of mucin mRNAs metabolism in cancer » Lucie Coppin, Audrey Vincent, Frédéric Frénois, Belinda Duchêne, Fatima Lahdaoui, Laurence Stechly, Florence Renaud, Céline Villenet, Isabelle van Seuningen, Emmanuelle Leteurtre, Johann Dion, Cyrille Grandjean, Françoise Poirier, Martin Figeac, Delphine Delacour, Nicole Porchet & Pascal Pigny, Biochemical society Londres, 4-7 septembre 2016 “Galectin-3 interacts with large exons mucin transcripts and prevents MUC4 mRNA decay” Lucie Coppin, Frédéric Frénois, Fatima Lahdaoui, Laurence Stechly, Florence Renaud, Evelyne Crème, Claudine Grutzmacher, Emmanuelle Leteurtre, Isabelle Van seuningen, Martin Figeac, Nicole Porchet & Pascal Pigny Journée André Verbert, 11 septembre 2014 Valorisation des travaux “Galectin-3 regulates MUC1 and MUC4 expression : evidence for a new role of galectin- 3 in the control of mRNA stability » Lucie Coppin, Frédéric Frénois, Laurence Stechly, Fatima Lahdaoui, Martin Figeac, Evelyne Crème, Isabelle Van Seuningen, Nicole Porchet & Pascal Pigny, Journée Jeunes chercheurs Arc, 23-24 Octobre 2013 “Galectin-3 regulates MUC1 and MUC4 expression: Evidence for a new role of galectin- 3 in the control of mRNA stability” Lucie Coppin, Frédéric Frénois, Laurence Stechly, Fatima Lahdaoui, Martin Figeac, Evelyne Crème, Isabelle Van Seuningen, Nicole Porchet & Pascal Pigny EMBO symposium, Strasbourg, avril 2013 “Galectin-3 regulates MUC1 and MUC4 expression: Evidence for a new role of galectin- 3 in the control of mRNA stability” Lucie Coppin, Frédéric Frénois, Laurence Stechly, Fatima Lahdaoui, Martin Figeac, Evelyne Crème, Isabelle Van Seuningen, Nicole Porchet & Pascal Pigny Journée des doctorants, Mars 2013 “Galectin-3 regulates MUC1 and MUC4 expression: Evidence for a new role of galectin- 3 in the control of mRNA stability” Lucie Coppin, Frédéric Frénois, Laurence Stechly, Fatima Lahdaoui, Evelyne Crème, Isabelle Van Seuningen, Nicole Porchet & Pascal Pigny EMBO meeting, Nice, septembre 2012 “Rôle de la galectine-3 dans la régulation de l'expression des mucines membranaires MUC1 et MUC4” Lucie Coppin, Evelyne Crème, Isabelle Van Seuningen, Nicole Porchet & Pascal Pigny Cancéropôle Nord-Ouest, Deauville, mai 2012 Résumé/Summary Résumé/Summary Résumé/Summary L’adénocarcinome pancréatique canalaire s’accompagne d’une néoexpression de la mucine membranaire MUC4 et d’une surexpression des mucines membranaires MUC1 et MUC16. Ces O-glycoprotéines de haut poids moléculaire sont codées par des ARNm possédant des particularités inhabituelles par rapport aux autres transcrits humains, comme une longue demi-vie et une très grande taille. La galectine-3, une lectine endogène également surexprimée au cours du cancer pancréatique, exerce de très nombreuses fonctions biologiques, en particulier dans le domaine du trafic intracellulaire des glycoprotéines et de l’épissage des pré-ARNm. Cependant, l’implication de cette galectine à un autre niveau du cycle de vie des ARNm n’avait pas été explorée jusque-là dans la littérature. De précédents travaux du laboratoire
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