title: Growth factor receptor binding protein 14 inhibition triggers insulin-induced mouse hepatocyte proliferation and is associated with hepatocellular carcinoma.
abstract: Metabolic diseases such as obesity and type 2 diabetes are recognized as independent risk factors for hepatocellular carcinoma (HCC). Hyperinsulinemia, a hallmark of these pathologies, is suspected to be involved in HCC development. The molecular adapter growth factor receptor binding protein 14 (Grb14) is an inhibitor of insulin receptor catalytic activity, highly expressed in the liver. To study its involvement in hepatocyte proliferation, we specifically inhibited its liver expression using a short hairpin RNA strategy in mice. Enhanced insulin signaling upon Grb14 inhibition was accompanied by a transient induction of S-phase entrance by quiescent hepatocytes, indicating that Grb14 is a potent repressor of cell division. The proliferation of Grb14-deficient hepatocytes was cell-autonomous as it was also observed in primary cell cultures. Combined Grb14 down-regulation and insulin signaling blockade using pharmacological approaches as well as genetic mouse models demonstrated that Grb14 inhibition-mediated hepatocyte division involved insulin receptor activation and was mediated by the mechanistic target of rapamycin complex 1-S6K pathway and the transcription factor E2F1. In order to determine a potential dysregulation in GRB14 gene expression in human pathophysiology, a collection of 85 human HCCs was investigated. This revealed a highly significant and frequent decrease in GRB14 expression in hepatic tumors when compared to adjacent nontumoral parenchyma, with 60% of the tumors exhibiting a reduced Grb14 mRNA level.
  
  
  
  Our study establishes Grb14 as a physiological repressor of insulin mitogenic action in the liver and further supports that dysregulation of insulin signaling is associated with HCC. (Hepatology 2017;65:1352-1368).
authors.affiliation: Inserm, U1016, Institut Cochin, Paris, France.|CNRS, UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, France.
authors.forename: Lucille
authors.initials: L
authors.lastname: Morzyglod
authors.affiliation: Inserm, U1016, Institut Cochin, Paris, France.|CNRS, UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, France.
authors.forename: Michèle
authors.initials: M
authors.lastname: Caüzac
authors.affiliation: Inserm, U1016, Institut Cochin, Paris, France.|CNRS, UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Popineau
authors.affiliation: Department of Physiology, University of Lausanne, Lausanne, Switzerland.|Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Pierre-Damien
authors.initials: PD
authors.lastname: Denechaud
authors.affiliation: Department of Physiology, University of Lausanne, Lausanne, Switzerland.|Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Lluis
authors.initials: L
authors.lastname: Fajas
authors.affiliation: Inserm, U1016, Institut Cochin, Paris, France.|CNRS, UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Ragazzon
authors.affiliation: Inserm, U1016, Institut Cochin, Paris, France.|CNRS, UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Fauveau
authors.affiliation: Inserm, U1016, Institut Cochin, Paris, France.|CNRS, UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Planchais
authors.affiliation: UMR IRD 242, UPEC, CNRS 7618, UPMC 113, INRA 1392, Paris, and Institut d'Ecologie et des Sciences de l'Environnement de Paris, Bondy, France.|Sorbonne Universités, Paris, France.|Institut National de la Santé et de la Recherche Médicale, Paris, France.
authors.forename: Mireille
authors.initials: M
authors.lastname: Vasseur-Cognet
authors.affiliation: APHP, Hôpital La Pitié Salpêtrière, Service d'Hépato-Gastroentérologie, Paris, France.|Sorbonne Universités, UPMC Université Paris 06, INSERM, Centre de Recherche Saint-Antoine, Paris, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Fartoux
authors.affiliation: Sorbonne Universités, UPMC Université Paris 06, INSERM, Centre de Recherche Saint-Antoine, Paris, France.|APHP, Hôpital La Pitié-Salpêtrière, Service de Chirurgie Hépatobiliaire et Transplantation, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Scatton
authors.affiliation: APHP, Hôpital La Pitié Salpêtrière, Service d'Hépato-Gastroentérologie, Paris, France.|Sorbonne Universités, UPMC Université Paris 06, INSERM, Centre de Recherche Saint-Antoine, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Rosmorduc
authors.affiliation: Inserm, U1016, Institut Cochin, Paris, France.|CNRS, UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Guilmeau
authors.affiliation: Inserm, U1016, Institut Cochin, Paris, France.|CNRS, UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Postic
authors.affiliation: Inserm, U1016, Institut Cochin, Paris, France.|CNRS, UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Desdouets
authors.affiliation: Sorbonne Universités, UPMC Université Paris 06, INSERM, Centre de Recherche Saint-Antoine, Paris, France.
authors.forename: Christèle
authors.initials: C
authors.lastname: Desbois-Mouthon
authors.affiliation: Inserm, U1016, Institut Cochin, Paris, France.|CNRS, UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, France.
authors.forename: Anne-Françoise
authors.initials: AF
authors.lastname: Burnol
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000453:epidemiology / Q000378:metabolism / Q000503:physiopathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D015536:Down-Regulation; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000453:epidemiology / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011897:Random Allocation; D011972:Receptor, Insulin / Q000378:metabolism*; D012680:Sensitivity and Specificity
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C099655:GRB14 protein, human; D011972:Receptor, Insulin