Growth factor receptor binding protein 14 inhibition triggers insulin‐induced mouse hepatocyte proliferation and is associated with hepatocellular carcinoma

• DOI: 10.1002/hep.28972
• Publication Date: 2016-12-17T14:07:29Z
• Authors: Lucille Morzyglod; Michèle Caüzac; Lucie Popineau; Pierre‐Damien Den...; Lluis Fajas; Bruno Ragazzon; Véronique Fauveau; Julien Planchais; Mireille Vasseur‐...; Laetitia Fartoux; Olivier Scatton; Olivier Rosmorduc; Sandra Guilmeau; Catherine Postic; Chantal Desdouets; Christèle Desbois...; Anne‐Françoise Bu...
• Keywords: Hepatocyte nuclear factors

Metabolic diseases such as obesity and type 2 diabetes are recognized 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) an inhibitor insulin catalytic activity, highly expressed the liver. To study its involvement hepatocyte proliferation, we specifically inhibited liver expression using short hairpin RNA strategy mice. Enhanced signaling upon Grb14 inhibition was accompanied by transient induction S-phase entrance quiescent hepatocytes, indicating that potent repressor cell division. proliferation Grb14-deficient hepatocytes cell-autonomous it also observed primary cultures. Combined down-regulation blockade pharmacological approaches well genetic mouse models demonstrated inhibition-mediated division activation mediated mechanistic target rapamycin complex 1-S6K pathway transcription E2F1. In order determine potential dysregulation GRB14 gene human pathophysiology, collection 85 HCCs investigated. This revealed significant frequent decrease hepatic tumors when compared adjacent nontumoral parenchyma, with 60% exhibiting reduced mRNA level.Our establishes physiological mitogenic action further supports associated HCC. (Hepatology 2017;65:1352-1368).