Grb14 inhibition triggers insulin-induced mouse hepatocyte proliferation and is associated with hepatocellular carcinoma.
- 1Inserm, U1016, Institut Cochin, Paris, France.
- 2CNRS, UMR8104, Paris, France.
- 3Université Paris Descartes, Sorbonne Paris Cité, France.
- 4Department of Physiology, University of Lausanne, Lausanne, CH-1015, Switzerland.
- 5Center for Integrative Genomics, University of Lausanne, Lausanne, CH-1015, Switzerland.
- 6UMR IRD 242, UPEC, CNRS 7618, UPMC 113, INRA 1392, Paris7 113, Institut d’Ecologie et des Sciences de l’Environnement de Paris, 93140, Bondy, France.
- 7Sorbonne Universités, Paris, France.
- 8Institut National de la Santé et de la Recherche Médicale, Paris, France.
- 9APHP, Hôpital La Pitié Salpêtrière, Service d’Hépato-Gastroentérologie, F-75013, Paris, France.
- 10Sorbonne Universités, UPMC Univ Paris 06, INSERM, Centre de Recherche Saint-Antoine (CRSA), F-75012, Paris, France.
- 11APHP, Hôpital La Pitié-Salpêtrière, Service de Chirurgie Hépatobiliaire et Transplantation, F-75013, Paris, France.
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 Grb14 is an inhibitor of insulin receptor (IR) catalytic activity, highly expressed in the liver. To study its involvement in hepatocyte proliferation we specifically inhibited its liver expression using an shRNA strategy in mice. Enhanced insulin signaling upon Grb14 downregulation (Grb14i) 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 downregulation and insulin signaling blockade using pharmacological approaches as well as genetic mouse models demonstrated that Grb14i-mediated hepatocyte division involved IR activation and was mediated by the mTORC1-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 HCC was investigated. This revealed a highly significant and frequent decrease in GRB14 expression in hepatic tumors when compared to adjacent nontumoral parenchyma, 60% of the tumors exhibiting 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. This article is protected by copyright. All rights reserved.
© 2016 by the American Association for the Study of Liver Diseases.
E2F1; IR-A/IR-B; S6K; adenoviral shRNA; insulin signaling