Oncotarget

Research Papers:

Hepatitis C virus core protein targets 4E-BP1 expression and phosphorylation and potentiates Myc-induced liver carcinogenesis in transgenic mice

Cosette Abdallah, Charlène Lejamtel, Nassima Benzoubir, Serena Battaglia, Nazha Sidahmed-Adrar, Christophe Desterke, Matthieu Lemasson, Arielle R. Rosenberg, Didier Samuel, Christian Bréchot, Delphine Pflieger, François Le Naour _ and Marie-Françoise Bourgeade

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Oncotarget. 2017; 8:56228-56242. https://doi.org/10.18632/oncotarget.17280

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Abstract

Cosette Abdallah1,2,8,9, Charlène Lejamtel1,2,9, Nassima Benzoubir1,2,9, Serena Battaglia1,2, Nazha Sidahmed-Adrar1,2,9, Christophe Desterke3,4,9, Matthieu Lemasson10, Arielle R. Rosenberg10, Didier Samuel1,2,5,9, Christian Bréchot6, Delphine Pflieger7,8,11, François Le Naour1,2,3,4,9 and Marie-Françoise Bourgeade1,2,5,9

1Inserm, Unité 1193, Villejuif, F-94800, France

2University Paris-Sud, UMR-S 1193, Villejuif, F-94800, France

3Inserm, UMS33, Villejuif, F-94800, France

4Univ Paris-Sud, UMS33, Villejuif, F-94800, France

5AP-HP Hôpital Paul Brousse, Centre Hépatobiliaire, Villejuif, F-94800, France

6University Paris-Sud, UMS33, Villejuif, F-94800, France

7CNRS, LAMBE, UMR 8587, Université d’Evry Val d’Essonne, Evry, F-91000, France

8Université Evry Val d’Essonne (UEVE), LAMBE, Evry, F-91000, France

9DHU Hepatinov, Villejuif, F-94800, France

10Université Paris Descartes, EA4474, Paris, F-75014, France

11Present address: EDyP, Laboratoire Biologie à Grande Echelle, Institut de Biosciences et Biotechnologies de Grenoble, CEA, Grenoble, F-38054, France

Correspondence to:

François Le Naour, email: [email protected]

Keywords: HCV core, 4E-BP1 phosphorylation, hepatocellular carcinoma, phosphoproteomics, SILAC

Received: December 07, 2015     Accepted: March 27, 2017     Published: April 20, 2017

ABSTRACT

Hepatitis C virus (HCV) is a leading cause of liver diseases including the development of hepatocellular carcinoma (HCC). Particularly, core protein has been involved in HCV-related liver pathologies. However, the impact of HCV core on signaling pathways supporting the genesis of HCC remains largely elusive. To decipher the host cell signaling pathways involved in the oncogenic potential of HCV core, a global quantitative phosphoproteomic approach was carried out. This study shed light on novel differentially phosphorylated proteins, in particular several components involved in translation. Among the eukaryotic initiation factors that govern the translational machinery, 4E-BP1 represents a master regulator of protein synthesis that is associated with the development and progression of cancers due to its ability to increase protein expression of oncogenic pathways. Enhanced levels of 4E-BP1 in non-modified and phosphorylated forms were validated in human hepatoma cells and in mouse primary hepatocytes expressing HCV core, in the livers of HCV core transgenic mice as well as in HCV-infected human primary hepatocytes. The contribution of HCV core in carcinogenesis and the status of 4E-BP1 expression and phosphorylation were studied in HCV core/Myc double transgenic mice. HCV core increased the levels of 4E-BP1 expression and phosphorylation and significantly accelerated the onset of Myc-induced tumorigenesis in these double transgenic mice. These results reveal a novel function of HCV core in liver carcinogenesis potentiation. They position 4E-BP1 as a tumor-specific target of HCV core and support the involvement of the 4E-BP1/eIF4E axis in hepatocarcinogenesis.


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