Hepatitis C virus core protein targets 4E-BP1 expression and phosphorylation and potentiates Myc-induced liver carcinogenesis in transgenic mice
Résumé
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.
Mots clés
complementary DNA
core protein
in vivo study
in vitro study
human cell
human
Huh-7 cell line
host cell
liver carcinogenesis
liver cell
mouse
intracellular signaling
Hermes antigen
initiation factor 4E
initiation factor 4E binding protein 1
insulin receptor
membrane protein
mitogen activated protein kinase p38
Myc protein
protein MTA1
unclassified drug
vimentin
animal cell
animal experiment
animal model
animal tissue
Article
cancer growth
controlled study
gene amplification
Hepatitis C virus
hepatocellular carcinoma cell line
nonhuman
phosphoproteomics
protein expression
protein phosphorylation
protein transport
quantitative analysis
RNA translation
signal transduction
transcription regulation
transgenic mouse
tumor growth
upregulation
validation process
HCV core
4E-BP1 phosphorylation
hepatocellular carcinoma
SILAC
Origine | Publication financée par une institution |
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