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.
Highlights
Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and the second most common cause of cancer-related deaths worldwide
The strategy exhibited the major advantage to allow simultaneously identification and accurate quantification of phosphorylated proteins under the different conditions. This state-of-the-art proteomic approach was applied to the cellular models in three independent SILAC experiments and led to the identification of 7 proteins down-phosphorylated and 24 proteins hyper-phosphorylated in Hepatitis C virus (HCV) core expressing cells (Table 1)
16 out of the 35 differentially phosphorylated peptides exhibited a modulation of phosphorylation within the (Ser/Thr)-Pro motif, broadly recognized as potential MAP kinase and mTORC1 target sites [14], indicating that the (Ser/Thr)-Pro motif is essential for dynamic signaling transduction in HCVcore-expressing cells [15]
Summary
Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and the second most common cause of cancer-related deaths worldwide. Hepatitis C Virus (HCV) infection is one of the major etiologies of HCC. Major progress in HCV therapy leads to envisage the eradication of HCV infection in a near future. These new treatments do not directly interfere with liver carcinogenesis and many patients already at the stage of HCV-induced cirrhosis will still develop HCC. There is accumulating evidence that there are common pathways and related mechanisms that likely account for viral and non-viral pathogenesis of cancers [2]. Elucidating the pathways implicated in the progression of HCV-induced liver disease and HCC is still an unmet need for developing novel therapeutic approaches
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