Abstract
Direct acting antivirals (DAAs) revolutionized the therapy of chronic hepatitis C infection. However, unexpected high recurrence rates of hepatocellular carcinoma (HCC) after DAA treatment became an issue in patients with advanced cirrhosis and fibrosis. In this study, we aimed to investigate an impact of DAA treatment on the molecular changes related to HCC development and progression in hepatoma cell lines and primary human hepatocytes. We found that treatment with sofosbuvir (SOF), a backbone of DAA therapy, caused an increase in EGFR expression and phosphorylation. As a result, enhanced translocation of EGFR into the nucleus and transactivation of factors associated with cell cycle progression, B-MYB and Cyclin D1, was detected. Serine/threonine kinase profiling identified additional pathways, especially the MAPK pathway, also activated during SOF treatment. Importantly, the blocking of EGFR kinase activity by erlotinib during SOF treatment prevented all downstream events. Altogether, our findings suggest that SOF may have an impact on pathological processes in the liver via the induction of EGFR signaling. Notably, zidovudine, another nucleoside analogue, exerted a similar cell phenotype, suggesting that the observed effects may be induced by additional members of this drug class.
Highlights
With approximately 71 million chronically infected patients, hepatitis C virus (HCV) represents one of the leading etiologies for the development of hepatocellular carcinoma (HCC) worldwide [1,2].Cells 2020, 9, 1003; doi:10.3390/cells9041003 www.mdpi.com/journal/cellsRecently introduced direct acting antivirals (DAAs) have dramatically improved the treatment of chronic HCV infection
Since SOF belongs to a broad group of nucleotide analogues (NAs), we further investigated if the altered phenotype in hepatoma cells can be detected with other nucleoside analogues
Despite data supporting an improvement of liver function after Direct acting antivirals (DAAs) therapy [5], several other reports presented findings questioning the impact of IFN-free treatment on the risk of HCC development [6,7]
Summary
With approximately 71 million chronically infected patients, hepatitis C virus (HCV) represents one of the leading etiologies for the development of hepatocellular carcinoma (HCC) worldwide [1,2].Cells 2020, 9, 1003; doi:10.3390/cells9041003 www.mdpi.com/journal/cellsRecently introduced direct acting antivirals (DAAs) have dramatically improved the treatment of chronic HCV infection. DAAs allow a sustained virological response to be achieved in more than 95% of patients without major side effects [3,4,5]. Even though these new drugs represent a huge breakthrough for a majority of chronically HCV-infected patients, the benefit of interferon-(IFN)-free therapies for a subset of patients has recently been questioned by several groups. Two studies showed an increase in the recurrence rates of HCC (27% and 29%) after DAA treatment in patients who had been successfully treated for HCC prior to the start of DAA therapy and were disease free for different periods of time [6,7]. The recurrent tumors exhibited signs of microvascular invasion and were characterized by a more aggressive phenotype with faster progression to advanced stages [8]
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