TY  - JOUR
A1  - Bojkova, Denisa
A1  - Westhaus, Sandra
A1  - Costa, Rui
A1  - Timmer, Lejla
A1  - Funkenberg, Nora
A1  - Korencak, Marek
A1  - Streeck, Hendrik
A1  - Vondran, Florian
A1  - Bröring, Ruth
A1  - Heinrichs, Stefan
A1  - Lang, Karl Sebastian
A1  - Ciesek, Sandra
T1  - Sofosbuvir activates EGFR-Dependent pathways in hepatoma cells with implications for liver-related pathological processes
T2  - Cells
N2  - 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.
KW  - direct-acting antivirals
KW  - HCV
KW  - HCC recurrence
KW  - nucleotide analogue
KW  - EGFR pathway
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/55297
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-552976
SN  - 2073-4409
N1  - © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
VL  - 9
IS  - 4, art. 1003
SP  - 1
EP  - 18
PB  - MDPI
CY  - Basel
ER  -