Sofosbuvir Activates EGFR-Dependent Pathways in Hepatoma Cells with Implications for Liver-Related Pathological...

Area of Science:

• Hepatology
• Oncology
• Molecular Biology

Background:

• Direct acting antivirals (DAAs) have transformed hepatitis C treatment.
• However, increased hepatocellular carcinoma (HCC) recurrence post-DAA therapy is a concern in advanced liver disease.
• The underlying molecular mechanisms remain unclear.

Purpose of the Study:

• To investigate the molecular impact of DAA treatment on HCC development.
• To explore the role of epidermal growth factor receptor (EGFR) signaling in DAA-induced effects.
• To identify potential therapeutic strategies to mitigate HCC recurrence.

Main Methods:

• Treatment of hepatoma cell lines and primary human hepatocytes with sofosbuvir (SOF).
• Analysis of EGFR expression, phosphorylation, and nuclear translocation.
• Assessment of cell cycle-related factors (B-MYB, Cyclin D1) and kinase pathway activation (MAPK).
• Inhibition studies using erlotinib to block EGFR activity.

Main Results:

• Sofosbuvir (SOF) treatment increased EGFR expression and phosphorylation.
• SOF induced EGFR nuclear translocation, leading to B-MYB and Cyclin D1 activation.
• The MAPK pathway was also activated by SOF.
• Erlotinib blocked SOF-induced downstream signaling events.
• Zidovudine showed similar effects, suggesting a class effect.

Conclusions:

• Sofosbuvir (SOF) may promote HCC development through EGFR signaling induction.
• EGFR pathway activation is a key mechanism linking SOF to cell cycle progression.
• Targeting EGFR signaling could be a strategy to prevent HCC recurrence after DAA treatment.
• Nucleoside analogues may share similar oncogenic potential.