Sorafenib-associated translation reprogramming in hepatocellular carcinoma cells

Area of Science:

• Molecular Biology
• Biochemistry
• Oncology

Background:

• Sorafenib (Sfb) is a multikinase inhibitor used for advanced hepatocellular carcinoma (HCC), modestly improving survival.
• Sfb inhibits protein synthesis initiation in cancer cells.
• The global impact of Sfb on mRNA translation in HCC remains unexplored.

Purpose of the Study:

• To investigate the genome-wide changes in mRNA translation following Sfb treatment in HCC cells.
• To identify specific genes and pathways affected by Sfb-induced translational reprogramming.
• To understand the mechanisms underlying Sfb's effect on translation and its implications for therapy.

Main Methods:

• Genome-wide polysome profiling analysis in Sfb-treated HCC cells.
• Correlation analysis of translation efficiency with mRNA cis-acting elements and protein factors (e.g., DAP5, ARE-binding proteins).
• Analysis of biological processes affected by Sfb-induced translational changes.

Main Results:

• Global translation is repressed by Sfb, but a subset of genes shows sustained or induced translation.
• Translational control is linked to mRNA cis-acting elements and specific RNA-binding proteins.
• Sfb treatment down-regulates translation of mitochondrial metabolism and collagen synthesis genes.
• Sfb up-regulates translation of pathways involved in cellular adaptation and stress response.

Conclusions:

• Sorafenib (Sfb) induces an adaptive translational reprogramming in hepatocellular carcinoma (HCC) cells.
• This reprogramming involves selective gene translation modulation, influenced by mRNA elements and RNA-binding proteins.
• Findings provide insights into Sfb's mechanism of action and suggest potential for novel combination therapies.