Ribosome biogenesis is increased in hepatocellular carcinoma and represents a potential therapeutic target.

Globally, liver cancer is the sixth most prevalent cancer type and the third leading cause of cancer-related deaths, making the need for improved treatment evident. We conducted a pan-cancer tissue microarray analysis to identify cancer types with upregulated ribosome biogenesis, potentially suitable for treatment with nucleolar-targeting compounds. Our screening identified liver cancer as a potential candidate. Gene expression analysis confirmed upregulation of nucleolar factors facilitating ribosome biogenesis that correlated with poor prognosis. In hepatocellular carcinoma (HCC) cell lines, constituting around 80% of liver cancer cases, we confirmed the upregulation of the nucleolar proteins Treacle, UBF, and Fibrillarin, involved in transcription and processing of ribosomal RNA (rRNA). Measurements of rRNA also confirmed increased nucleolar activity. We treated the HCC cell lines with nucleolar-targeting compounds and observed increased sensitivity in the HCC cell lines. Notably, nucleolar targeting compounds demonstrated a broader therapeutic window than that observed for Sorafenib, a clinically approved targeted therapy. Furthermore, we investigated how nucleolar factors change during HCC stages and found a progressive increase in Treacle and Fibrillarin in advanced stages of HCC. Our results demonstrate aberrant nucleolar activity in HCC and propose targeting ribosome biogenesis as a therapeutic strategy to improve HCC patient outcomes.