Beta-Hydroxyisovaleryl-Shikonin Eradicates Epithelial Cell Adhesion Molecule-Positive Liver Cancer Stem Cells by...

Area of Science:

• Hepatocellular Carcinoma Research
• Cancer Stem Cell Biology
• Drug Discovery

Background:

• Cancer stem cells (CSCs) drive hepatocellular carcinoma (HCC) development, chemoresistance, and metastasis.
• Epithelial cell adhesion molecule-positive (EpCAM+) liver CSCs, activated by Wnt signaling, are key drivers of HCC.
• Dihydrouracil pyrophosphatase (dUTPase) is implicated in chemoresistance to 5-fluorouracil.

Purpose of the Study:

• To evaluate dUTPase expression in EpCAM+ HCC cells.
• To assess the effect of beta-hydroxyisovaleryl-shikonin (β-HIVS) on HCC CSCs.
• To identify potential therapeutic targets for liver CSCs.

Main Methods:

• Expression analysis of EpCAM and dUTPase in liver tissues and HCC cells.
• Flow cytometry sorting of EpCAM+ CSCs.
• In vitro and in vivo experiments using Wnt signaling activator BIO and β-HIVS.

Main Results:

• EpCAM and dUTPase were found in fetal hepatoblasts, adult hepatic progenitors, and a subset of HCC cells.
• EpCAM+ CSCs exhibited higher nuclear dUTPase accumulation compared to EpCAM-negative cells.
• β-HIVS treatment reduced dUTPase expression, decreased EpCAM+ CSC population, and suppressed tumor growth.

Conclusions:

• dUTPase is a potential therapeutic target for eradicating 5-fluorouracil-resistant liver CSCs.
• β-HIVS shows promise as a small molecule inhibitor targeting EpCAM+ liver CSCs by decreasing dUTPase expression.