Phenethyl isothiocyanate inhibits CD133+/CD90+ liver cancer stem cells by modulation of microRNA-214-β-catenin epigenome axis

Abstract

Hepatocellular carcinoma (HCC) represents one of the most prevalent and lethal type of malignancies around the globe. Despite the advancement in medical research and therapeutics development, HCC still remains a taunting challenge in clinical settings. Recent studies indicate that the presence of cancer stem cells (CSCs) may be the underlying factor for treatment failure, distant metastasis, and disease recurrence. Elevated stemness gene expression has been correlated to disease stage and poorer prognosis in HCC patients. Initially, we established that β-catenin is highly expressed in HCC clinical samples. We subsequently re-validated the idea that CD133+/CD90+ subpopulation cells exhibited CSCs properties including elevated stemness expression (β-catenin, Nanog, c-Myc, and Twist1), increased self-renewal capacity and metastatic potential. Using this cell model, we tested the potential anti-CSCs effects of phenethyl isothiocynanate (PEITC), a phytochemical isolated from cruciferous vegetables. Treatment of PEITC led to a decreased percentage of CD133+/CD90+ cells in both Huh7 and Sk-Hep1 cell lines. In addition, PEITC suppressed stemness gene expression, self-renewal ability, and metastatic potential in HCC CSCs. Mechanistically, PEITC conveyed its anti-CSCs effects via upregulating microRNA-214, a negative regulator of β-catenin. In conclusion, we provided evidence that PEITC could suppress HCC CSCs generation/maintenance. With further clinical testing, PEITC could be used either alone or in combination with currently available chemotherapeutic agents to achieve improved efficacy.