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[Hepatocellular Carcinoma Cells with Downregulated ZEB2 Become Resistant to Resveratrol by Concomitant Induction of

P Balcik-Ercin1, M Cetin1, I Yalim-Camci1

  • 1Department of Molecular Biology and Genetics, Laboratory of Molecular Oncology, Gebze Technical University, Gebze, Kocaeli, 41400 Turkey.

Molekuliarnaia Biologiia
|March 13, 2020
PubMed

Insights

Cancer stem cells (CSCs) in hepatocellular carcinoma (HCC) are linked to treatment resistance. This study found ZEB2 and ABCG2 expression interplay in HCC-CSCs, with resveratrol impacting CSC behavior and potentially overcoming resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Cancer stem cells (CSCs) drive hepatocellular carcinoma (HCC) progression, contributing to drug resistance, epithelial-mesenchymal transition (EMT), and relapse.
  • ZEB1 and ZEB2 are key EMT transcription factors implicated in CSC phenotypes.
  • ABCG2 is a transporter protein often overexpressed in CSCs, conferring multidrug resistance.

Purpose of the Study:

  • To investigate the expression profiles of ZEB1, ZEB2, and ABCG2 in HCC-CSCs.
  • To explore the role of the EMT promoter ZEB2 in HCC-CSCs treated with resveratrol.
  • To elucidate the relationship between ZEB family transcription factors, ABCG2, and resveratrol's effects on HCC-CSCs.

Main Methods:

  • Isolation and characterization of CD133+/CD44+ HCC-CSCs from the PLC/PRF/5 cell line.
  • Analysis of ZEB1, ZEB2, and ABCG2 transcript expression.
  • ZEB2 knockdown experiments in SNU398 cell clones.
  • Treatment of HCC cells with resveratrol and assessment of proliferation, cell cycle, and apoptosis.

Main Results:

  • An inverse correlation was observed between ZEB1/ZEB2 and ABCG2 levels in HCC-CSCs and ZEB2-knockdown cells.
  • Resveratrol treatment significantly reduced cell viability and induced cell cycle arrest in a ZEB2-independent manner.
  • Resveratrol-treated cells with low ZEB2 levels exhibited resistance to apoptosis.

Conclusions:

  • The interplay between ABCG2 expression and ZEB family EMT transcription factors may establish CSC-like phenotypes in HCC cells.
  • These findings suggest a potential mechanism for resveratrol resistance in HCC, highlighting the role of ZEB2 and ABCG2.
  • Targeting ZEB factors and ABCG2 could be a therapeutic strategy to overcome CSC-mediated resistance in HCC.
Keywords:
ABCG2ZEB2cancer stem cellsdrug resistanceepithelial-to-mesenchymal transitionhepatocellular carcinomaresveratrol

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