All-Trans Retinoic Acid-Induced Deficiency of the Wnt/β-Catenin Pathway Enhances Hepatic Carcinoma Stem Cell Differentiation

PLoS One. 2015 Nov 16;10(11):e0143255. doi: 10.1371/journal.pone.0143255. eCollection 2015.

Abstract

Retinoic acid (RA) is an important biological signal that directly differentiates cells during embryonic development and tumorigenesis. However, the molecular mechanism of RA-mediated differentiation in hepatic cancer stem cells (hCSCs) is not well understood. In this study, we found that mRNA expressions of RA-biosynthesis-related dehydrogenases were highly expressed in hepatocellular carcinoma. All-trans retinoic acid (ATRA) differentiated hCSCs through inhibiting the function of β-catenin in vitro. ATRA also inhibited the function of PI3K-AKT and enhanced GSK-3β-dependent degradation of phosphorylated β-catenin. Furthermore, ATRA and β-catenin silencing both increased hCSC sensitivity to docetaxel treatment. Our results suggest that targeting β-catenin will provide extra benefits for ATRA-mediated treatment of hepatic cancer patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AC133 Antigen
  • Antigens, CD / metabolism
  • Apoptosis
  • Cell Differentiation / drug effects*
  • Cell Line, Tumor
  • Docetaxel
  • Glycoproteins / metabolism
  • Hep G2 Cells
  • Humans
  • Immunohistochemistry
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Neoplastic Stem Cells / cytology
  • Neoplastic Stem Cells / metabolism
  • Oxidoreductases / metabolism
  • Peptides / metabolism
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Real-Time Polymerase Chain Reaction
  • Taxoids / pharmacology
  • Tretinoin / pharmacology*
  • Wnt Signaling Pathway / drug effects
  • beta Catenin / antagonists & inhibitors
  • beta Catenin / genetics
  • beta Catenin / metabolism

Substances

  • AC133 Antigen
  • Antigens, CD
  • Glycoproteins
  • Peptides
  • RNA, Small Interfering
  • Taxoids
  • beta Catenin
  • Docetaxel
  • Tretinoin
  • Oxidoreductases

Grants and funding

Yunnan Province New Academic Talent Award 2014 (No. YN201418), study design, data collection and analysis, decision to publish, and preparation of the manuscript. Yunnan Province Science and Technology Agency Researching Program of Basic and Applied Sciences (No. 2013FZ292), study design, decision to publish, and preparation of the manuscript. National Natural Science Foundation of China (No. 81271330), http://www.nsfc.gov.cn/, study design, data collection and analysis, decision to publish, and preparation of the manuscript. National Natural Science Foundation of China (No. 31160237), http://www.nsfc.gov.cn/, study design, data collection and analysis, decision to publish, and preparation of the manuscript. National Natural Science Foundation of China No. 31260276), http://www.nsfc.gov.cn/, study design, data collection and analysis, decision to publish, and preparation of the manuscript. Yunnan Province Science and Technology Innovation Team (No. 2011CI123), http://www.ynstc.gov.cn/, study design, data collection and analysis, decision to publish, and preparation of the manuscript. Talent Program of Yunnan Province (No. W8110305), http://www.ynstc.gov.cn/ study design, data collection and analysis, decision to publish, and preparation of the manuscript. Foundation of School of Life Sciences of Yunnan University (No. 2012S301), http://www.ynusky.ynu.edu.cn/, study design, data collection and analysis, decision to publish, and preparation of the manuscript. Natural Science Foundation of Yunnan Province (No. 2011BC003), http://www.ynstc.gov.cn/, study design, data collection and analysis, decision to publish, and preparation of the manuscript.