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

• Published in: PloS one Vol. 10; no. 11; p. e0143255
• Main Authors: Zhu, Xinfeng, Wang, Wenxue, Zhang, Xia, Bai, Jianhua, Chen, Gang, Li, Li, Li, Meizhang
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 16.11.2015; Public Library of Science (PLoS)
• Subjects: 1-Phosphatidylinositol 3-kinase; AC133 Antigen; Acids; AKT protein; Antigens, CD - metabolism; Apoptosis; beta Catenin - antagonists & inhibitors; beta Catenin - genetics; beta Catenin - metabolism; Biochemistry; Biosynthesis; Cancer; Cancer therapies; Cell culture; Cell cycle; Cell differentiation; Cell Differentiation - drug effects; Cell Line, Tumor; Dehydrogenases; Differentiation (biology); Docetaxel; Embryogenesis; Embryonic growth stage; Glycoproteins - metabolism; Hep G2 Cells; Hepatocellular carcinoma; Humans; Immunoglobulins; Immunohistochemistry; Kinases; Laboratories; Leukemia; Life sciences; Liver cancer; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Molecular biology; mRNA; Neoplastic Stem Cells - cytology; Neoplastic Stem Cells - metabolism; Oxidoreductases - metabolism; Peptides - metabolism; Phosphorylation; Proteins; Real-Time Polymerase Chain Reaction; Retinoic acid; RNA Interference; RNA, Small Interfering - metabolism; Stem cells; Taxoids - pharmacology; Tretinoin - pharmacology; Tumorigenesis; Tumors; Wnt protein; Wnt Signaling Pathway - drug effects; β-Catenin; United States > US; China; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0143255

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.