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

PLOS ONE, Dec 2019

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.

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

November All-Trans Retinoic Acid-Induced Deficiency of the Wnt/β-Catenin Pathway Enhances Hepatic Carcinoma Stem Cell Differentiation Xinfeng Zhu 0 1 Wenxue Wang 0 1 Xia Zhang 0 1 Jianhua Bai 0 1 Gang Chen 0 1 Li Li 0 1 Meizhang Li 0 1 0 1 Affiliated Calmette Hospital of Kunming Medical University , Kunming, Yunnan Province, 650011 , P. R. China , 2 Laboratory of Biochemistry and Molecular Biology, School of Life Sciences, Yunnan University , Kunming, Yunnan Province, 650091 , P. R. China 1 Editor: Michael Schubert, Laboratoire de Biologie du Développement de Villefranche-sur-Mer , FRANCE Retinoic acid (RA) is an important biological signal that directly differentiates cells during embryonic development and tumorigenesis. However, the molecular mechanism of RAmediated 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 ATRAmediated treatment of hepatic cancer patients. - OPEN ACCESS Data Availability Statement: All relevant data are within the paper and its Supporting Information files. 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 Introduction Cancer stem cells (CSCs) represent a small but unique population of cancer cells that can sustain their self-renewal and multipotentiality. These cells are also considered cancer-initiating cells (CICs) because their tumorigenic potency allows CSCs/CICs to form de novo tumors [ 1– 2 ]. Clinical studies suggest that CSCs/CICs are resistant to traditional chemo- or radio-therapies due to their specialized microenvironments [ 3–4 ]. It has been proposed that both microenvironment-providing signals and their intracellular molecule transductions are essential for protecting and maintaining CSCs/CICs. Several important pathways such as Notch, Hedgehog and Wnt have been identified in the maintenance or differentiation of CSCs/CICs (5). Liver cancer is one of the most common and lethal cancers worldwide [ 5–6 ]. Unfortunately, clinical therapies for liver cancer are still not available due to the heterogeneous nature of the cellular components within the tumors [5]. In hepatocellular carcinoma (HCC), cell membrane proteins such as CD133, CD13, CD90, EpCAM and CD44 have been widely applied to isolate 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. Competing Interests: The authors have declared that no competing interests exist. Abbreviations: RA, retinoic acid; ATRA, all-trans retinoic acid; CSCs, cancer stem cells; CICs, cancerinitiating cells; hCSCs, hepatic cancer stem cells; HCC, hepatocellular carcinoma; RDH, retinol dehydrogenases; ADH, alcohol dehydrogenases; RALDH, retinaldehyde dehydrogenases; DOC, docetaxel; RAREs, retinoic acid elements. different types of hepatic cancer stem cells (hCSCs) [ 7–13 ]. These hCSCs have demonstrated similar resistance to anti-cancer drugs [ 10,14 ]. Wnt/β-catenin has been traditionally considered the diff (...truncated)


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Xinfeng Zhu, Wenxue Wang, Xia Zhang, Jianhua Bai, Gang Chen, Li Li, Meizhang Li. All-Trans Retinoic Acid-Induced Deficiency of the Wnt/β-Catenin Pathway Enhances Hepatic Carcinoma Stem Cell Differentiation, PLOS ONE, 2015, Volume 10, Issue 11, DOI: 10.1371/journal.pone.0143255