全反式维甲酸诱导的Wnt/β-连环蛋白信号通路缺陷增强肝癌干细胞分化。
All-Trans Retinoic Acid-Induced Deficiency of the Wnt/β-Catenin Pathway Enhances Hepatic Carcinoma Stem Cell Differentiation.
作者信息
Zhu Xinfeng, Wang Wenxue, Zhang Xia, Bai Jianhua, Chen Gang, Li Li, Li Meizhang
机构信息
Affiliated Calmette Hospital of Kunming Medical University, Kunming, Yunnan Province, 650011, P. R. China.
Laboratory of Biochemistry and Molecular Biology, School of Life Sciences, Yunnan University, Kunming, Yunnan Province, 650091, P. R. China.
出版信息
PLoS One. 2015 Nov 16;10(11):e0143255. doi: 10.1371/journal.pone.0143255. eCollection 2015.
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.
维甲酸（RA）是一种重要的生物信号，在胚胎发育和肿瘤发生过程中可直接诱导细胞分化。然而，RA介导肝癌干细胞（hCSCs）分化的分子机制尚不清楚。在本研究中，我们发现RA生物合成相关脱氢酶的mRNA表达在肝细胞癌中高表达。全反式维甲酸（ATRA）在体外通过抑制β-连环蛋白的功能来诱导hCSCs分化。ATRA还抑制PI3K-AKT的功能，并增强GSK-3β依赖的磷酸化β-连环蛋白的降解。此外，ATRA和β-连环蛋白沉默均增加了hCSCs对多西他赛治疗的敏感性。我们的结果表明，靶向β-连环蛋白将为ATRA介导的肝癌患者治疗带来额外益处。
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