miR-19 targeting of GSK3beta mediates sulforaphane suppression of lung cancer stem cells.
miR-19 targeting of GSK3beta mediates sulforaphane suppression of lung cancer stem cells.
复制标题
miR-19 靶向 GSK3beta 介导萝卜硫素抑制肺癌干细胞。
DOI：
10.1016/j.jnutbio.2017.02.020
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发表时间：
2017
影响因子：
5.6
通讯作者：
Han Hongyu
中科院分区：
文献类型：
--
作者：
Zhu Jianyun;Wang Shijia;Chen Yue;Li Xiaoting;Jiang Ye;Yang Xue;Li Yuan;Wang Xiaoqian;Meng Yu;Zhu Mingming;Ma Xiao;Huang Cong;Wu Rui;Xie Chunfeng;Geng Shanshan;Wu Jieshu;Zhong Caiyun;Han Hongyu
肿瘤干细胞(CSCs)在癌症的发生发展中起着核心作用。规范的Wnt/β-Catenin途径对于维持CSCs的茎是至关重要的。来自饮食化合物的植物化学物质具有抗肿瘤干细胞的特性，已被认为是预防和治疗许多癌症的有前途的治疗剂。到目前为止，miR-19作为一种关键的致癌miRNA，在调节Wnt/β-catenin途径和肺肿瘤干细胞中的参与和功能还不清楚。同时，萝卜硫素(SFN)对肺CSCs的作用也尚不清楚。在此，我们报道了肺肿瘤干细胞上调miR-19a和miR-19b的表达。MiR-19a/19b的过表达增强了肿瘤球体的形成能力，上调了肺肿瘤干细胞标志物的表达，增加了肺肿瘤干细胞Wnt/β-catenin通路的激活和β-catenin/Tcf的转录活性。相反，miR-19的下调抑制了肺CSCs的活性和Wnt/β-catenin的激活。我们进一步揭示了miR-19通过直接靶向Wnt/β-catenin途径的关键负调制子GSK3β来激活该途径。此外，我们还发现三七总皂苷通过抑制miR-19和Wnt/β-catenin途径对肺间充质干细胞具有抑制作用。综上所述，这些数据说明了miR-19在调节肺CSCs特性中的作用以及miR-19/GSK3β/β-catenin轴在SFN干预肺CSCs中的作用。这项研究的发现可能为肺CSCs调控的分子机制及其靶向干预提供重要的新见解。
Cancer stem cells (CSCs) play a central role in the development of cancer. The canonical Wnt/β-catenin pathway is critical for maintaining stemness of CSCs. Phytochemicals from dietary compounds possess anti-CSCs properties and have been characterized as promising therapeutic agents for the prevention and treatment of many cancers. To date, the involvement and function of miR-19, a key oncogenic miRNA, in regulating Wnt/β-catenin pathway and lung CSCs has not been defined. Meanwhile, the effect of sulforaphane (SFN) on lung CSCs also remains to be elucidated. Here, we reported that lung CSCs up-regulated miR-19a and miR-19b expression. Overexpression of miR-19a/19b enhanced the ability of tumorsphere formation, up-regulated the expression of lung CSCs markers, increased Wnt/β-catenin pathway activation and β-catenin/TCF transcriptional activity in lung CSCs. In contrary, down-regulation of miR-19 suppressed lung CSCs activity and Wnt/β-catenin activation. We further revealed that miR-19 activated Wnt/β-catenin pathway by directly targeting GSK3β, the key negative modulator of this pathway. Moreover, we showed that SFN exhibited inhibitory effect on lung CSCs through suppressing miR-19 and Wnt/β-catenin pathway. Taken together, these data illustrate the role of miR-19 in regulating lung CSCs traits and miR-19/GSK3β/β-catenin axis in SFN intervention of lung CSCs. Findings from this study could provide important new insights into the molecular mechanisms of lung CSCs regulation as well as its target intervention.