PBX3 is targeted by multiple miRNAs and is essential for liver tumour-initiating cells
PBX3 is targeted by multiple miRNAs and is essential for liver tumour-initiating cells
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PBX3 是多种 miRNA 的靶标，对于肝脏肿瘤起始细胞至关重要
DOI：
10.1038/ncomms9271
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发表时间：
2015-09-01
影响因子：
16.6
通讯作者：
Zhang, Zhiqian
中科院分区：
文献类型：
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作者：
Han, Haibo;Du, Yantao;Zhang, Zhiqian
肿瘤起始细胞（TIC）被认为是维持和更新完全建立的恶性肿瘤的持续力量;然而，负责这些特性的分子机制是难以捉摸的。我们以前证明电压门控钙通道α2δ1亚基标记肝细胞癌（HCC）TIC。在此我们直接证实α2δ1是HCC TIC表面标志物，并鉴定let-7 c、miR-200 b、miR-222和miR-424为α2δ1+HCC TIC的抑制因子。有趣的是，所有四种miRNAs协同靶向PBX 3，这对于TIC特性的获得和维持是足够和必要的。此外，PBX 3驱动一个必要的转录程序，激活对HCC TIC干性至关重要的基因的表达，包括CACNA 2D 1、EpCAM、SOX 2和NOTCH 3。CACNA 2D 1和PBX 3 mRNA的表达是HCC患者预后不良的预测指标。总的来说，我们的研究确定了一个控制HCC TIC表型转换的重要信号通路。
Tumour-initiating cells (TICs) are advocated to constitute the sustaining force to maintain and renew fully established malignancy; however, the molecular mechanisms responsible for these properties are elusive. We previously demonstrated that voltage-gated calcium channel α2δ1 subunit marks hepatocellular carcinoma (HCC) TICs. Here we confirm directly that α2δ1 is a HCC TIC surface marker, and identify let-7c, miR-200b, miR-222 and miR-424 as suppressors of α2δ1+HCC TICs. Interestingly, all the four miRNAs synergistically targetPBX3, which is sufficient and necessary for the acquisition and maintenance of TIC properties. Moreover, PBX3 drives an essential transcriptional programme, activating the expression of genes critical for HCC TIC stemness includingCACNA2D1, EpCAM,SOX2andNOTCH3. In addition, the expression ofCACNA2D1andPBX3mRNA is predictive of poor prognosis for HCC patients. Collectively, our study identifies an essential signalling pathway that controls the switch of HCC TIC phenotypes.