Y-box binding protein-1 promotes hepatocellular carcinoma-initiating cell progression and tumorigenesis via Wnt/β-catenin pathway.
Y-box binding protein-1 promotes hepatocellular carcinoma-initiating cell progression and tumorigenesis via Wnt/β-catenin pathway.
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DOI：
10.18632/oncotarget.13733
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发表时间：
2017-01-10
期刊：
影响因子：
--
通讯作者：
Chern E
中科院分区：
文献类型：
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作者：
Chao HM;Huang HX;Chang PH;Tseng KC;Miyajima A;Chern E
Y盒结合蛋白-1（YB-1）是一种多效性分子，其结合DNA以在转录水平上调节核中的基因，并结合RNA以调节细胞质中的基因翻译。在我们以前的研究中，YB-1也被表征为一种胎肝蛋白，它调节肝细胞的成熟，并在肝再生过程中上调。此外，YB-1已显示在人肝细胞癌（HCC）中表达。然而，YB-1在HCC中的作用仍不清楚。在这里，我们的目的是描述YB-1在HCC中的作用。基于流体动力学基因递送在HCC中的功能丧失和在小鼠肝脏中的功能获得的结果，YB-1在体外和体内促进肝细胞增殖。YB-1还参与肝癌细胞的增殖、迁移和耐药性。极有限稀释法成球分析和癌起始细胞标志物分析结果也表明YB-1维持了肝癌起始细胞群。YB-1还诱导上皮-间质转化和干细胞相关基因的表达。YB-1基因的敲除抑制了Wnt配体和β-catenin的表达，破坏了Wnt/β-catenin信号通路，减少了HCC起始细胞的数量。此外，YB-1显示核定位，特别是在肝癌起始细胞，EpCAM+细胞或球细胞。我们的研究结果表明，YB-1是肝癌发生的关键因素，并维持肝癌起始细胞群。
Y-box binding protein-1 (YB-1) is a pleiotropic molecule that binds DNA to regulate genes on a transcriptional level in the nucleus and binds RNA to modulate gene translation in the cytoplasm. In our previous studies, YB-1 was also characterized as a fetal hepatic protein that regulates the maturation of hepatocytes and is upregulated during liver regeneration. Moreover, YB-1 has been shown to be expressed in human hepatocellular carcinoma (HCC). However, the role of YB-1 in HCC remains unclear. Here, we aimed to characterize the role of YB-1 in HCC. Based on the results of loss-of-function in HCC and gain-of-function in mice liver using hydrodynamic gene delivery, YB-1 promoted hepatic cells proliferation in vitro and in vivo. YB-1 was also involved in HCC cell proliferation, migration, and drug-resistance. The results of extreme limiting dilution sphere forming analysis and cancer initiating cell marker analysis were also shown that YB-1 maintained HCC initiating cells population. YB-1 also induced the epithelial-mesenchymal transition and stemness-related gene expression. Knockdown of YB-1 suppressed the expression of Wnt ligands and β-catenin, impaired Wnt/β-catenin signaling pathway and reduced the numbers of HCC initiating cells. Moreover, YB-1 displayed nuclear localization particularly in the HCC initiating cells, the EpCAM+ cells or sphere cells. Our findings suggested that YB-1 was a key factor in HCC tumorigenesis and maintained the HCC initiating cell population.