Twist2 promotes self-renewal of liver cancer stem-like cells by regulating CD24
Twist2 promotes self-renewal of liver cancer stem-like cells by regulating CD24
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Twist2通过调节CD24促进肝癌干细胞样细胞的自我更新
DOI：
10.1093/carcin/bgt364
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发表时间：
2014-03-01
期刊：
影响因子：
4.7
通讯作者：
Ouyang, Gaoliang
中科院分区：
文献类型：
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作者：
Liu, Allan Yi;Cai, Yao;Ouyang, Gaoliang
Twist2是一种高度保守的碱性螺旋-环-螺旋转录因子，在胚胎发育中起关键作用。最近的证据表明，Twist2的异常表达有助于肿瘤的进展，然而，Twist2在人肝细胞癌中的作用及其潜在机制尚不清楚。在这份报告中，我们证明了Twist2在人类肝细胞癌中过表达。我们发现，Twist2的异位表达可以诱导上皮间充质转化表型，增强细胞在体外的迁移、侵袭和集落形成能力，并促进体内肿瘤的生长。此外，我们还发现在Twist2转导的肝癌细胞中有较高比例的CD24肝癌干细胞。表达Twist2的细胞表现出干细胞标志物Bmi-1、Sox2、CD24和Nanog的表达增加，自我更新能力增强。在HepG2/Twist2细胞中，CD24基因的敲除降低了Sox2、pSTAT3和Nanog的水平，并逆转了Twist2异位表达诱导的肿瘤干细胞表型。此外，Twist2通过直接与CD24启动子中的E-box区结合来调控CD24的表达。因此，我们的数据表明，Twist2以CD24依赖的方式增强肝癌干细胞样细胞的自我更新。Twist2CD24STAT3Nanog通路可能在调节肝癌干细胞样细胞自我更新中发挥重要作用。Twist2-CD24信号通路的发现为靶向肝癌干细胞提供了一种潜在的治疗途径。
Twist2 is a highly conserved basic helix-loop-helix transcription factor that plays a critical role in embryogenesis. Recent evidence has revealed that aberrant Twist2 expression contributes to tumor progression; however, the role of Twist2 in human hepatocellular carcinoma (HCC) and its underlying mechanisms remain undefined. In this report, we demonstrate that Twist2 is overexpressed in human HCC tumors. We show that ectopic expression of Twist2 induces epithelialmesenchymal transition phenotypes, augments cell migration and invasion and colony-forming abilities in human HCC cells in vitro, and promotes tumor growth in vivo. Moreover, we found a higher percentage of CD24 liver cancer stem-like cells in Twist2-transduced HCC cells. Twist2-expressing cells exhibited an increased expression of stem cell markers Bmi-1, Sox2, CD24 and Nanog and an increased capacity for self-renewal. Knockdown of CD24 in HepG2/Twist2 cells decreased the levels of Sox2, pSTAT3 and Nanog, and reversed the cancer stem-like cell phenotypes induced by ectopic expression of Twist2. Furthermore, Twist2 regulated the CD24 expression by directly binding to the E-box region in CD24 promoter. Therefore, our data demonstrated that Twist2 augments liver cancer stem-like cell self-renewal in a CD24-dependent manner. Twist2CD24STAT3Nanog pathway may play a critical role in regulating liver cancer stem-like cell self-renewal. The identification of the Twist2-CD24 signaling pathway provides a potential therapeutic approach to target cancer stem cells in HCCs.