LncRNA HOTTIP modulates cancer stem cell properties in human pancreatic cancer by regulating HOXA9
LncRNA HOTTIP modulates cancer stem cell properties in human pancreatic cancer by regulating HOXA9
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LncRNA HOTTIP 通过调节 HOXA9 调节人胰腺癌中的癌症干细胞特性
DOI：
10.1016/j.canlet.2017.09.019
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发表时间：
2017-12-01
期刊：
影响因子：
9.7
通讯作者：
Chen, Rufu
中科院分区：
文献类型：
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作者：
Fu, Zhiqiang;Chen, Changhao;Chen, Rufu
我们先前的研究表明，长非编码RNA(Long Non-Coding RNA，LncRNA)热尖端在PDAC中高表达，并促进癌细胞进展和上皮向间充质转化(EMT)。大量研究表明，LncRNAs或EMT支持癌症干细胞。然而，HotIP在胰腺癌干细胞(PCSCs)中的作用尚不清楚。在此，我们评估了HotTip在PCSCs中的作用和机制。首先，我们分析了90例PDAC根治性切除术后HotTip的表达与总体或无病生存率的关系。HotTip高表达的患者比低表达的患者无病生存期和总生存期更短。激光捕获显微切割(LCM)检测热休克蛋白等lncRNAs在PCSCs和非PCSCs中的表达。HotTip在PCSCs中高表达。此外，体外分析表明，热尖改变会影响硬挺度，包括球形性、致瘤性、干细胞因子(LIN28、NANOG、OCT4和SOX2)和标志物(ALDH1、CD44和CD133)。机制上，HotIP通过与PCSCs中的WDR5结合，介导HOXA9增强Wnt/β-catenin途径。在体内的结果表明，HotTip或HOXA9的改变影响了茎的生长。我们的结果表明，HotTip/WDR5/HOXA9/WNT轴参与了PCSC的严厉，是PDAC潜在的治疗靶点。(C)2017年作者。爱思唯尔出版公司(Elsevier B.V.)
Our previous study demonstrated that long non-coding RNA (lncRNA) HOTTIP was maximally expressed in PDAC, and promoted cancer cell progression and epithelial to mesenchymal transition (EMT). Numerous studies indicated that lncRNAs or EMT supported cancer stem cells. However, the role of HOTTIP in pancreatic cancer stem cells (PCSCs) remains unclear. Here, we evaluated the role and mechanism of HOTTIP in PCSCs. First, we analyzed the relationship between HOTTIP expression and overall or disease-free survival in 90 patients with PDAC after radical resection. Patients with higher HOTTIP expression had shorter disease-free survival and overall survival than those with lower expression. Expression of HOTTIP and other lncRNAs was detected in PCSCs and non-PCSCs by laser capture microdissection (LCM). HOTTIP was highly expressed in PCSCs. In addition, in vitro assays showed that HOTTIP alterations affected sternness, including sphericity, tumorigenesis, and stem factors (LIN28, NANOG, OCT4, and SOX2) and markers (ALDH1, CD44, and CD133). Mechanistically, HOTTIP mediated HOXA9 to enhance the Wnt/beta-catenin pathway by binding to WDR5 in PCSCs. In vivo results showed that HOTTIP or HOXA9 alterations influenced stemness. Our results indicate that the HOTTIP/WDR5/HOXA9/Wnt axis contributes to PCSC sternness and is a potential therapeutic target for PDAC. (C) 2017 The Authors. Published by Elsevier B.V.