miR-589-5p inhibits MAP3K8 and suppresses CD90(+) cancer stem cells in hepatocellular carcinoma.
miR-589-5p inhibits MAP3K8 and suppresses CD90(+) cancer stem cells in hepatocellular carcinoma.
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miR-589-5p 抑制 MAP3K8 并抑制肝细胞癌中的 CD90( ) 癌症干细胞
DOI：
10.1186/s13046-016-0452-6
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发表时间：
2016-11-11
期刊：
影响因子：
--
通讯作者：
Li X
中科院分区：
文献类型：
--
作者：
Zhang X;Jiang P;Shuai L;Chen K;Li Z;Zhang Y;Jiang Y;Li X
肿瘤干细胞（cancer stem cells，CSCs）在肝细胞癌（hepatocellular carcinoma，HCC）的发生、发展过程中起着重要作用。微小RNA（miRNAs）在HCC中调节CD 133+和EpCAM+ CSC中起关键作用，尽管目前尚不清楚miRNAs是否调节HCC中的CD 90 + CSC。使用miRNA微阵列和定量实时PCR（qRT-PCR）分析CD 90+和CD 90- HCC细胞的miRNA谱。通过多能性相关基因的qRT-PCR和Western blot、克隆和球体形成试验、transwell迁移试验和裸鼠致瘤性试验来检测CSC特性。使用miR-589- 5 p模拟物转染在体外过表达miR-589- 5 p。分别采用免疫组化和qRT-PCR方法检测HCC组织中CD 90和miR-589- 5 p的表达。miR-589- 5 p和miR-33 b-5 p在CD 90+细胞中下调。miR-589- 5 p的过表达抑制了CD 90 + CSC的特征，如Oct 4、Sox 2和Nanog表达、形成细胞球的高可能性、高侵袭性和高致瘤性。荧光素酶报告基因分析表明，miR-589- 5 p直接与丝裂原活化蛋白激酶8（MAP 3 K8）mRNA的3 ′端非翻译区结合，外源性miR-589- 5 p下调MAP 3 K8的表达。此外，MAP 3 K8的siRNA抑制也抑制了CD 90 + CSC特征，即使在没有miR-589- 5 p过表达的情况下。在HCC组织中，miR-589- 5 p表达与CD 90表达呈负相关，高CD 90表达和低miR-589- 5 p表达与血管浸润和复发呈正相关，临床分析显示无病生存率和总生存率显著降低。在HCC中，miR-589- 5 p部分通过沉默MAP 3 K8下调CD 90 + CSC的干性特征。CD 90和miR-589- 5 p表达可预测HCC的预后，并可能成为HCC治疗的新分子靶点。本文的在线版本（doi：10.1186/s13046-016-0452-6）包含补充材料，可供授权用户使用。
Cancer stem cells (CSCs) are important in the tumorigenesis and progression of hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) play crucial roles regulating CD133+ and EpCAM+ CSCs in HCC, although it is unclear whether miRNAs regulate CD90+ CSCs in HCC. The miRNA profiles of CD90+ and CD90- HCC cells were analyzed using a miRNA microarray and quantitative real-time PCR (qRT-PCR). CSC characteristics were examined by qRT-PCR and Western blot of pluripotency-associated genes, clone and sphere formation assay, transwell migration assay, and nude mice tumorigenicity assay. miR-589-5p mimic transfection was used to overexpress miR-589-5p in vitro. The CD90 and miR-589-5p expressions of HCC samples were detected by immunohistochemistry and qRT-PCR, respectively. miR-589-5p and miR-33b-5p were down-regulated in CD90+ cells. Overexpression of miR-589-5p suppressed CD90+ CSC characteristics such as Oct4, Sox2 and Nanog expression, a high likelihood of forming cell spheres, high invasiveness and high tumorigenicity. Luciferase reporter assays demonstrated that miR-589-5p directly binds to the 3ˈ-untranslated region of mitogen-activated protein kinase kinase kinase 8 (MAP3K8) mRNA, and exogenous miR-589-5p down-regulated MAP3K8 expression. In addition, siRNA inhibition of MAP3K8 also suppressed CD90+ CSC characteristics, even in the absence of miR-589-5p overexpression. In HCC tissues, miR-589-5p expression was inversely correlated with CD90 expression, and high CD90 expression and low miR-589-5p expression were positively correlated with vascular invasion and recurrence and significantly decreased disease-free and overall survival by clinical analysis. In HCC, miR-589-5p down-regulates the stemness characteristics of CD90+ CSCs in part by silencing MAP3K8. CD90 and miR-589-5p expression predict HCC outcomes and might be novel molecular targets for HCC treatment. The online version of this article (doi:10.1186/s13046-016-0452-6) contains supplementary material, which is available to authorized users.
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