Identification of microRNA-181 by genome-wide screening as a critical player in EpCAM-positive hepatic cancer stem cells.
Identification of microRNA-181 by genome-wide screening as a critical player in EpCAM-positive hepatic cancer stem cells.
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DOI：
10.1002/hep.22989
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发表时间：
2009-08
期刊：
影响因子：
13.5
通讯作者：
Wang, Xin Wei
中科院分区：
文献类型：
--
作者：
Ji, Junfang;Yamashita, Taro;Budhu, Anuradha;Forgues, Marshonna;Jia, Hu-Liang;Li, Cuiling;Deng, Chuxia;Wauthier, Elaine;Reid, Lola M.;Ye, Qing-Hai;Qin, Lun-Xiu;Yang, Wen;Wang, Hong-Yang;Tang, Zhao-You;Groce, Carlo M.;Wang, Xin Wei
微小RNA（microRNAs，miRNAs）是一类内源性小分子非编码RNA，其调控基因表达，与肿瘤发生密切相关。肝细胞癌（HCC）是最常见的肝癌类型，其临床结局和生物学活性具有异质性。最近，我们已经从AFP+肿瘤中鉴定出具有癌症干/祖细胞特征的高度侵袭性EpCAM + HCC细胞的亚群，即，在体内自我更新、分化和引发侵袭性肿瘤的能力。在这里，使用基于全球微阵列的microRNA分析方法，然后用定量逆转录聚合酶链反应进行验证，我们已经证明了保守的miR-181家族成员在EpCAM + AFP + HCC和从AFP+肿瘤分离的EpCAM + HCC细胞中上调。此外，miR-181家族成员在胚胎肝和分离的肝干细胞中高度表达。重要的是，miR-181的抑制导致EpCAM + HCC细胞数量和肿瘤起始能力的降低，而HCC细胞中的外源性miR-181表达导致EpCAM + HCC细胞的富集。我们已经发现miR-181可以直接靶向分化的肝转录调节因子（即，CDX2和GATA 6）和wnt/β-连环蛋白信号传导抑制剂（即，NLK）。总而言之，我们的结果定义了miR-181与人EpCAM+肝癌干细胞/祖细胞之间的新型调节联系，并意味着miR-181的分子靶向可以根除HCC。
MicroRNAs (miRNAs) are endogenous small non-coding RNAs that regulate gene expression with functional links to tumorigenesis. Hepatocellular carcinoma (HCC) is the most common type of liver cancer and it is heterogeneous in clinical outcomes and biological activities. Recently, we have identified a subset of highly invasive EpCAM+ HCC cells from AFP+ tumors with cancer stem/progenitor cell features, i.e., the abilities to self-renew, differentiate and initiate aggressive tumors in vivo. Here, using a global microarray-based microRNA profiling approach followed by validation with quantitative reverse transcription polymerase chain reaction, we have demonstrated that conserved miR-181 family members were upregulated in EpCAM+AFP+ HCCs and in EpCAM+ HCC cells isolated from AFP+ tumors. Moreover, miR-181 family members were highly expressed in embryonic livers and in isolated hepatic stem cells. Importantly, inhibition of miR-181 led to a reduction in EpCAM+ HCC cell quantity and tumor initiating ability, while exogenous miR-181 expression in HCC cells resulted in an enrichment of EpCAM+ HCC cells. We have found that miR-181 could directly target hepatic transcriptional regulators of differentiation (i.e., CDX2 and GATA6) and an inhibitor of wnt/β-catenin signaling (i.e., NLK). Taken together, our results define a novel regulatory link between miR-181s and human EpCAM+ liver cancer stem/progenitor cells and imply that molecular targeting of miR-181 may eradicate HCC.
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