Identification of microRNAs specific for epithelial cell adhesion molecule-positive tumor cells in hepatocellular carcinoma.
Identification of microRNAs specific for epithelial cell adhesion molecule-positive tumor cells in hepatocellular carcinoma.
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DOI：
10.1002/hep.27886
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发表时间：
2015-09
期刊：
影响因子：
--
通讯作者：
Wang XW
中科院分区：
文献类型：
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作者：
Ji J;Zheng X;Forgues M;Yamashita T;Wauthier EL;Reid LM;Wen X;Song Y;Wei JS;Khan J;Thorgeirsson SS;Wang XW
针对癌症干细胞(CSCs)的治疗方法在消除癌症负担方面前景光明。然而，正常干细胞很可能成为靶点，因为它们与CSCs相似。已证实EpCAM是正常肝干细胞的生物标志物，EpCAM+AFP+肝细胞癌细胞具有丰富的肝CSCs。我们试图确定肝干细胞中是否存在正常肝干细胞中不表达的特定miRNAs。我们对从两个原发性肝癌标本以及两个胎肝和三个健康成人肝脏供体中分离的EpCAM+和相应的EpCAM−细胞的miRNA转录组进行了配对比较。我们发现miR-150、miR-155和miR-223在EpCAM+肝癌细胞中优先高表达，进一步证实了这一点。在292名肝细胞癌患者的队列中，通过miRNA和信使核糖核酸图谱鉴定，他们的基因替代与患者的预后有关。我们进一步证明miR155在EpCAM+肝癌细胞中的表达高于相应的EpCAM−肝癌细胞、富含正常肝脏祖细胞的胎儿肝脏和富含成熟肝细胞的正常成人肝脏。抑制miR-155导致肝癌细胞中EpCAM+的比例降低，并减少肝癌细胞在体外的集落形成、迁移和侵袭。已识别的miR-155靶点水平的降低预示着肝细胞癌患者总生存期和复发时间的缩短。结论：在EpCAM+肝癌细胞中，miR-155水平显著升高，可能成为消除人肝癌中EpCAM+CSC群体的分子靶点。
Therapies that target cancer stem cells (CSCs) hold promise in eliminating cancer burden. However, normal stem cells are likely to be targeted due to their similarities to CSCs. It is established that EpCAM is a biomarker for normal hepatic stem cells and EpCAM+AFP+ hepatocellular carcinoma (HCC) cells have enriched hepatic CSCs. We sought to determine if specific miRNAs exist in hepatic CSCs that are not expressed in normal hepatic stem cells. We performed a pair-wised comparison of the miRNA transcriptome of EpCAM+ and corresponding EpCAM− cells isolated from two primary HCC specimens, as well as from two fetal livers and three healthy adult liver donors via small RNA deep sequencing. We found that miR-150, miR-155 and miR-223 were preferentially highly expressed in EpCAM+ HCC cells, which was further validated. Their gene surrogates, identified using miRNA and mRNA profiling in a cohort of 292 HCC patients, were associated with patient prognosis. We further demonstrated that miR-155 was highly expressed in EpCAM+ HCC cells compared to corresponding EpCAM− HCC cells, fetal livers with enriched normal hepatic progenitors, and normal adult livers with enriched mature hepatocytes. Suppressing miR-155 resulted in a decreased EpCAM+ fraction in HCC cells and reduced HCC cell colony formation, migration and invasion in vitro. The reduced levels of identified miR-155 targets predicted the shortened overall survival and time to recurrence of HCC patients. Conclusion: MiR-155 was highly elevated in EpCAM+ HCC cells and might serve as a molecular target to eradicate the EpCAM+ CSC population in human HCCs.