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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >Identification of microRNAs specific for epithelial cell adhesion molecule-positive tumor cells in hepatocellular carcinoma
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Identification of microRNAs specific for epithelial cell adhesion molecule-positive tumor cells in hepatocellular carcinoma

机译：肝细胞癌中上皮细胞粘附分子阳性肿瘤细胞特异的微小RNA的鉴定

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Therapies that target cancer stem cells (CSCs) hold promise in eliminating cancer burden. However, normal stem cells are likely to be targeted owing to their similarities to CSCs. It is established that epithelial cell adhesion molecule (EpCAM) is a biomarker for normal hepatic stem cells (HpSCs), and EpCAM(+)AFP(+) hepatocellular carcinoma (HCC) cells have enriched hepatic CSCs. We sought to determine whether specific microRNAs (miRNAs) exist in hepatic CSCs that are not expressed in normal HpSCs. We performed a pair-wise 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 by 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 messenger RNA 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 is highly elevated in EpCAM(+) HCC cells and might serve as a molecular target to eradicate the EpCAM(+) CSC population in human HCCs. (Hepatology 2015;62:829-840)
机译：靶向癌症干细胞（CSC）的疗法有望消除癌症负担。但是，由于正常干细胞与CSC相似，因此很可能成为靶向。已确定上皮细胞粘附分子（EpCAM）是正常肝干细胞（HpSCs）的生物标记，并且EpCAM（+）AFP（+）肝细胞癌（HCC）细胞具有丰富的肝CSC。我们试图确定是否在正常HpSCs中不表达的肝CSC中存在特定的microRNA（miRNA）。我们通过小RNA深度测序对从两个主要HCC标本以及两个胎儿肝脏和三个健康成人肝脏供体中分离出的EpCAM（+）和对应的EpCAM（-）细胞的miRNA转录组进行了成对比较。我们发现miR-150，miR-155和miR-223在EpCAM（+）HCC细胞中优先高表达，这得到了进一步验证。在292名HCC患者队列中使用miRNA和信使RNA分析法鉴定了他们的基因替代物，与患者的预后相关。我们进一步证明，与相应的EpCAM（-）HCC细胞，具有丰富的正常肝祖细胞的胎儿肝脏和具有丰富的成熟肝细胞的正常成人肝脏相比，miR-155在EpCAM（+）HCC细胞中高度表达。抑制miR-155导致HCC细胞中EpCAM（+）分数降低，并降低了HCC细胞集落的形成，迁移和体外侵袭。鉴定出的miR-155靶标水平降低，预示了肝癌患者的总体生存时间和复发时间缩短。结论：miR-155在EpCAM（+）HCC细胞中高度升高，可能作为根除人类HCC中EpCAM（+）CSC种群的分子靶标。 （肝病2015; 62：829-840）

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