ICAM-1-Related Noncoding RNA in Cancer Stem Cells Maintains ICAM-1 Expression in Hepatocellular Carcinoma
ICAM-1-Related Noncoding RNA in Cancer Stem Cells Maintains ICAM-1 Expression in Hepatocellular Carcinoma
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DOI：
10.1158/1078-0432.ccr-14-3106
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发表时间：
2016-04-15
影响因子：
11.5
通讯作者：
Liu, Shanrong
中科院分区：
文献类型：
--
作者：
Guo, Weixing;Liu, Shupeng;Liu, Shanrong
目的：门静脉癌栓（PVTT）是肝细胞癌（HCC）的主要并发症，与患者的生存率密切相关。长链非编码RNA（lncRNA）有助于HCC转移，但lncRNA是否以及如何影响PVTT的发展仍不清楚。在本研究中，一种新的高表达lncRNA（ICAM-1相关，ICR）被确定在ICAM 1（-）肝癌干细胞（CSC）。实验设计：我们使用微阵列和生物信息学分析来鉴定差异表达的lncRNA。实时PCR和蛋白质印迹法用于评估细胞系和肿瘤中的基因表达。进行球体形成测定以研究体外肿瘤细胞的干细胞性质。结果：PVTT与相应的原发肿瘤相比，表达不同的lncRNA和mRNA，包括上调的lncRNA、ICR和ICAM-1。ICR通过RNA双链体的形成增加ICAM-1 mRNA的稳定性来调节ICAM-1的表达，从而调节ICAM-1（+）HCC细胞的CSC特性。Nanog可调节ICAM-1（+）HCC细胞中ICR的转录，原位抑制ICR可显著降低体内肿瘤中ICAM-1表达和ICAM-1（+）HCC细胞。此外，ICR和ICAM-1在肿瘤中的表达升高与PVTT的发展和不良的临床outcomes.Conclusions：我们的研究表明，ICR特异性调节CSC特性的ICAM-1（+）HCC细胞和ICR有助于PVTT的发展。因此，ICR可能是HCC治疗的一个有希望的靶点。(C)2015年AACR。
Purpose: Portal vein tumor thrombus (PVTT) is a major complication of hepatocellular carcinoma (HCC) and is associated with poor survival. Long noncoding RNAs (lncRNA) contribute to HCC metastasis, but whether and how lncRNAs affect PVTT development remains unclear. In the present study, a novel highly expressed lncRNA (ICAM-1-related, ICR) was identified in ICAM1(-) cancer stem cells (CSC) in HCC. This lncRNA regulated CSC properties and contributed to PVTT development.Experimental Design: We used microarray and bioinformatics analyses to identify differentially expressed lncRNAs. Real-time PCR and Western blotting were used to assess gene expression in cell lines and tumors. Sphere formation assays were performed to investigate stem cell properties of tumor cells in vitro. Retrospective and prospective studies were used to investigate the relationship between ICR expression and clinical outcomes.Results: Compared with the corresponding primary tumors, PVTT expressed different lncRNAs and mRNAs, including the upregulated lncRNA ICR and ICAM-1. ICR regulated ICAM-1 expression by increasing the stability of its mRNA through RNA duplex formation, which modulated the CSC properties of ICAM1(+) HCC cells. ICR transcription in ICAM-1(+) HCC cells was regulated by Nanog, and inhibition of ICR in situ significantly reduced ICAM-1 expression and ICAM-1(+) HCC cells in tumors in vivo. Moreover, elevated ICR and ICAM-1 expression in tumors was correlated with PVTT development and poor clinical outcomes.Conclusions: Our study demonstrates that ICR specifically regulates CSC properties of ICAM-1(+) HCC cells and that ICR contributes to PVTT development. Therefore, ICR may be a promising target for HCC therapy. (C) 2015 AACR.