ICAM-1-Related Noncoding RNA in Cancer Stem Cells Maintains ICAM-1 Expression in Hepatocellular Carcinoma

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.