Long non-coding RNA DILC regulates liver cancer stem cells via IL-6/STAT3 axis

• Published in: Journal of hepatology Vol. 64; no. 6; pp. 1283 - 1294
• Main Authors: Wang, Xue, Sun, Wen, Shen, Weifeng, Xia, Mingyang, Chen, Cheng, Xiang, Daimin, Ning, Beifang, Cui, Xiuliang, Li, Hengyu, Li, Xiaofeng, Ding, Jin, Wang, Hongyang
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.06.2016
• Subjects: Animals; Carcinoma, Hepatocellular - etiology; Carcinoma, Hepatocellular - pathology; Gastroenterology and Hepatology; Hepatocellular carcinoma; Humans; Interleukin-6; Interleukin-6 - genetics; Interleukin-6 - physiology; Janus Kinase 2 - antagonists & inhibitors; Janus Kinase 2 - physiology; Liver cancer stem cell; Liver Neoplasms - etiology; Liver Neoplasms - pathology; Long non-coding RNA; Mice; Neoplastic Stem Cells - physiology; NF-kappa B - physiology; Promoter Regions, Genetic; RNA, Long Noncoding - physiology; Signal Transduction; STAT3 Transcription Factor - antagonists & inhibitors; STAT3 Transcription Factor - physiology; NF-κB; Liver cancer stem cell; lncRNA; LCSC; OS; STAT3; HCC; Hepatocellular carcinoma; lnc-DILC; IL-6; Long non-coding RNA; Interleukin-6; nuclear factor kappa B; lncRNA downregulated in liver cancer stem cells; signal transducer and activator of transcription 3; liver cancer stem cell; interleukin-6; overall survival; long non-coding RNA; hepatocellular carcinoma
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2016.01.019

[Display omitted] Emerging evidence has demonstrated the aberrant expression of long non-coding RNAs (lncRNAs) in various malignancies including HCC. However, the knowledge of cancer stem cell-related lncRNAs remains limited. lnc-DILC (lncRNA downregulated in liver cancer stem cells (LCSCs)) was identified by microarray and validated by real-time PCR. The role of lnc-DILC in LCSCs was assessed both in vitro and in vivo. Pull down assay and oligoribonucleotides or oligodeoxynucleotides treatment were conducted to evaluate the interaction between lnc-DILC and interleukin-6 (IL-6) promoter. Depletion of lnc-DILC markedly enhanced LCSC expansion and facilitated HCC initiation and progression, whereas ectopic expression of lnc-DILC dramatically inhibited LCSC expansion. Mechanistically, lnc-DILC inhibited the autocrine IL-6/STAT3 signaling. The putative binding locus of lnc-DILC within IL-6 promoter was confirmed by pull down assay. Consistently, the oligoribonucleotide mimics and an oligodeoxynucleotide decoy of lnc-DILC abrogated the effects on IL-6 transcription, STAT3 activation and LCSC expansion triggered by lnc-DILC depletion and lnc-DILC overexpression. Moreover, our data suggested that lnc-DILC mediated the crosstalk between TNF-α/NF-κB signaling and IL-6/STAT3 cascade. Clinical investigation demonstrated the reduction of lnc-DILC in patient HCCs, and suggested the correlation between lnc-DILC levels and IL-6, EpCAM or CD24 expression. Decreased lnc-DILC expression in HCCs predicts early recurrence and short survival of patients, highlighting its prognostic value. lnc-DILC mediates the crosstalk between TNF-α/NF-κB signaling and autocrine IL-6/STAT3 cascade and connects hepatic inflammation with LCSC expansion, suggesting that lnc-DILC could be not only a potential prognostic biomarker, but also a possible therapeutic target against LCSCs.