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

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• 作者：Xue Wang¹ ; ^&dagger ; ; Wen Sun¹ ; ^&dagger ; ; Weifeng Shen² ; ^&dagger ; ; Mingyang Xia¹ ; ^&dagger ; ; Cheng Chen¹ ; Daimin Xiang¹ ; Beifang Ning³ ; Xiuliang Cui¹ ; Hengyu Li¹ ; Xiaofeng Li¹ ; Jin Ding¹ ; ⁴ ; ^{dingjin1103@163.com" class="auth_mail" title="E-mail the corresponding author} ; Hongyang Wang¹ ; ⁴ ; ^{hywangk@vip.sina.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：HCC ; hepatocellular carcinoma ; lncRNA ; long non-coding RNA ; lnc-DILC ; lncRNA downregulated in liver cancer stem cells ; LCSC ; liver cancer stem cell ; IL-6 ; interleukin-6 ; STAT3 ; signal transducer and activator of transcription 3 ; NF-κB ; nuclear factor kappa B ; OS ; overall survival
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：June 2016
• 年：2016
• 卷：64
• 期：6
• 页码：1283-1294
• 全文大小：4389 K

文摘

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.

Methods

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.

Results

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.

Conclusions

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.