title: Long non-coding RNA DILC regulates liver cancer stem cells via IL-6/STAT3 axis.
abstract: 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.
authors.affiliation: The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 200438 Shanghai, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Wang
authors.affiliation: The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 200438 Shanghai, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Sun
authors.affiliation: The Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 200438 Shanghai, China.
authors.forename: Weifeng
authors.initials: W
authors.lastname: Shen
authors.affiliation: The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 200438 Shanghai, China.
authors.forename: Mingyang
authors.initials: M
authors.lastname: Xia
authors.affiliation: The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 200438 Shanghai, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Chen
authors.affiliation: The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 200438 Shanghai, China.
authors.forename: Daimin
authors.initials: D
authors.lastname: Xiang
authors.affiliation: The Department of Gastroenterology, Changzheng Hospital, 200003 Shanghai, China.
authors.forename: Beifang
authors.initials: B
authors.lastname: Ning
authors.affiliation: The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 200438 Shanghai, China.
authors.forename: Xiuliang
authors.initials: X
authors.lastname: Cui
authors.affiliation: The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 200438 Shanghai, China.
authors.forename: Hengyu
authors.initials: H
authors.lastname: Li
authors.affiliation: The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 200438 Shanghai, China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Li
authors.affiliation: The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 200438 Shanghai, China; National Center for Liver Cancer, 201805 Shanghai, China. Electronic address: dingjin1103@163.com.
authors.forename: Jin
authors.initials: J
authors.lastname: Ding
authors.affiliation: The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 200438 Shanghai, China; National Center for Liver Cancer, 201805 Shanghai, China. Electronic address: hywangk@vip.sina.com.
authors.forename: Hongyang
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000473:pathology; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000502:physiology*; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000502:physiology; D008113:Liver Neoplasms / Q000209:etiology* / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000502:physiology; D014411:Neoplastic Stem Cells / Q000502:physiology*; D011401:Promoter Regions, Genetic; D062085:RNA, Long Noncoding / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D016328:NF-kappa B; D062085:RNA, Long Noncoding; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C507924:JAK2 protein, human; D053614:Janus Kinase 2
keywords: Hepatocellular carcinoma; Interleukin-6; Liver cancer stem cell; Long non-coding RNA