A long noncoding RNA activated by TGF-β promotes the invasion-metastasis cascade in hepatocellular carcinoma

Cancer Cell. 2014 May 12;25(5):666-81. doi: 10.1016/j.ccr.2014.03.010. Epub 2014 Apr 24.

Abstract

The role of TGF-β-induced epithelial-mesenchymal transition (EMT) in cancer cell dissemination is well established, but the involvement of lncRNAs in TGF-β signaling is still unknown. In this study, we observed that the lncRNA-activated by TGF-β (lncRNA-ATB) was upregulated in hepatocellular carcinoma (HCC) metastases and associated with poor prognosis. lncRNA-ATB upregulated ZEB1 and ZEB2 by competitively binding the miR-200 family and then induced EMT and invasion. In addition, lncRNA-ATB promoted organ colonization of disseminated tumor cells by binding IL-11 mRNA, autocrine induction of IL-11, and triggering STAT3 signaling. Globally, lncRNA-ATB promotes the invasion-metastasis cascade. Thus, these findings suggest that lncRNA-ATB, a mediator of TGF-β signaling, could predispose HCC patients to metastases and may serve as a potential target for antimetastatic therapies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / pathology*
  • Epithelial-Mesenchymal Transition / genetics
  • Gene Expression Profiling
  • Homeodomain Proteins / biosynthesis
  • Homeodomain Proteins / metabolism
  • Humans
  • Interleukin-11 / genetics
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / pathology*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • MicroRNAs / metabolism
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Neoplasm Transplantation
  • Prognosis
  • RNA, Long Noncoding / genetics*
  • RNA, Messenger / metabolism
  • Repressor Proteins / biosynthesis
  • Repressor Proteins / metabolism
  • STAT3 Transcription Factor / metabolism
  • Transcription Factors / biosynthesis
  • Transcription Factors / metabolism
  • Transforming Growth Factor beta / metabolism*
  • Transplantation, Heterologous
  • Tumor Cells, Cultured
  • Up-Regulation
  • Zinc Finger E-box Binding Homeobox 2
  • Zinc Finger E-box-Binding Homeobox 1

Substances

  • Homeodomain Proteins
  • IL11 protein, human
  • Interleukin-11
  • MIRN200 microRNA, human
  • MicroRNAs
  • Mirn200 microRNA, mouse
  • RNA, Long Noncoding
  • RNA, Messenger
  • Repressor Proteins
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Transcription Factors
  • Transforming Growth Factor beta
  • ZEB1 protein, human
  • ZEB2 protein, human
  • Zinc Finger E-box Binding Homeobox 2
  • Zinc Finger E-box-Binding Homeobox 1
  • long non-coding RNA ATB, human

Associated data

  • GEO/GSE54797
  • GEO/GSE54798
  • GEO/GSE54799