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

Ji-hang Yuan; Fu Yang; Fang Wang; Jin-zhao Ma; Ying-jun Guo; Qi-fei Tao; Feng Liu; Wei Pan; Tian-tian Wang; Chuan-chuan Zhou; Shao-bing Wang; Yu-zhao Wang; Yuan Yang; Ning Yang; Wei-ping Zhou; Guang-shun Yang; Shu-han Sun

doi:10.1016/j.ccr.2014.03.010

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.

Authors

Ji-hang Yuan¹, Fu Yang¹, Fang Wang¹, Jin-zhao Ma¹, Ying-jun Guo¹, Qi-fei Tao², Feng Liu¹, Wei Pan¹, Tian-tian Wang¹, Chuan-chuan Zhou¹, Shao-bing Wang¹, Yu-zhao Wang¹, Yuan Yang², Ning Yang³, Wei-ping Zhou², Guang-shun Yang³, Shu-han Sun⁴

Affiliations

¹ Department of Medical Genetics, Second Military Medical University, Shanghai, 200433, China.
² The Third Department of Hepatic Surgery, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai, 200433, China.
³ The Fifth Department of Hepatic Surgery, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai, 200433, China.
⁴ Department of Medical Genetics, Second Military Medical University, Shanghai, 200433, China. Electronic address: shsun@vip.sina.com.

PMID: 24768205
DOI: 10.1016/j.ccr.2014.03.010

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