Long noncoding RNA GIHCG promotes hepatocellular carcinoma progression through epigenetically regulating miR-200b/a/429

J Mol Med (Berl). 2016 Nov;94(11):1281-1296. doi: 10.1007/s00109-016-1442-z. Epub 2016 Jul 5.


Long noncoding RNAs (lncRNAs) have been reported to play pivotal roles in a variety of cancers. However, lncRNAs involved in hepatocellular carcinoma (HCC) initiation and progression remain largely unclear. In this study, we identified an lncRNA gradually increased during hepatocarcinogenesis (lncRNA-GIHCG) using publicly available microarray data. Our results further revealed that GIHCG is upregulated in HCC tissues in comparison with adjacent non-tumor tissues. High GIHCG expression is correlated with large tumor size, microvascular invasion, advanced BCLC stage, and poor survival of HCC patients. Functional experiments showed that GIHCG promotes HCC cells proliferation, migration, and invasion in vitro, and promotes xenografts growth and metastasis in vivo. Mechanistically, we demonstrated that GIHCG physically associates with EZH2 and the promoter of miR-200b/a/429, recruits EZH2 and DNMT1 to the miR-200b/a/429 promoter regions, upregulates histone H3K27 trimethylation and DNA methylation levels on the miR-200b/a/429 promoter, and dramatically silences miR-200b/a/429 expression. Furthermore, the biological functions of GIHCG on HCC are dependent on the silencing of miR-200b/a/429. Collectively, our results demonstrated the roles and functional mechanisms of GIHCG in HCC, and indicated GIHCG may act as a prognostic biomarker and potential therapeutic target for HCC. KEY MESSAGE: lncRNA-GIHCG is upregulated in HCC and associated with poor survival of patients. GIHCG significantly promotes tumor growth and metastasis of HCC. GIHCG physically associates with EZH2. GIHCG upregulates H3K27me3 and DNA methylation levels on the miR-200b/a/429 promoter. GIHCG epigenetically silences miR-200b/a/429 expression.

Keywords: DNA methylation; Hepatocellular carcinoma; Histone methylation; Long noncoding RNA; MicroRNA; Progression.

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / pathology*
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Proliferation / genetics
  • DNA (Cytosine-5-)-Methyltransferase 1 / metabolism
  • Disease Progression
  • Down-Regulation / genetics
  • Enhancer of Zeste Homolog 2 Protein / metabolism
  • Epigenesis, Genetic*
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Gene Silencing
  • Humans
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / pathology
  • Male
  • Mice, Inbred BALB C
  • Mice, Nude
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Middle Aged
  • Neoplasm Metastasis
  • Promoter Regions, Genetic
  • Protein Binding
  • RNA, Long Noncoding / genetics*
  • RNA, Long Noncoding / metabolism
  • Survival Analysis


  • MIRN200 microRNA, human
  • MIRN429 microRNA, human
  • MicroRNAs
  • RNA, Long Noncoding
  • long non-coding RNA GIHCG, human
  • DNA (Cytosine-5-)-Methyltransferase 1
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein