microRNA-29 can regulate expression of the long non-coding RNA gene MEG3 in hepatocellular cancer

Oncogene. 2011 Nov 24;30(47):4750-6. doi: 10.1038/onc.2011.193. Epub 2011 May 30.

Abstract

The human genome is replete with long non-coding RNAs (lncRNA), many of which are transcribed and likely to have a functional role. Microarray analysis of >23,000 lncRNAs revealed downregulation of 712 (~3%) lncRNA in malignant hepatocytes, among which maternally expressed gene 3 (MEG3) was downregulated by 210-fold relative to expression in non-malignant hepatocytes. MEG3 expression was markedly reduced in four human hepatocellular cancer (HCC) cell lines compared with normal hepatocytes by real-time PCR. RNA in situ hybridization showed intense cytoplasmic expression of MEG3 in non-neoplastic liver with absent or very weak expression in HCC tissues. Enforced expression of MEG3 in HCC cells significantly decreased both anchorage-dependent and -independent cell growth, and induced apoptosis. MEG3 promoter hypermethylation was identified by methylation-specific PCR and MEG3 expression was increased with inhibition of methylation with either 5-Aza-2-Deoxycytidine, or siRNA to DNA Methyltransferase (DNMT) 1 and 3b in HCC cells. MiRNA-dependent regulation of MEG3 expression was studied by evaluating the involvement of miR-29, which can modulate DNMT 1 and 3. Overexpression of mir-29a increased expression of MEG3. GTL2, the murine homolog of MEG3, was reduced in liver tissues from hepatocyte-specific miR-29a/b1 knock-out mice compared with wild-type controls. These data show that methylation-dependent tissue-specific regulation of the lncRNA MEG3 by miR-29a may contribute to HCC growth and highlight the inter-relationship between two classes of non-coding RNA, miRNAs and lncRNAs, and epigenetic regulation of gene expression.

MeSH terms

  • Carcinoma, Hepatocellular / genetics*
  • DNA Methylation
  • Epigenesis, Genetic
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Liver Neoplasms / genetics*
  • MicroRNAs / physiology*
  • Organ Specificity
  • Proteins / genetics*
  • RNA, Long Noncoding
  • RNA, Untranslated / genetics*

Substances

  • MEG3 non-coding RNA, human
  • MIRN29 microRNA, human
  • MicroRNAs
  • Proteins
  • RNA, Long Noncoding
  • RNA, Untranslated