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

C. Braconi, T. Kogure, N. Valeri, N. Huang, G. Nuovo, S. Costinean, M. Negrini, E. Miotto, C. M. Croce, T. Patel

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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.

Original languageEnglish (US)
Pages (from-to)4750-4756
Number of pages7
JournalOncogene
Volume30
Issue number47
DOIs
StatePublished - Nov 24 2011

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Keywords

  • HCC
  • MEG3
  • Methylation
  • Non-coding RNA

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Braconi, C., Kogure, T., Valeri, N., Huang, N., Nuovo, G., Costinean, S., Negrini, M., Miotto, E., Croce, C. M., & Patel, T. (2011). MicroRNA-29 can regulate expression of the long non-coding RNA gene MEG3 in hepatocellular cancer. Oncogene, 30(47), 4750-4756. https://doi.org/10.1038/onc.2011.193