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

Oncogene volume 30, pages 4750–4756 (2011)Cite this article

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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.

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Authors and Affiliations

  1. College of Medicine, and the Ohio State University Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA

    C Braconi, T Kogure, N Valeri, N Huang, S Costinean, C M Croce & T Patel

  2. Mayo Clinic, Jacksonville, FL, USA

    T Kogure & T Patel

  3. Department of Pathology, Ohio State University, Columbus, OH, USA

    G Nuovo

  4. Department of Experimental and Diagnostic Medicine, University of Ferrara, Ferrara, Italy

    M Negrini & E Miotto

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  1. C Braconi
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  2. T Kogure
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  3. N Valeri
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  4. N Huang
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  5. G Nuovo
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  6. S Costinean
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  9. C M Croce
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  10. T Patel
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Correspondence to T Patel.

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Braconi, C., Kogure, T., Valeri, N. et al. microRNA-29 can regulate expression of the long non-coding RNA gene MEG3 in hepatocellular cancer. Oncogene 30, 4750–4756 (2011). https://doi.org/10.1038/onc.2011.193

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  • DOI: https://doi.org/10.1038/onc.2011.193

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