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Long noncoding RNAs and their role in the liver cancer axis

We read with great interest the excellent comprehensive Review by Szabo and Bala (MicroRNAs in liver disease. Nat. Rev. Gastroenterol. Hepatol. 10, 542–552 [2013]), detailing the most advanced knowledge of the role of microRNAs in the pathogenesis of liver disease.1 MicroRNAs have been proposed to have a pivotal role in the onset and development of hepatocellular carcinoma (HCC). Moreover, as potential robust biomarkers for both diagnostics and prognostics for HCC, they are important in therapeutic development.

Strategies for using microRNAs in therapeutic interventions for HCC are currently under investigation and are focused on the upregulation of oncosuppressive microRNAs and deregulation of oncomicroRNAs.2 In this regard, long noncoding RNAs (lncRNAs) are non-protein-coding genes comprising >200 nucleotides that are extensively transcribed in key biological processes and often deregulated in various diseases.3 In fact, in the past 5 years, accumulating evidence suggests that lncRNAs are tumorigenic candidates actively involved in gene regulation through the recruitment or inhibition of transcription factors to their target genes, protein modulation and/or chromatin modification events.4,5 On reading the discussion by Szabo and Bala1 of epigenetic modifications of lncRNA MEG3 by microRNA-29 (miR-29) in HCC, we wanted to emphasize the potential crosstalk that exists between noncoding RNAs. The interaction of MEG3 and miR-29 is a perfect example of our proposal that lncRNAs are an important consideration in HCC.1

A well-organized intrinsic network between lncRNAs and microRNAs has been proposed to exist, and lncRNAs are known to regulate microRNA recognition elements.6 In silico analysis using the miRcode network revealed that when lncRNA MEG3 is inputted in the miRcode databank, it recognizes 135 microRNA targeting sites, including sites for miR-122 at chromosome 14. Interestingly, MEG3 and miR-122 are both aberrantly expressed in patients with HCC.7,8 Although no direct investigation of MEG3–miR-122 interactions has been conducted, several studies have demonstrated a two-way regulatory communication between lncRNAs and microRNAs in HCC.7,9 In our opinion, the abundance and tissue specificity of lncRNAs make them perfect potential biomarkers for diagnostics and prognostic elements of liver diseases associated with HCC in a similar manner to microRNAs. As lncRNAs share similar characteristics with microRNAs, they have great potential as biomarkers for liver diseases that might result in HCC; indeed, the investigation of the lncRNA MEG3 could prove valuable in the search for future biomarker panels for HCC.

Overall, although the knowledge of lncRNA in hepatopathogenesis is still at an early stage, an understanding of the intrinsic linkage between lncRNAs and microRNAs will clearly provide an extra layer to the role of microRNAs in HCC. We believe that the inclusive combination of lncRNAs and microRNAs could lead to discoveries of more robust and reliable diagnostic, prognostic and therapeutic agents for HCC.

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Correspondence to Matthew W. Lawless.

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Zhao, J., Lawless, M. Long noncoding RNAs and their role in the liver cancer axis. Nat Rev Gastroenterol Hepatol 10, 703 (2013). https://doi.org/10.1038/nrgastro.2013.87-c1

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