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MicroRNAs and other non-coding RNAs as targets for anticancer drug development

Key Points

  • Mature microRNAs (miRNAs) are single-stranded RNAs that are 19–24 nucleotides in length and are produced in a multistep process involving the ribonuclease enzymes Drosha and Dicer.

  • miRNAs act via diverse mechanisms. In the 'canonical' mechanism, miRNAs bind to the 3′ untranslated (3′ UTR) region of mRNAs and reduce their protein output. Several unexpected mechanisms — such as miRNA binding to other RNA regions or DNA regulatory elements — and direct or indirect upregulation of protein translation have been demonstrated recently.

  • Extracellular miRNAs such as those secreted in exosomes can act on recipient cells through hormone-like mechanisms.

  • miRNAs are drivers or cofactors of carcinogenesis as well as tumour metastasis by controlling the expression of multiple protein-coding genes.

  • Aberrant miRNA expression in cancer can be corrected by replacement using miRNA mimics or blocking with anti-miR approaches.

  • The main advantages of miRNA therapeutics are their multi-targeting effects. Despite substantial challenges associated with miRNA therapeutics, the strategies of replacing tumour suppressor miRNAs with mimics have generated the first miRNA therapeutic agent (MRX34), which is in clinical trials for the treatment of cancer.

  • The combination of miRNAs with chemotherapeutic drugs or small interfering RNAs may synergistically improve the anticancer therapeutic efficacy and can be developed for cancer treatment.

  • Long non-coding RNAs (lncRNAs), including long intergenic ncRNAs (lincRNAs), transcribed ultraconserved regions (T-UCRs) and natural antisense transcripts (NATs), have been found to be involved in human cancers.

  • Many of the lncRNAs are predominately localized in the nucleus and thus act through different mechanisms than miRNAs. The unique features of such lncRNAs can be exploited for the development of specific and novel therapeutic strategies against cancer.

Abstract

The first cancer-targeted microRNA (miRNA) drug — MRX34, a liposome-based miR-34 mimic — entered Phase I clinical trials in patients with advanced hepatocellular carcinoma in April 2013, and miRNA therapeutics are attracting special attention from both academia and biotechnology companies. Although miRNAs are the most studied non-coding RNAs (ncRNAs) to date, the importance of long non-coding RNAs (lncRNAs) is increasingly being recognized. Here, we summarize the roles of miRNAs and lncRNAs in cancer, with a focus on the recently identified novel mechanisms of action, and discuss the current strategies in designing ncRNA-targeting therapeutics, as well as the associated challenges.

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Figure 1: Mechanisms of action of miRNAs and the use of therapeutic agents to block or activate their function.
Figure 2: Interfering with miRNA exocrine function.
Figure 3: Mechanisms of action of lncRNAs and the use of therapeutic agents to regulate their function.

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Acknowledgements

G.A.C. is The Alan M. Gewirtz Leukemia & Lymphoma Society Scholar. He is also supported as a Fellow at The University of Texas MD Anderson Research Trust, as a University of Texas System Regents Research Scholar and by the CLL Global Research Foundation. Work in G.A.C.'s laboratory is supported in part by the US National Institutes of Health (NIH)/US National Cancer Institute (NCI) grant CA135444; a US Department of Defense Breast Cancer Idea Award; Developmental Research Awards in breast cancer, ovarian cancer, brain cancer, prostate cancer, multiple myeloma and leukaemia (P50 CA100632) as well as head and neck cancer (P50 CA097007) from the Specialized Programs of Research Excellence (SPOREs); a Sister Institution Network Fund (SINF) grant from the MD Anderson Cancer Center and the German Cancer Research Center (DKFZ) in chronic lymphocytic leukaemia; a SINF grant in colorectal cancer, the Laura and John Arnold Foundation; the RGK Foundation; and The Estate of C. G. Johnson, Jr. H.L. is an Odyssey Fellow and his work is supported in part by the Odyssey Program and The Estate of C. G. Johnson, Jr. M.F.'s laboratory is supported by the Jean Perkins Foundation, by Nautica Malibu Triathlon Funds, by the Pablove Foundation, by the St. Baldrick's Foundation, by the Southern California Clinical and Translational Science Institute, by Funds from the Saban Research Institute, by award number P30CA014089 from the NCI, by the Hugh and Audy Lou Colvin Foundation, and by the T. J. Martell Foundation. The authors apologize to all colleagues whose work was not cited because of space restrictions.

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Non-coding RNAs

(ncRNAs). RNA molecules that are not translated into protein.

miRNA cluster

A group of at least two microRNAs located close together on the genome (usually several hundreds of bases apart) that are generally transcribed in a unique transcript and also commonly regulated.

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Ling, H., Fabbri, M. & Calin, G. MicroRNAs and other non-coding RNAs as targets for anticancer drug development. Nat Rev Drug Discov 12, 847–865 (2013). https://doi.org/10.1038/nrd4140

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