Long Noncoding RNAs and Cancer


Long noncoding RNAs (lncRNAs), products of pervasive transcription of the human genome, have emerged as important epigenetic regulators of cancer development and progression. LncRNAs, with transcript size ranging from 200 bp to 100 Kb, perform a diverse array of biological roles including chromatin modification, pre‐ and post‐transcriptional regulation, control of cell division, cell‐cycle growth and proliferation and imprinting. They exhibit cell‐specific expression patterns as well as restricted subcellular distribution, and have shown to play a role in multiple cancers such as cancers of the breast, pancreas, liver, lung and colon. Owing to the role they play in cancer initiation and progression, they have emerged as a new class of prognostic indicators, markers of chemotherapy response and finally show promise as targeted therapy against cancer. This article explores the characteristics of lncRNAs, function and association with multiple cancers and highlights the recent progress made on these new molecules especially with respect to cancer.

Key Concepts:

  • Long noncoding RNAs are a new class of epigenetic regulatory molecules that are actively transcribed from the human genome.

  • Involved in multiple biological functions including imprinting, transcriptional and post‐transcriptional regulation of gene expression, cell growth, proliferation and differentiation.

  • Dysregulation of lncRNA observed in multiple cancer types, involved in cancer progression and metastasis.

  • LncRNAs can serve as biomarkers, prognostic indicators and predictors of chemotherapy response.

  • Attractive targets for a new group of targeted therapy.

Keywords: long noncoding RNAs; epigenetic regulation; chromatin remodelling; cancer initiation and progression; biomarkers; targeted therapy

Figure 1.

Generalised mechanisms and associated examples of lncRNAs involved in cancer progression. LncRNAs act through a variety of mechanisms such as remodelling of chromatin (a), transcriptional coactivation or transcriptional repression (b), protein inhibition (c), post‐transcriptional modifiers (d) or decoy elements (e). Consequently, misexpression of lncRNAs can lead to changed expression profiles of various target genes involved in different aspects of cell homoeostasis. Reprinted from Cheetham et al. (), with permission of Macmillan Publishers Ltd on behalf of Cancer Research UK. © Nature Publishing Group.

Figure 2.

Mechanisms of lncRNA‐targeting agents. (a) siRNAs are short‐stretched (19–30 nt) double‐stranded RNAs that target unpaired lncRNA molecules via sequence complementarity. (b) antisense oligonucleotides (ASOs) are single‐stranded DNAs or RNAs (between 8 and 50 nt) that target specific RNAs via sequence complementarity. The hybrids are recognised by endogenous RNAse H1 that cleaves the target lncRNA molecules. (c) Hammerhead ribozyme (HamRz) is a single‐stranded RNA in neutral condition and undergo folding in cells to expose the binding arms. The binding of HamRz to target sequence depends on complementary match with the homologous target site. Both arms of HamRz have to bind with target sites correctly in order to form functional catalytic motif. After binding, HamRz catalyses the cleavage of the flanked RNA region downstream via destabilising the phosphodiester backbone of target RNA. (d) Aptamers are short DNA or RNA oligonucleotides, or peptides that have a stable three‐dimensional structure in vivo. They specifically bind to their target lncRNAs that relies on fitting three‐dimensional shape of the lncRNA structures. Aptamers antagonise their lncRNA targets by blocking the interactions between lncRNAs and critical factors. (e) Small molecules are synthesised to specifically bind to the RNA‐binding pockets of lncRNAs. They compete with protein factors or intracellular small ligands for the binding of lncRNAs. The binding of small molecules may also induce conformational change within the lncRNA molecules and disrupt the formation of important lncRNA structures. Reprinted from Li and Chen (), with permission of Elsevier. © Elsevier.



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Further Reading

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Garzon, Ramiro, and Ranganathan, Parvathi(Jun 2014) Long Noncoding RNAs and Cancer. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0025252]