Platinum Priority – Collaborative Review – OncologyEditorial by Axel Bex on pp. 682–683 of this issueMicroRNA in Prostate, Bladder, and Kidney Cancer: A Systematic Review☆
Introduction
It is vital for normal cells that protein synthesis occur in a controlled manner. There are numerous tiers to this control, including the structure and expression of a gene. This expression may be regulated at the genetic or epigenetic level. Genetic mechanisms are often irreversible and include DNA mutation or chromosomal translocation, deletion, and amplification. Epigenetic mechanisms are mostly reversible and are defined as inheritable changes that alter expression without changing gene sequence or chromosomal structure. Known epigenetic mechanisms involve biochemical modifications of the histone proteins that support DNA, modification of DNA itself, and expression of noncoding RNAs (ncRNA). Epigenetic changes are dynamic and respond to events such as embryogenesis or environmental factors. Loss of epigenetic control is common in cancer, and here we focus on ncRNA [1].
RNA can be divided into protein-coding and noncoding RNA. Most RNA does not get translated to form proteins, and this ncRNA is classified according to size and location. MicroRNAs (miRNA) are small ncRNAs (on average, 22 bases) transcribed from DNA into RNA hairpins. They were first identified in plants, before their phylogenetic orthologues were discovered in more advanced species. This preservation in primitive species points to their importance in cell function and led to the current interest in their function [2]. MiRNAs are processed, exported outside the nucleus, and cleaved to create mature miRNAs. These miRNAs bind to complementary sequences within protein-coding messenger RNAs to alter their translation.
The 5′ end of an miRNA includes the targeting “seed” region that binds complementary sequences within messenger RNA (mRNA) tails (3′ untranslated region; Fig. 1). The affinity of this bond depends on the sequence and number of complementary seeds [2]. The miRNA–mRNA pair recruits a silencing complex to modulate mRNA expression. Most miRNAs produce a modest reduction (less than two-fold) in their target mRNA concentration (to “fine-tune” protein expression) [2]. A small proportion causes upregulation, or the complete destruction of their target [2], [3], [4]. Currently, around 1000 human miRNAs are known, and each may target hundreds to thousands of genes. It should be stated that our knowledge regarding the role of miRNAs in gene regulation is currently incomplete. New evidence regularly appears suggesting further complexity—for example, the targeting of pseudogenes by miRNAs [5]. Coding genes may have defunct siblings, known as pseudogenes, that have lost their ability to code for proteins or are no longer expressed within a cell. Whilst their function is unknown, recent data suggest that they can act as decoys to attract miRNAs and enable the expression of their active sibling genes.
The importance of miRNA in cancer was suggested when miRNA genes were found to be specifically deleted in leukaemia [1], [3]. Subsequent reports have shown that miRNAs are altered in many cancers, and they can initiate carcinogenesis or drive progression [1]. MiRNA expression is dynamic, so their expression or target may be altered within the same cell depending on circumstance. This variability makes them potent modulators of cellular behaviour, as a single protein may cascade its message using few miRNAs onto many genes. For example, miRs-34a/b/c are directly regulated by p53 within a positive feedback loop to affect numerous proapoptotic proteins [6]. However, this feature is also a vulnerability that cancers can exploit. Thus, loss of p53 prevents the production of miRs-34a/b/c and so enables a cell to avoid apoptosis at numerous levels and affect other targets of these miRNAs.
Alterations of miRNA expression have been described in most cancers and can arise from either genetic or epigenetic means. Many miRNAs are located within fragile chromosomal sites, and these are often deleted or rearranged in cancer [7]. Rarely, miRNA mutations have been found [8], which may reflect their low specificity for gene targeting and thus the low selection pressure associated with their mutation. A more important event may be mutation within the mRNA target site for specific miRNAs. With respect to epigenetic regulation, between 20% and 40% of miRNA genes are located close to CpG islands [9], suggesting that they may be susceptible to epigenetic silencing; reports have demonstrated this event in urologic cancers [10], [11], [12]. Of note, the reciprocal regulation of the DNA and histone methylation machinery by miRNAs is also seen [13].
MiRNA genes can be located within coding mRNAs (40% are intronic or exonic) or on their own (in the intergenic regions) [9]. They are either solitary or grouped into clusters. Around one-third of miRNAs are clustered, and in these clusters, a single event may affect several miRNAs to alter thousands of protein targets [10]. For example, the oncogene MYC transcriptionally activates the miR-17-92 cluster on chromosome 13 to initiate carcinogenesis [14]. Humans have several large clusters, including those at chromosome 14q32 and chromosome 19q13 (each with >50 miRNAs). Many miRNAs have two or more duplicate genes that encode their mature RNA. This redundancy ensures that loss at one region has little impact on a cell but doubles the chance of upregulation through chromosomal gain or amplification. Notable examples include miR-1302, which has eight miRNA genes. In general, the expression of an intronic/exonic miRNA and its host coding gene are linked [15]. For example, in prostate cancer (PCa), two of the most upregulated miRNAs are located within highly expressed protein-coding genes (MCM7 [miR-106b-25 cluster] and C9orf5 [miR-32]) [16].
The translational applications for knowledge about miRNAs include their use as disease biomarkers, in prognostic prediction, and as novel treatments. This last application is potentially the most exciting, as it enables disease-specific individualised therapeutic targeting. This personalised medicine represents the future of oncology. Examples of miRNA therapies include the administration of synthesised anti-miRNAs to normalise disease-related upregulated miRNA expression [17], [18] and the manipulation of lethal gene expression using endogenous miRNAs [19], [20].
Section snippets
Literature search
We undertook a detailed literature search of the Embase and Pubmed repositories, with strings for microRNA, non-coding RNA, miRNAs, miRNA, cancer, prostate, bladder, urothelial, kidney, and renal on 18 October 2010.
Literature selection
We selected articles written in English in which scientific detail and reporting were sufficient to enable our understanding and that had novel findings. In cases of multiple or serial reports, we selected either the first or the most detailed report for inclusion. We preferentially
Evidence synthesis
Our literature search retrieved 237 manuscripts. We selected 89 that were of sufficient reporting rigor or novelty. We mostly used articles that revealed mechanistic data about the biology of these cancers.
Conclusions
MiRNAs are important modulators of gene expression. They are frequently altered in urologic cancers and as such offer the potential to be used as biomarkers or novel therapeutic targets. Better evidence is required to test their use in both of these fields.
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