MicroRNA polymorphisms as markers of risk, prognosis and treatment response in hematological malignancies
Introduction
MicroRNAs (miRNAs) are a class of small (∼22 nucleotide) non-coding RNAs that have emerged as key factors in the posttranscriptional regulation of gene expression. To date more than 2500 mature human miRNAs have been identified [1] and they are predicted to regulate over 60% of human protein-coding genes [2]. MiRNA-mediated regulatory networks can be very complex as one miRNA may potentially target several mRNAs, and a given mRNA may be regulated by several miRNAs. MiRNAs recognize their specific target transcripts by pairing with complementary sequences in the mRNA, which are usually located in the 3′ untranslated region (3′UTR), but can also be present in the 5′UTR or in the coding region. The minimum requirement is complementarity of the nucleotides 2–7 of the miRNA (so called ‘seed region’) but the miRNA–mRNA interaction can be enhanced by pairing of additional nucleotides of the miRNA [3]. This binding usually results in translational repression and/or degradation of the target mRNA but pairing of a miRNA with sequences located in the 5′UTR or the promoter can induce translation and transcription, respectively [4], [5].
MiRNA genes are located in introns of protein-coding genes or form independent clusters in the genome. In the process of miRNA biogenesis the primary long transcript (pri-miRNA) generated by RNA polymerase II is first processed by the Drosha complex to release a hairpin-structured miRNA precursor (pre-miRNA). Pre-miRNAs are exported to the cytoplasm by Exportin-5, where they undergo cleavage by Dicer to produce the mature double-stranded 22 nt miRNA. One strand is loaded into an Ago protein, a component of the RNA-induced silencing complex (RISC) and guides RISC to the target mRNAs leading to repression of translation or mRNA degradation [6], [7].
MiRNAs have been shown to control a wide variety of biological processes, including development, proliferation, metabolism, apoptosis, hematopoiesis and differentiation [8], and disruption of miRNA regulatory networks has been linked with various diseases, including cancer [9]. MiRNAs can act as both oncogenes and tumor suppressors. Examples of oncogenic miRNAs that are amplified or overexpressed in cancers include miR-17-92 cluster, miR-21, miR-155 and miR-372/373, while tumor suppressor miRNAs commonly deleted or with reduced expression in cancers are represented by miR-15a and miR-16-1, miR-34 family, let-7 family and miR-29 [10]. It has become evident that miRNAs play crucial role in normal hematopoiesis by controlling the differentiation of hematopoietic stem cells, while deregulation of miRNAs in hematopoietic cells has been linked to hematological malignancies [11], [12]. Leukemias and lymphomas are characterized by aberrant miRNA expression profiles [13], [14] and these specific miRNA expression signatures can accurately discriminate different leukemia subtypes and often have great prognostic significance [15], [16], [17], [18], [19]. Apart from genomic and epigenetic alterations, deregulation of the miRNA networks may result from polymorphisms in the miRNA regulatory pathway (miRSNPs). In the recent years several studies have shown association of miRSNPs with cancer and other diseases [20], [21]. MiRSNPs can be classified into three categories: (1) SNPs in genes involved in miRNA biogenesis and processing; (2) SNPs in miRNA genes; and (3) SNPs in miRNA-binding sites in target genes [22]. Their relevance for cancer can be considered in terms of risk of developing a disease, prognosis for the disease progression and survival, and treatment response.
This review focuses on miRSNPs in hematological malignancies and discusses their potential contribution to the development of blood cancers and their role as prognostic factors and markers of treatment outcome.
Section snippets
SNPs in genes involved in miRNA biogenesis and processing
Polymorphisms affecting expression or function of proteins involved in the biogenesis of miRNAs may interfere with miRNA regulatory networks in the cell. This class of miRSNPs would likely have the broadest impact on the miRNA-mediated regulation as they could affect global miRNA biogenesis and deregulate the whole microRNAome of the cell, affecting expression of all genes targeted by miRNAs (Fig. 1A). Several potentially functional polymorphisms in genes involved in various steps of miRNA
SNPs in miRNA genes
Polymorphism in pri- and pre-miRNAs can influence their processing, whereas polymorphisms in mature miRNAs can affect their binding to target transcripts. Also SNPs in promoters of miRNA genes or miRNA host genes may have impact on the expression of miRNAs. This class of miRSNPs would possibly have quite broad impact for the cell, as any miRNA can potentially regulate many genes involved in various processes (Fig. 1B).
SNPs in miRNA-binding sites in target genes
Polymorphisms in miRNA-binding sites in target genes may alter the strength of miRNA–mRNA interactions, thus deregulating protein levels. This class of miRSNPs would likely have the most limited impact for the cell, affecting only expression of the gene harboring the SNP. However, indirect effect of SNPs in miRNA-binding sites may be much wider as they will influence the pool of miRNAs available for other transcripts that are also regulated by a given miRNA (Fig. 1C). This could lead to
Conclusions
In the recent years it has become evident that microRNAs play fundamental role in the regulation of gene expression and that disruption of miRNA regulatory networks can lead to cancer. Polymorphisms in miRNA pathways may interfere with miRNA expression and function, which in turn can affect expression of several genes.
This review summarizes the growing knowledge in the field of miRNA polymorphisms (miRSNPs) in hematological malignancies. From the presented data, miRSNPs emerge as potential
Conflict of interest statement
The author declares no conflict of interest.
Reviewers
Dr Africa Garcia-Orad, University of the Basque Country, Genetics, Physical Anthropology/Animal Physiology, Barrio Sarriena s/n, ES-48940 Leioa, Bizhaia, Spain.
Dr Alfons Navarro, Molecular Oncology and Embryology Laboratory, Human Anatomy Unit, School of Medicine, University of Barcelona, IDIBAPS, Barcelona, Spain.
Acknowledgment
This work was supported by Ministry of Science and Higher Education grant No. N N401 570740.
Agnieszka Dzikiewicz-Krawczyk, Ph.D., is a postdoctoral research fellow at the Institute of Human Genetics, Polish Academy of Sciences, Poland. Her current research focuses on the role of microRNAs and long non-coding RNAs in leukemias.
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Agnieszka Dzikiewicz-Krawczyk, Ph.D., is a postdoctoral research fellow at the Institute of Human Genetics, Polish Academy of Sciences, Poland. Her current research focuses on the role of microRNAs and long non-coding RNAs in leukemias.