Targeting microRNAs involved in human diseases: A novel approach for modification of gene expression and drug development

doi:10.1016/j.bcp.2011.08.007

Biochemical Pharmacology

Volume 82, Issue 10, 15 November 2011, Pages 1416-1429

https://doi.org/10.1016/j.bcp.2011.08.007 Get rights and content

Abstract

The identification of all epigenetic modifications (i.e. DNA methylation, histone modifications and expression of noncoding RNAs such as microRNAs) involved in gene regulation is one of the major steps forward for understanding human biology in both normal and pathological conditions and for development of novel drugs. In this context, microRNAs play a pivotal role. This review article focuses on the involvement of microRNAs in the regulation of gene expression, on the possible role of microRNAs in the onset and development of human pathologies, and on the pharmacological alteration of the biological activity of microRNAs. RNA and DNA analogs, which can selectively target microRNAs using Watson–Crick base pairing schemes, provide a rational and efficient way to modulate gene expression. These compounds, termed antago-miR or anti-miR have been described in many examples in the recent literature and have proved to be able to perform regulatory as well as therapeutic functions. Among these, a still not fully exploited class is that of peptide nucleic acids (PNAs), promising tools for the inhibition of miRNA activity, with important applications in gene therapy and in drug development. PNAs targeting miR-122, miR-155 and miR-210 have already been developed and their biological effects studied both in vitro and in vivo.

Graphical abstract

MicroRNAs regulate gene expression and anti-sense microRNA molecules and microRNA mimics are proposed in diagnostics and therapy. Peptide nucleic acids (PNAs) efficiently target microRNAs, leading to therapeutic effects.

Introduction

The identification of all epigenetic modifications involved in gene expression is one of the major steps forward for understanding human biology in both normal and pathological conditions. This field is referred to as epigenomics, and it is defined as epigenetic changes (i.e. DNA methylation, histone modification and expression of noncoding RNAs such as microRNAs) on a genomic scale [1]. In this context, microRNAs play a pivotal role.

MicroRNAs (miRNAs, miRs) are a family of small (19–25 nucleotides in length) noncoding RNAs that regulate gene expression by sequence-selective targeting of mRNAs, leading to a translational repression or mRNA degradation, depending on the degree of complementarity between miRNAs and the target mRNA sequences [2], [3], [4], [5]. Since their discovery and first characterization, the number of microRNA sequences deposited in the miRBase databases is growing [6], [7], [8], [9], [10]. Considering that a single miRNA can target several mRNAs and a single mRNA might contain in the 3′UTR sequence several signals for miRNA recognition, it is calculated that at least 10–40% of human mRNAs are a target for microRNAs [10], [11], [12], [13]. Hence, great interest is concentrated on the identification of validated targets of microRNAs.

This specific field of microRNA research has confirmed that the complex networks constituted by miRNAs and RNA targets coding for structural and regulatory proteins lead to the control of highly regulated biological functions, such as differentiation, cell cycle and apoptosis [1], [2], [3]. Low expression of a given miRNA is expected to be linked with a potential expression of targets mRNAs. Conversely, high expression of miRNAs is expected to induce low expression of biological functions of the target mRNAs [1], [2], [3].

Alteration of microRNA expression has been demonstrated to be associated with human pathologies as well as guided alterations of miRNAs have been suggested as a novel approach to develop innovative therapeutic protocols. MicroRNA therapeutics appears as a novel field in which miRNA activity is the major target of the intervention [14], [15], [16], [17]. MiRNA inhibition can be readily achieved by the use of small miR-inhibitor oligomers, including RNA, DNA, DNA analogs (miRNA anti-sense therapy) [14], [15]. On the contrary, increase of miRNA function (miRNA replacement therapy) can be achieved by the use of modified, suitably delivered miRNAs mimetics, transfection using recombinant vectors or lentivirus carrying miRNA gene sequences [16], [17].

This review article focuses on the involvement of microRNAs in the regulation of gene expression, on the possible role of microRNAs in the onset and development of human pathologies, and on the pharmacological alteration of the biological activity of microRNAs using anti-miR molecules.

Section snippets

Biogenesis of microRNAs and drug design

Some miRNAs are encoded by unique genes (intergenic miRNAs) [18], [19], [20], [21], [22], [23] and others are embedded into the intronic regions of protein-coding genes (intragenic miRNAs) [24], [25], [26], [27], [28]. Examples of intergenic miRNA are miR-210, miR-10a, miR-21, and miR-222/miR-221, which are encoded by unique genes located in the chromosome 11, 17, 17, 6 and X, respectively. The transcription is controlled, as protein-coding genes, by a promoter which is regulated by specific

Involvement of microRNAs in the control of gene expression

The basic mechanism leading to alteration of gene expression is based on the recruitment of mature miRNA at the level of the RISC silencing complex [32], [33], [34], [35], [36], [37]. This process occurs in the cytoplasm, where the pre-miRNA hairpin is cleaved by the RNase III enzyme Dicer, which interacts with the 3′ end of the hairpin and cuts away the loop joining the 3′ and 5′ arms, yielding an imperfect miRNA/miRNA duplex. One of the strands is incorporated into the RISC, where it binds to

MicroRNAs in erythropoiesis

Increasing numbers of published studies report the involvement of microRNAs in erythropoiesis [13], [38], [39], [40], [41]. Different cellular experimental systems were used in these studies. Huang et al. employed human embryonic stem cells (hESCs) as a model system to study early human hematopoiesis [42]. These authors differentiated hESCs by embryoid body (EB) formation and compared the miR expression profile of undifferentiated hESCs to CD34(+) EB cells, demonstrating the function of

MicroRNAs and human pathologies

Strong evidences are reported by a number of authors suggesting the concept that the inappropriate expression of miRNA is associated with cancer [56], [57], [58], [59], [60], [61] and a variety of other pathologies [62], [63], [64], [65], [66], [67], [68], [69], [70], [71]. For example, let-7 miRNA prevents proliferation of cancer stem cells [72]. miRNAs have roles in obesity [73], [74] and diabetes [75], hearing loss in humans [76], development of liver diseases [77], osteopenic diseases [63],

MicroRNA and cancer

MicroRNAs play a pivotal role in cancer [102], [103], [104], [105], [106], [107], [108]. The literature on this specific issue is impressive (see the Human MicroRNA Disease Database, http://202.38.126.151/hmdd/mirna/md/) [61], [62], [102], [103], [104], [105], [106], [107], [108], [109], [110], [111], [112], [113], [114], [115], [116], [117], [118], [119], [120], [121], [122], [123], [124], [125], [126], [127], [128], [129], [130], [131], [132], [133], [134], [135], [136], [137], [138], [139],

Bioactive molecules altering miR metabolism

Given the role of miRNAs in epigenetic regulation of gene expression, miRNAs have been proposed as possible candidates for drug targeting with the objective of interfering with biological functions, altering the expression of the mRNAs specifically regulated by the targeted miRNAs [15], [144], [145], [146], [147], [148], [149], [150], [151], [152]. Mature miRNAs can be targeted with short RNA sequences, oligodeoxyribonucleotides (ODNs) and ODN-analogs (such as LNAs). Other molecular targets are

Peptide nucleic acids

PNAs (Figs. 4F and 5A) are DNA analogs in which the sugar-phosphate backbone is replaced by N-(2-aminoethyl)glycine units [153], [154], [155], [156], [157], [158], [159], [160], [161], [162]. These molecules efficiently hybridize with complementary DNA and RNA, forming double helices with Watson–Crick base pairing [153], [154], [155], [156], [157], [158], [159], [160], [161], [162], [163], [164], [165], [166], [167]. In addition, they generate triple helix formation with double stranded DNA and

MicroRNA therapeutics and clinical trials

On the basis of the studies demonstrating that microRNAs are promising candidates for drug targeting, many activities aiming at developing possible reagents for therapy and diagnostics are in progress in order to bring this research to industrial exploitation and to clinical settings [71], [190]. At present, miRNAs are likely to be used as biomarkers in clinical settings sooner than as therapeutic reagents. This is evident by looking at patents and clinical trials (Table 4). As far as clinical

Conclusions and perspectives

MicroRNAs are promising candidates for drug targeting: the aim is to develop possible molecular systems for experimental therapy of human pathologies in which microRNAs appears to be deeply involved. PNAs are bioactive molecules and promising tools for the inhibition of miRNA activity. This effect can be very important in obtaining gene modulation in a simple way, with major applications in gene therapy and in drug development. The issue of delivering PNA to their targets is still open,

Acknowledgments

This work was supported by a grant by MIUR (Italian Ministry of University and Research, PRIN-2007). RG is granted by Fondazione Cariparo (Cassa di Risparmio di Padova e Rovigo), CIB, by UE ITHANET Project (Infrastructure for the Thalassaemia Research Network), by Telethon GGP10124 and by FIRB-2007. This research is also supported by Associazione Veneta per la Lotta alla Talassemia (AVLT), Rovigo. We thank Dr. Amanda Julie Neville for her help in producing the English text.

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Targeting microRNAs involved in human diseases: A novel approach for modification of gene expression and drug development

Abstract

Graphical abstract

Introduction

Section snippets

Biogenesis of microRNAs and drug design

Involvement of microRNAs in the control of gene expression

MicroRNAs in erythropoiesis

MicroRNAs and human pathologies

MicroRNA and cancer

Bioactive molecules altering miR metabolism

Peptide nucleic acids

MicroRNA therapeutics and clinical trials

Conclusions and perspectives

Acknowledgments

Curr Opin Struct Biol

Cell

Drug Discov Today

Mol Ther

J Biol Chem

J Biol Chem

J Biol Chem

Mol Cell

Mol Cell Endocrinol

Mol Cell

Biochem Biophys Res Commun

J Biol Chem

Exp Hematol

Blood

Blood

J Biol Chem

Exp Hematol

Blood

Transl Res

Trends Mol Med

Transl Res

J Invest Dermatol

Blood

Exp Hematol

Biochem Biophys Res Commun

J Biol Chem

Epigenomics in cancer management

Cancer Manag Res

MicroRNAs: small RNAs with a big role in gene regulation

Nat Rev Genet

miRBase: integrating microRNA annotation and deep-sequencing data

Nucleic Acids Res

The widespread regulation of microRNA biogenesis, function and decay

Nat Rev Genet

MicroRNAs as gatekeepers of apoptosis

J Cell Physiol

Cell cycle regulation by microRNAs in embryonic stem cells

Cancer Res

MicroRNA functions in animal development and human disease

Development

UCbase & miRfunc: a database of ultraconserved sequences and microRNA function

Nucleic Acids Res

MicroRNAs in common diseases and potential therapeutic applications

Clin Exp Pharmacol Physiol

MicroRNAs in embryonic stem cell function and fate

Genes Dev

Expression of miR-210 during erythroid differentiation and induction of γ-globin gene expression

BMB Rep

Exploiting the therapeutic potential of microRNAs in viral diseases: expectations and limitations

Mol Diagn Ther

The promise of microRNA replacement therapy

Cancer Res

miR-15 and miR-16 are direct transcriptional targets of E2F1 that limit E2F-induced proliferation by targeting cyclin E

Mol Cancer Res

Glucocorticoid-regulated microRNAs and mirtrons in acute lymphoblastic leukemia

Leukemia

A potential role for intragenic miRNAs on their hosts’ interactome

BMC Genomics

Cigarette smoke induces C/EBP-β-mediated activation of miR-31 in normal human respiratory epithelia and lung cancer cells

PLoS One

Versatile applications of microRNA in anti-cancer drug discovery: from therapeutics to biomarkers

Curr Drug Discov Technol

Circulating microRNA in body fluid: a new potential biomarker for cancer diagnosis and prognosis

Cancer Sci

Modeling RNA interference in mammalian cells