MicroRNAs as biomarkers for CNS cancer and other disorders

doi:10.1016/j.brainres.2010.03.103

Brain Research

Volume 1338, 18 June 2010, Pages 100-111

https://doi.org/10.1016/j.brainres.2010.03.103 Get rights and content

Abstract

The use of miRNAs as biomarkers has gained growing interest in the last few years. Their role in regulating a great variety of targets and, as a consequence, multiple pathways, makes their use in diagnostics a powerful tool to be exploited for early detection of disease, risk assessment and prognosis and for the design of innovative therapeutic strategies. While still not fully validated, profiling of blood cells, exosomes or body fluid miRNAs would represent a tremendous and promising advance in non-invasive diagnostics of CNS disorders. A major challenge is represented by technological aspects of miRNA detection and discovery aiming to genome-wide high throughput, sensitive and accurate analysis.

Although there is much to be learned in the field, this review will highlight the potential role of miRNA as a new class of biomarkers in several CNS disorders, including neurodegenerative diseases such as Alzheimer, Huntington and Parkinson diseases, schizophrenia and autism as well as different types of cancer (e.g. gliomas and medulloblastomas).

Introduction

The central nervous system (CNS) is formed by a very complex network of different cellular types and structures, which requires finely regulated developmental and functional processes and extraordinarily coordinated homeostatic mechanisms (e.g. neuronal regeneration and loss during tissue remodeling, intercellular connections). A yet undetermined but conspicuous number of genes is involved in the development and functions of the CNS, and alteration of the pattern of gene expression may be the cause for the onset of pathologies, which include CNS cancers and neurodegenerative diseases.

In the last few years, post-transcriptional gene regulation has emerged as a primary mechanism of modulation of gene expression, thanks to the discovery of microRNAs (miRNAs) a class of small (22 nucleotides) non-coding RNAs (Ambros, 2004). MiRNAs are generated from a long primary transcript (pri-miRNA) which is cleaved in the nucleus by a complex formed by the protein DGCR8/Pasha and the RNAse III Drosha to a shorter hair-pin structure (50–120 nt) which constitutes the miRNA precursor (pre-miRNA) (Winter et al., 2009). The pre-miRNA is then exported to the cytoplasm, where it is processed by the RNAse III enzyme Dicer to a 22-nucleotide duplex and then loaded into the miRNA-containing RNA-induced silencing complex (miRISC) where miRNA duplex is unwound and the single stranded 22 nt mature miRNA, which originates from one arm of the pre-miRNA hairpin, is bound to an Argonaute protein. Mature miRNAs bind to partially complementary sites mostly within the 3' untranslated region (UTR) of target mRNAs, targeting them for degradation or translation arrest (Bartel, 2009). Notably, increasing evidences also point to effective miRNA binding at other sites such as the 5' UTR of target genes, which will need to be further investigated. Multiple miRNA may target the 3' UTR of a single gene, while at the same time a single miRNA may have hundreds of targets (Baek et al., 2008, Selbach et al., 2008), so miRNA networks are emerging as important mechanisms which allow coordinated and fine modulation of gene expression (Cao et al., 2006, Chekulaeva and Filipowicz, 2009, Mattick and Makunin, 2005).

The identification of miRNAs has significantly expanded the knowledge of the regulatory mechanisms of gene expression in the CNS. Of relevance, approximately 70% of the miRNAs identified are expressed in the brain and discrete populations of them are brain or brain-region specific, supporting homeostatic functions on brain gene expression (Cao et al., 2006, Gustincich et al., 2006).

In this review, we discuss the present knowledge on the role of miRNAs as biomarkers for CNS diseases.

Section snippets

Role of miRNAs as biomarkers

Biomarkers are objectively measurable biologic characteristics which can be used as indicators of normal or pathologic processes. Thanks to recent advances in molecular biology, the range of potential biomarkers has expanded to include genomic profiling, transcriptomic and proteomic analysis. As a matter of fact, new molecular approaches have allowed us to move from a concept of pathogenesis based on a single event to the idea of a disease arising from alterations of entire biosystems. To this

Technological issues in miRNA analysis

MiRNAs are promising reliable biomarkers of neurological disorders due to their stability (compared to mRNA ) being less susceptible to chemical modification and RNAse degradation. This aspect of miRNAs allows their detection not only from fresh/frozen tissues, but also from body fluids such as blood (both as free circulating nucleic acids and in mononuclear cells), plasma, serum (Cortez and Calin, 2009, Keller et al., 2009a, Mitchell et al., 2008) and even from formalin-fixed paraffin-embedded

Expression and localization of miRNAs in the CNS

Several research groups have identified miRNAs which exhibit tissue specific expression in the CNS, allowing the characterization of specific “miRNomes” for the different CNS regions (Bak et al., 2008, Cao et al., 2006, Dogini et al., 2008, Trivedi and Ramakrishna, 2009).

Microarray analyses have also indicated a modulation of many of the CNS- or neural-specific miRNAs during mammalian brain development, suggesting their role in regulating brain structure and function, and in fact miRNA

MiRNAs as biomarkers of CNS cancer

miRNAs have been described to be critical in cancer initiation and progression, and consequently some of them could be considered as clinical biomarkers for cancer diagnosis, prognosis and prediction of therapeutic response (Calin and Croce, 2006, Lu et al., 2005).

The first demonstration of the link between misregulated expression of miRNAs and human cancer has been reported by Calin et al. (2002), identifying the role of mir-15 and 16 in the pathogenesis of chronic lymphocytic leukemia.

miRNAs as biomarkers in other CNS disorders

MiRNA are also involved in a range of neurodegenerative diseases, due to accelerated loss of neuronal function or reduced regeneration. Since the field is relatively young, in some cases there is a lack of consensus on specific miRNA modulation, probably due to different sampling and extraction strategies and methods of data analysis, which are not yet standardized. Another issue to be taken into account is the still limited amount of samples analyzed and in some cases the inappropriate use of

MiRNAs in early detection of cancers and other disorders in body fluids

The development of biomarkers useful to improve diagnosis, detecting early stage tumors and associate to clinical outcomes is important for personalized therapeutical approaches. To this regard miRNAs have been found in tissues and in body fluids, including serum and plasma, in a stable form that is protected from endogenous RNase activity in association with RISC, either free in blood (Mitchell et al., 2008) or in exosomes (endosome-derived organelles) (Simpson et al., 2009).

Exosomes are

Conclusions and perspectives

MiRNAs play an important role in regulating a great variety of targets and, as a consequence, multiple pathways making their use in diagnostics a powerful tool to be exploited in the holistic evaluation of CNS diseases, early detection of disease, risk assessment and innovative therapeutic strategies.

In particular, miRNAs profiling of body fluids represents the most attractive and promising advance in non-invasive diagnostics. Of course there is still the need for a considerable amount of data

Acknowledgments

We apologize to all scientists whose work could not be cited due to space constraints. The authors are supported by Telethon Grant GGP07118, Associazione Italiana per la Ricerca sul Cancro, the Italian Ministry of University and Research (FIRB, PRIN), the Italian Ministry of Health, Mariani Foundation, Roma Foundation and the Pasteur Institute, Cenci Bolognetti Foundation.

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ReviewMicroRNAs as biomarkers for CNS cancer and other disorders

Abstract

Introduction

Section snippets

Role of miRNAs as biomarkers

Technological issues in miRNA analysis

Expression and localization of miRNAs in the CNS

MiRNAs as biomarkers of CNS cancer

miRNAs as biomarkers in other CNS disorders

MiRNAs in early detection of cancers and other disorders in body fluids

Conclusions and perspectives

Acknowledgments

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Review
MicroRNAs as biomarkers for CNS cancer and other disorders