Circulating microRNAs: Association with disease and potential use as biomarkers

https://doi.org/10.1016/j.critrevonc.2010.11.004Get rights and content

Abstract

The control of gene expression by microRNAs influences many cellular processes and has been implicated in the control of many (patho)physiological states. Recently, microRNAs have been detected in serum and plasma, and circulating microRNA profiles have now been associated with a range of different tumour types, diseases such as stroke and heart disease, as well as altered physiological states such as pregnancy. Here we review the disease-specific profiles of circulating microRNAs, and the methodologies used for their detection and quantification. We also discuss possible functions of circulating microRNAs and their potential as non-invasive biomarkers.

Introduction

The presence of nucleic acids in the serum has long been recognised, with circulating DNA released from tumours readily detected in the blood. Numerous studies have demonstrated fetal DNA in the maternal blood, leading to a number of clinical tests. Recently microRNAs (miRNAs) circulating in blood have attracted considerable attention. MiRNAs are a newly discovered class of short RNAs, 18–25 nucleotides in length, which regulate gene expression in a post-transcriptional manner, via sequence-specific interaction with target sites in mRNAs [1]. Through partial homology to the 3′UTR in target mRNAs, miRNAs effect control of gene expression via repression of translation as well as reducing mRNA levels directly [2]. Many genes have target sites for regulation by miRNAs and the complexity of this regulatory network is increased by the ability of an individual miRNA to modulate expression of multiple genes [3]. In humans, over 800 miRNAs are known, and expression of many occurs at specific stages of development or in a tissue-specific manner [2].

The expression of characteristic miRNA profiles has been implicated in the control of various developmental and disease states [2]. In cancer, miRNAs can act as tumour suppressor genes or oncogenes [4], as well as controlling various aspects of cancer biology such as chemoresistance [5] and metastasis [6]. The tissue- and disease-specific miRNA expression profiles reported are often more informative and discriminatory than mRNA profiles. This has been exploited in particular in oncology, for which a link between (loss of) miRNA expression and cancer was first demonstrated for chronic lymphocytic leukemia [7]. In a subsequent landmark study, the tissue of origin of poorly differentiated tumours was more accurately determined from miRNA profiles than from mRNA profiles [8]. These early studies have led to tumour-specific miRNA profiles published for many tumour types (reviewed in [2]) and the appearance of diagnostic tests based on the expression of discriminatory miRNA signatures [9], [10].

Complementing the informative potential of miRNA expression profiles is the unexpected stability of these short RNAs. Compared with mRNA and other longer RNAs, the short miRNA sequences are extremely stable. This property has enabled the analysis of miRNAs in archival tissue blocks, a source of little utility in mRNA profiling [11]. Recently, cell-free miRNAs have been detected in serum and plasma samples. The stability of miRNAs is similarly high in both fresh and archived serum and plasma, making the miRNAs in these samples potentially useful candidates for diagnostic and other clinical applications.

In this review, we summarise the studies of circulating cell-free miRNAs to date. In addition to commenting on their potential as non-invasive biomarkers for a number of diseases, we describe recent studies shedding light on the source of these miRNAs in the circulation and their possible functions.

Section snippets

Circulating miRNAs associated with (patho)physiological states

Circulating miRNAs have been investigated in a wide variety of patient samples and animal models (Table 1). Since the report of an association between circulating miRNAs and lymphoma [12], miRNA profiles have been associated with different tumour types, a range of diseases such as cardiovascular disease, stroke and multiple sclerosis, as well as altered physiological states such as pregnancy and liver injury. We review each of these in the following sections.

Measuring and quantifying circulating miRNAs

In comparing the reports to date, circulating miRNAs have been isolated and detected using different methodologies and from different source materials (Table 1), and quantified employing varying reference gene and normalisation strategies (Table 4). The contribution of these factors to differences in the reported results can be significant and is addressed below.

Remaining questions

Despite the unarguable potential for circulating miRNAs to act as non-invasive biomarkers, studies to date have raised a number of questions that remain to be answered.

Conclusion and perspectives

Over the last two years the presence of circulating miRNAs has now been detected in a variety of conditions. These miRNAs are extremely stable, often found in association with exosomes, and represent potentially informative biomarkers for a range of diseases. As with any field in its infancy, methodologies for the detection and quantification of circulating miRNAs suffer from a lack of convention, similar to the problems that were associated with the rapid early adoption of microarrays in gene

Reviewers

Graeme Doran, M.D., Ph.D., Massachusetts Institute of Technology, Center for Cancer Research, Cambridge, MA, United States.

Marcel Dinger, M.D., Ph.D., The University of Queensland, Institute of Molecular Bioscience, 306 Carmody Road, St Lucia, Brisbane, QLD 4072, Australia.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Acknowledgements

We thank our colleagues for helpful discussions and reviewing the manuscript.

Glen Reid graduated from Georg-August-Universität Göttingen in 2000. He worked as a postdoc in the group of Piet Borst at the Netherlands Cancer Institute in Amsterdam, studying multidrug resistance in cancer. More recently he was Principal Investigator at Genesis Research & Development a biotech company in Auckland, where his focus was the development of siRNA as a therapeutic. He is currently Senior Research Scientist at the ADRI, and is investigating the role of microRNAs in malignant

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    Glen Reid graduated from Georg-August-Universität Göttingen in 2000. He worked as a postdoc in the group of Piet Borst at the Netherlands Cancer Institute in Amsterdam, studying multidrug resistance in cancer. More recently he was Principal Investigator at Genesis Research & Development a biotech company in Auckland, where his focus was the development of siRNA as a therapeutic. He is currently Senior Research Scientist at the ADRI, and is investigating the role of microRNAs in malignant mesothelioma.

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