Circulating microRNAs: Association with disease and potential use as 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
References (85)
MicroRNAs: genomics, biogenesis, mechanism, and function
Cell
(2004)- et al.
Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets
Cell
(2005) - et al.
Validation of a microRNA-based qRT-PCR test for accurate identification of tumor tissue origin
Mod Pathol
(2010) - et al.
Accurate molecular characterization of formalin-fixed, paraffin-embedded tissues by microRNA expression profiling
J Mol Diagn
(2008) - et al.
Exosomal microRNA: a diagnostic marker for lung cancer
Clin Lung Cancer
(2009) - et al.
MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer
Gynecol Oncol
(2008) - et al.
The detection of differentially expressed microRNAs from the serum of ovarian cancer patients using a novel real-time PCR platform
Gynecol Oncol
(2009) - et al.
Circulating miR-210 as a Novel Hypoxia Marker in Pancreatic Cancer
Transl Oncol
(2010) - et al.
miR-24 up-regulation in oral carcinoma: positive association from clinical and in vitro analysis
Oral Oncol
(2010) - et al.
Circulating microRNA-1 as a potential novel biomarker for acute myocardial infarction
Biochem Biophys Res Commun
(2010)
Serum miR-146a and miR-223 as potential new biomarkers for sepsis
Biochem Biophys Res Commun
Technical variables in high-throughput miRNA expression profiling: much work remains to be done
Biochim Biophys Acta
Analysis of circulating microRNA biomarkers in plasma and serum using quantitative reverse transcription-PCR (qRT-PCR)
Methods
Exosomes—vesicular carriers for intercellular communication
Curr Opin Cell Biol
Shedding microvesicles: artefacts no more
Trends Cell Biol
miR-24 Inhibits cell proliferation by targeting E2F2, MYC, and other cell-cycle genes via binding to “seedless” 3’UTR microRNA recognition elements
Mol Cell
Secreted monocytic miR-150 enhances targeted endothelial cell migration
Mol Cell
Bonmassar E. miR-155 gene: a typical multifunctional microRNA
Biochim Biophys Acta
MicroRNAs in cancer
Annu Rev Pathol
MicroRNAs in cancer
Annu Rev Med
MicroRNA and drug resistance
Cancer Gene Ther
Metastamir: the field of metastasis-regulatory microRNA is spreading
Cancer Res
Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia
Proc Natl Acad Sci USA
MicroRNA expression profiles classify human cancers
Nature
A diagnostic assay based on microRNA expression accurately identifies malignant pleural mesothelioma
J Mol Diagn
Detection of elevated levels of tumour-associated microRNAs in serum of patients with diffuse large B-cell lymphoma
Br J Haematol
Mature miR-184 as potential oncogenic microRNA of squamous cell carcinoma of tongue
Clin Cancer Res
Circulating microRNAs as stable blood-based markers for cancer detection
Proc Natl Acad Sci USA
Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases
Cell Res
Serum microRNA signatures identified in a genome-wide serum microRNA expression profiling predict survival of non-small-cell lung cancer
J Clin Oncol
Vesicle-related microRNAs in plasma of NSCLC patients and correlation with survival
Eur Respir J
Differential expression of microRNAs in plasma of patients with colorectal cancer: a potential marker for colorectal cancer screening
Gut
Plasma microRNAs are promising novel biomarkers for early detection of colorectal cancer
Int J Cancer
MicroRNAs in plasma of pancreatic ductal adenocarcinoma patients as novel blood-based biomarkers of disease
Cancer Prev Res (Phila Pa)
Circulating microRNAs in breast cancer and healthy subjects
BMC Res Notes
Circulating microRNAs as novel minimally invasive biomarkers for breast cancer
Ann Surg
Down-regulation of miR-92 in human plasma is a novel marker for acute leukemia patients
PLoS One
Circulating microRNAs in plasma of patients with gastric cancers
Br J Cancer
Increase of microRNA miR-31 level in plasma could be a potential marker of oral cancer
Oral Dis
MicroRNA-500 as a potential diagnostic marker for hepatocellular carcinoma
Biomarkers
Plasma miR-208 as a biomarker of myocardial injury
Clin Chem
Plasma MicroRNA 499 as a Biomarker of Acute Myocardial Infarction
Clin Chem
Cited by (402)
Discriminatory power of a circulating multi-noncoding RNA panel in acute coronary syndrome subtypes: Towards precision detection
2024, International Journal of Biochemistry and Cell BiologyAn ultrasensitive and multiplexed miRNA one-step real time RT-qPCR detection system and its application in esophageal cancer serum
2024, Biosensors and BioelectronicsIdentifying Stress-Exacerbated Thermal-Injury Induced MicroRNAs
2023, Journal of PainEmerging biomarkers for early diagnosis of noncommunicable diseases
2023, Health and Environmental Applications of Biosensing Technologies: Clinical and Allied Health Science PerspectiveAnalysis of circulating microRNA during early gestation in Japanese black cattle
2022, Domestic Animal Endocrinology
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.