Extracellular microRNA: a new source of biomarkers

Abstract

MicroRNAs (miRNAs) are a recently discovered class of small, non-coding RNAs that regulate protein levels post-transcriptionally. miRNAs play important regulatory roles in many cellular processes, including differentiation, neoplastic transformation, and cell replication and regeneration. Because of these regulatory roles, it is not surprising that aberrant miRNA expression has been implicated in several diseases. Recent studies have reported significant levels of miRNAs in serum and other body fluids, raising the possibility that circulating miRNAs could serve as useful clinical biomarkers. Here, we provide a brief overview of miRNA biogenesis and function, the identification and potential roles of circulating extracellular miRNAs, and the prospective uses of miRNAs as clinical biomarkers. Finally, we address several issues associated with the accurate measurement of miRNAs from biological samples.

Figure 1. The biogenesis of miRNAs

miRNA biogenesis begins with transcription of pri-miRNA transcripts by RNA polymerase II or III (1). In the nucleus, pri-miRNAs are processed by Drosha to produce pre-miRNA hairpins (2), which are then exported into the cytosol (3). Here, pre-miRNA hairpins are processed into 19-24 nucleotide mature miRNA duplexes by Dicer (4). One strand of the mature miRNA duplex is incorporated into the RISC complex where it can regulate expression of target mRNAs (5). The other strand may either be degraded, or possibly prepared for export from the cell (6). Some miRNAs have been found packaged in exosomes derived from multivesicular bodies (7). Others may be exported in the presence of RNA-binding proteins (8). Still others might be exported microvesicles shed during membrane blebbing (9). Once in the extracellular space, these miRNAs could be taken up by other cells, degraded by RNases, or excreted (10).

Figure 2. Plasma miR-499 levels in patients with myocardial infarction

The concentration of plasma troponin (bars) and miR-499 (gray squares) was determined from 6 individuals (X-axis) whom may suffer myocardial infarction. The concentration of troponin was displayed as ng/ml and the level of miR-499 was presented in ΔCt value (40-Ct).