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Extracellular miRNAs: the mystery of their origin and function

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Mature miRNAs are 19–24 nucleotide noncoding RNAs that post-transcriptionally regulate gene expression in living cells by mediating targeted hydrolysis and translation inhibition of mRNAs. In recent years, miRNAs have been detected in a variety of biological fluids as extracellular nuclease-resistant entities. Importantly, extracellular circulating miRNAs are aberrantly expressed in blood plasma or serum during the course of many diseases, including cancer, and are promising noninvasive biomarkers. However, the biological function of extracellular miRNAs remains questionable. In this article, we summarise the current theories regarding extracellular miRNA origin and function, and suggest that these miRNAs are mostly byproducts of cellular activity. Nevertheless, some extracellular miRNA species might also carry cell–cell signaling function.

Section snippets

The discovery of extracellular miRNA

More than 10 years have passed since Ambros and colleagues discovered miRNAs, a class of 19–24-nucleotide noncoding RNAs that negatively regulate the expression of target mRNAs [1]. Since then, miRNAs have been shown to participate in the regulation of diverse cellular functions and have been implicated in many diseases including cancer 2, 3, 4. The pioneering observation that miRNAs are present in biological fluids was made by Chim et al., who found placental miRNAs in maternal blood plasma in

Modes of packaging of extracellular miRNA

Shortly before the discovery of extracellular miRNA in biological fluids, the exosomes exported by cultured cells were shown to contain miRNAs [13]. This finding provoked the hypothesis that extracellular miRNA in the body can be encapsulated in microvesicles (a mixed population of exosomes and shedding vesicles) (Box 1). Microvesicles are impermeable to RNases, therefore, this hypothesis elegantly explains the remarkable stability of extracellular miRNA. Later, Hunter et al. detected miRNAs in

miRNA release from cells: selective or not?

The presence of miRNA in the extracellular environment has led many researchers to hypothesise the existence of selective miRNA export systems. An alternative opinion proposes that all types of the circulating miRNA in the biological fluids can be merely byproducts of cellular activity and cell death. Accumulating evidence, however, suggests that both theories can be true.

Both AGO2 protein and miRNA remain stable for several weeks in cell lysates without protease inhibitors, suggesting that

Organs contributing to miRNA in blood plasma

Blood cells extensively contact plasma; therefore, they can be major contributors to extracellular miRNA content in plasma. This hypothesis is supported by the observations that: (i) even small perturbations in blood cell counts and hemolysis significantly alter plasma miRNA level; and (ii) many circulating miRNA that have been previously reported as promising cancer biomarkers are also highly expressed in blood cells [30]. However, a recent comparative analysis of AGO1- and AGO2-associated

Functions of extracellular miRNA: are there any?

The early observations that some extracellular miRNAs are packaged in microvesicles, together with the evidence that miRNA and mRNA can be exchanged between cells via exosome-mediated transfer in vitro 13, 14, ignited a fascinating hypothesis: that microvesicle-encapsulated miRNAs can function as an intercellular and interorgan communication system in the body. Several recent reports clearly demonstrate that at least exosomal miRNA can participate in cell–cell communication during viral

Concluding remarks

Within the past few years, extracellular circulating miRNAs have been detected in a variety of biological fluids. These miRNAs clearly have many of the properties of ideal biomarkers, including stability in nuclease-rich body fluids, unique sequences, and tissue-specific expression. Accumulating data strongly suggest that extracellular circulating miRNAs are mostly microvesicle free and associated with the RNA-binding Argonaute proteins. Two theories regarding the export and the function of

Acknowledgements

We apologise to those whose work was not cited owing to space constraints. Our work was supported by the Dietmar–Hopp Foundation, the Helmholtz Society, and the German Cancer Research Center.

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