Biology Reference
In-Depth Information
Very recently, the so-called circulating miRNAs gained special
attention [
29
]. These miRNAs are found in blood and other body
fl uids, in which they are obviously resistant to rapid degradation
[
30
]. Circulating miRNAs are especially attractive as candidates for
novel biomarkers, since they can be easily obtained without the
need for biopsies and other invasive operations [
31
]. There are
many reports on signifi cant associations of circulating miRNA pat-
terns to certain disease states [
29
]. Since the mechanisms by which
circulating miRNAs are released to body fl uids are not fully under-
stood, it is not clear whether such miRNA species would also be
potential drug targets. It seems clear that circulating miRNAs are
not only remnants of dying cells, but they are also usually packaged
into lipid microvesicles like exosomes [
32
] or apoptotic bodies
[
33
]. Lipid vesicles not only contain distinct patterns of miRNAs,
suggesting a controlled mechanism of packaging which is depen-
dent on neutral sphingomyelinase-2 [
34
]. In addition, it has been
described that such wrapped miRNAs can affect regulatory pro-
cesses in other cells [
32
]. Vesicle-free miRNAs either bound to
HDL [
35
] or to proteins that are part of the miRISC like Argonaute
2 [
36
] are also known. Undoubtedly, the existence of circulating
miRNAs and their tightly regulated delivery to body fl uids add
another level of complexity to the question, why miRNAs are often
aberrantly expressed in the context of human pathology.
Although regulation of miRNA biogenesis is an important
matter, it has not been studied extensively enough yet. Surprisingly,
evidence rises that many miRNAs are controlled by the very targets
they regulate. Posttranscriptional regulation of miRNA biogenesis
in
C
.
elegans
is realized by a double-negative feedback loop:
Translation of Lin28 is inhibited by let7 miRNA, which turns out
to be inhibited by Lin28 protein [
37
]. This tightly regulated
mechanism of action also provides hints why miRNA is largely
involved into cancer initiation and progression. As a matter of fact,
miRNA expression profi les are useful for classifi cation, diagnosis,
and prognosis of human malignancies. Participation in essential
biological processes is proved for several miRNAs, among them
cell proliferation control, hematopoietic B-cell lineage fate, B-cell
survival, brain patterning, pancreatic cell insulin secretion, and adi-
pocyte development [
38
]. Of course, to gather the facts about
tumor suppressor and oncogenic miRNAs an armada of tools was
and is going to be developed to characterize cancer genomics as
precise as possible. miRNA microarrays [
39
] developed for high-
throughput miRNA fi ngerprint investigation in cells was the fi rst
step achievement followed by other technologies: macroarrays
[
40
], bead-based fl ow cytrometric miRNA expression [
18
], and
quantitative reverse transcription PCR [
41
]. Many more tech-
niques for a multiplexed and quantitative detection of miRNAs are
currently under development [
42
]. Besides the basic technologic
concerns with miRNA detection, a further important objective will
