Biology Reference
In-Depth Information
be the defi nition of standards for miRNA normalization in order to
allow for inter-study comparisons [
43
]. Usually, changes in miRNA
expression are normalized to other transcripts [
44
]. This can some-
times be error-prone due to inhomogeneities in miRNA ends.
In contrast, in miRNA quantifi cation by means of deep sequencing
the relative occurrence of an individual sequence is adequately
monitored [
45
]. A further step towards this direction might be
done by absolute quantifi cation of miRNAs [
46
].
5
miRNAs Directly Infl uencing Human Disease
Although the cause of miRNA misexpression in cancer is not quite
clear, it is known that many miRNAs reside in genomic regions
involved in cancer [
38
]. miRNAs appear to be able to contribute
to oncogenesis either as tumor suppressors (miR-15a and miR-
16-1) or oncogenes (mir-17-92 cluster, mir-122). Reasons of
abnormal expression of miRNA genes in malignant cells are muta-
tions, genomic amplifi cations or deletions, and chromosomal rear-
rangement—just as for protein-coding genes [
47
]. And because an
apparently high number of miRNA genes is located in cancer-
associated genomic regions, an aberrant expression causing cancer
is thought to be likely. One of the most common abnormalities in
human cancer is the dysregulated expression of c-Myc [
48
]. The
oncogene c-Myc encodes a transcription factor that regulates cell
proliferation and survival via several targets including E2F1 tran-
scription factor [
49
]. C-Myc activates E2F1 but also expression of
a six-membered miRNA cluster on human chromosome 13 (mir-
17-92 cluster). Two miRNAs among them negatively regulate
expression of E2F1, which leads to a strongly controlled prolifera-
tive signal. To emphasize, c-Myc is able to stimulate E2F1 tran-
scription and to withhold its translation via miRNA activation.
Tumor development studies in a mouse B-cell lymphoma model
indicate that miRNAs are able to modulate tumor formation impli-
cating the mir-17-92 cluster as potential human oncogene [
50
].
Human tumor samples of different types of lymphoma reveal sig-
nifi cant overexpression of pri-mir-17-92 in 65 % of the samples,
whereas colorectal carcinomas showed less overexpression from
this locus. Although it is suggested that miRNA overproduction
from that cluster weakens the proapoptotic response to elevated
Myc expression in vivo, it remains unclear how it is promoted
exactly. Lack of knowledge is also blamable on the lack of bio-
chemical strategies allowing to identify the
targets
of miRNAs.
More than 50 % of miRNA genes are found within regions
connected to amplifi cation, deletion, and translocation in cancer,
even though miRNAs represent only 1 % in the mammalian
genome [
51
]. Changes in miRNA function seem to be generated
mostly by abnormal gene expression pattern that is then
