Biomedical Engineering Reference
In-Depth Information
accessibility to the target is dependent on the physical state of the target; they
are subjected to post-transcriptional regulation; and they are capable of work-
ing as an integral part of networks (Buck and Lieb, 2006; Grimson et al., 2007;
Kawahara et al., 2007; Kedde et al., 2007; Lee et al., 2008; Robins et al., 2005;
Saetrom et al., 2007; Thomson et al., 2006). Apart from these similarities,
miRNA differ from transcription factors in many ways that perhaps allow
miRNAs to work in a wide range of cellular processes in a temporal and
context-dependent manner. The repressive function of miRNAs is restricted
by the availability of target mRNAs and the length of the 3
0
UTR of the target
mRNAs; thus, miRNAs function to fine-tune the existing gene expression
program in the cell and can only influence a sub-set of transcription-factor-
regulated processes (Hobert, 2008). Because miRNAs function to block protein
translation and can be located sub-cellularly, and their repression can be
reversible, they are better suited to work as more rapid effector molecules in
response to changing cellular environments and to maintain homeostasis, as
compared to transcription factors (Ashraf et al., 2006; Bhattacharyya et al.,
2006; Martin et al., 2000; Schratt et al., 2006).
5 MicroRNAs and Cancer
Mechanisms that are known to be responsible for changing the expression
patterns of tumor suppressor genes and oncogenes have also been implicated
in altering the expression patterns of miRNAs. Such mechanisms include wide-
scale genomic aberrations, mutations affecting expression and processing, and
epigenetic alterations. For miRNA, the mutations affecting target interactions
will also have a loss-of-function effect (Cowland et al., 2007).
The genomic locations of many miRNA genes are areas of chromosomes
that frequently undergo rearrangement, amplification, and deletion in various
types of cancers (Calin et al., 2004). The identification of miRNA genes in such
chromosome regions may explain the corresponding absence of any known or
putative oncogenes or tumor suppressor genes in these regions, which appear to
be important in cancers. The expression of miRNAs can be either up-regulated
(these miRNAs can function as oncogenes and are called onco-miRs) or down-
regulated (these miRNAs can function as tumor suppressors and are called
tumor suppressor miRs) (Costinean et al., 2006). This classification of miRNAs
as tumor suppressors or oncogenes is based on their effect on the target genes, as
mechanistically the miRNAs are repressor molecules only (Fig. 3). For exam-
ple, if the target of miRNA is a known tumor suppressor, the miRNA is an
onco-miR. Conversely, if the target is an oncogene, the miRNA is a tumor
suppressor miR. It is noteworthy that the same miRNA can be an onco-miR or
a tumor suppressor miR, depending on its tissue-specific targets. It has been
shown that in cases of chronic lymphocytic leukemia (CLL) miR-15a and mir-
16-1 genes are either deleted or down-regulated. These alterations in the
