Biomedical Engineering Reference
In-Depth Information
leukemia (ALL) or acute myeloblastic leukemia (AML) results in fusion ALL1
(MLL) protein, which targets the Drosha-containing microprocessor complex
to increase processing of specific miRNA precursors such as miR-191 (Naka-
mura et al., 2007).
Mouse models overexpressing single miRNA (miR-155) develop lympho-
blastic leukemia or high-grade lymphoma, suggesting that deregulation of a
single miRNA can cause cancer (Volinia et al., 2006). These cancers become
aggressive at slower than usual rates, suggesting that additional events may be
required for the cancer to progress at a faster rate. In many lung cancers, the
expression of Let-7 family members is either lost or lowered and, as a result,
RAS is overexpressed (Johnson et al., 2005). Similarly, loss of miR-15 and miR-
16-1 in CLL causes increased expression of Bcl2 and anti-apoptotic factor
(Cimmino et al., 2005). The tumor suppressor gene PTEN has been shown to
be a target of miR-21 (Meng et al., 2006). In many types of cancer involving
various tissues (breast, lung, prostate, etc.), lost or lowered expression of the
PTEN gene has been reported, along with increased expression of miR-21. It is
important to note that the miR-21-mediated loss of PTEN function has not
been observed in cases where a mutation in the PTEN gene occurred. This
distinction may have to be made in every tumor where a miRNA-mRNA pair
has been implicated to play a role. Questions about these observations still
remain. Are there any sub-groups of cells within the tumor mass that show a
different miRNA-mRNA expression profile as compared to the rest of the
tumor cells? Can this miRNA-mRNA expression profile be used to distinguish
cancer stem cells from the rest of the cancer cells within a given tumor?
5.1 miRNA-Mediated Mechanisms in Cancer
5.1.1 Epigenetics and miRNAs
Epigenetic regulations, such as hypermethylation of 5
0
regulatory regions of
miRNA genes, have been implicated in the down-regulation of miRNA genes in
cancers (Lujambio et al., 2007; Saito et al., 2006). Comparisons of the expres-
sion levels of miRNAs in normal versus tumor cells found that a sub-group of
miRNAs were down-regulated (Calin and Croce, 2006; Chen, 2005; Lu et al.,
2005). Since miRNAs are repressor molecules, these down-regulated miRNAs
in cancers are termed tumor suppressor miRs. Various studies discovered
an intricate link between tumor suppressor miRs and their cognate oncogene
pairs (e.g., let-7 and RAS; miR-15/miR-16 and BCL2) (Cimmino et al., 2005;
Johnson et al., 2005).
5.1.2 miRNAs in Cancer-Associated Genomic Regions (CAGRs)
Over the years, researchers have identified fragile sites (FRAs) and genomic
regions affected in various cancers known as cancer-associated genomic regions
