Biomedical Engineering Reference
In-Depth Information
biology. Many cancer stem cells have been found to be more resistant to
chemotherapeutic agents and radiation therapies, which points to the unique
intrinsic program of these cells. The uniqueness of these cells may stem from the
fact that the miRNAs may behave/function differently and thus alter the
phenotypic response (Bao et al., 2006a,b; Gilbertson and Rich, 2007). HIFa
factors are also known to up-regulate expression of Oct4 (an embryonic stem
cell transcription factor) (Covello et al., 2006). Several other factors have been
proposed to be regulated by HIFa including activation of Wnt signaling and
modulation of Notch activity, MDR1, and ABCG2 (Keith and Simon, 2007).
Interestingly, HIFa factors have been shown to induce the expression of various
miRNAs and help these cells survive in hypoxic conditions (Kulshreshtha et al.,
2007). The functions of miRNA appear to be altered under stress conditions
when their binding site on mRNA 3
0
UTR is adjacent to RNA binding proteins
(Bhattacharyya et al., 2006; Vasudevan and Steitz, 2007); it was observed in
these cases that the presence of RNA binding proteins like HuR and fragile X
protein FXR1 results in the up-regulation of target genes. It will be interesting
to see whether the environmental-stress-mediated alterations in the expression
of factors such as Oct4 and miRNAs in cancer cells, and perhaps in cancer stem
cells, play a critical role in the establishment and progression of cancers. That
stress conditions can not only change the expression patterns but also alter the
function of miRNA is fascinating, especially in the context of cancer stem cells.
It is now known that both stem cells and cancer cells (or CSCs?) have
somewhat lower overall levels of miRNAs compared to differentiated and
normal cells, respectively (Lu et al., 2005; Strauss et al., 2006). The profiles of
miRNAs have been useful in grouping various cancers according to their
developmental origins and as predictors of therapeutic outcome. There are
reports of epigenetic regulation of miRNAs; for example, in human bladder
cancer cells, chromatin-modifying drugs led to the up-regulation of a group of
miRNAs (Saito et al., 2006).
To date, there have been no reports of miRNA expression patterns in cancer
stem cells. Identification of stem-like cells with respect to expression of miRNA (a
set of miRNAs or individual miRNAs) within the tumor mass may serve as a useful
biomarker. It is not known how critical a role miRNAs play in events such as
reacquisition of ''stemness'' by somewhat restricted progenitors upon transforma-
tion or whether the miRNA expression pattern resident to the cell helps or resists
such a transformation event. The status of epigenetic machinery in CSCs and what
effect it might have on the expression patterns of miRNAs are also unknown.
7 Potential Therapeutic Targets
Small molecules have a distinct appeal as practical and efficient therapeutic
agents. In that respect, miRNAs, because they are small in size and are often
deregulated in various cancers, have significant therapeutic potential. There are
