Biomedical Engineering Reference
In-Depth Information
tools available now that can alter/interfere with miRNA functions in vivo. For
example, oncogenic miRNA function can be blocked by using small antisense
chemically stabilized RNAs, which can block miRNA inhibitory functions
(Li et al., 2006; Lui et al., 2007; Meister et al., 2004a; Weiler et al., 2006). In
cancers where loss of miRNA function has been attributed to tumorigenesis,
miRNA can be re-expressed by using viral vectors harboring miRNA genes/
short hairpin version of miRNAs (Li et al., 2006; Lin et al., 2006). In lung
cancers, it has been shown that overexpression of let-7 leads to the decreased
resistance of these cells to radiation therapies (Weidhaas et al., 2007). As stated
earlier, let-7 expression levels serve as a biomarker to estimate 5-year progres-
sion-free survival in breast cancer patients (Shell et al., 2007). It was shown that
a ratio of the let-7 target gene HMGA2 to let-7 was useful in prognosis.
Bcl2 is an anti-apoptotic factor commonly deregulated in cancers (e.g., B-cell
CLL), with associated loss of miR-15/16. Thus, restoring expression of miR-15/
16 in cancers seems a plausible therapy, as they can induce apoptosis by decreas-
ing Bcl2 protein levels. Suppression of miR-221/222 function has been shown in
lung cancer models, whereas expression of miR-221/222 in erythroleukemic cells
leads to a decrease in the proliferation of these cells. It has been shown that miR-
34a is a target of p53 and contributes to normal p53 function. Expression of miR-
34a promotes apoptosis and decreased proliferation in various cancers, including
lung and colon cancers (Chang et al., 2007; Tazawa et al., 2007). In human
gliomas, it has been observed that blockade of miR-21 function in combination
with S-TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) leads to
a marked decrease in tumor growth (Corsten et al., 2007).
The future of miRNA-centered therapies looks bright. Specific identification
of miRNA and its cognate target mRNA is very crucial and is likely to be a key
determinant in the success of such therapies. However, the fact that a single
miRNA can target multiple mRNAs (and thus affect multiple cellular path-
ways) remains both a strength and a weakness of such approaches.
8 Conclusions
Our knowledge of miRNA biogenesis and miRNA-dependent regulation of
gene expression continues to expand every day, and new pathways are sought
for miRNA-dependent control. Knowledge of the regulatory network of
miRNA and its targets is proving to be critical for a number of regulatory
processes involved in normal development as well as in cancers and other
diseases. However, a comprehensive understanding of the critical role of
miRNAs in various biological processes and contexts will require additional
functional analyses, including a precise identification of miRNA targets. This
process has begun in a number of laboratories, but progress will depend on
developing more efficient assays for deciphering the targets in different
contexts.
