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In-Depth Information
2007; Shi et al., 2007). Thus, the identification of miRNA-mRNA pairs in a
specific cellular context (normal or cancer) is of utmost importance; currently,
researchers are using a bioinformatics prediction approach, followed by experi-
mental validation, to gain better insights. However, a systems biology approach
may be needed to completely understand the role of miRNA in cancer, as effects
of individual miRNAs could be due to the synthetic effects of their targets.
5.2.1 Loss of miRNA Function and Cancer
The miRNAs that function as tumor suppressors (as their loss of function is
implicated in tumor pathogenesis) include the let-7 family, miR-15/16, and miR-
34. The let-7 miRNA family was first identified in C. elegans and was shown to be
important for developmental timing (Reinhart et al., 2000). In humans, the let-7
family comprises 11 homologous miRNAs and has been shown to be down-
regulated in ovarian, colon, breast, and lung cancers (Akao et al., 2006; Iorio
et al., 2005; Park et al., 2007; Takamizawa et al., 2004; Yu et al., 2007). The let-7
familymembers orchestrate their tumor suppressor functions by targeting known
oncogenes and genes known to be involved in cell cycle and cell division control.
Oncogenes such as RAS, MYC, and HMGA2 are some of the known targets of
the let-7 family of miRNAs (Johnson et al., 2005, 2007; Lee and Dutta, 2007;
Mayr et al., 2007; Yu et al., 2007). In ovarian cancers, let-7 may even serve as a
potential biomarker (Shell et al., 2007).
The genomic locus for the miR-15a and miR-16-1 cluster happens to be close
to 13q14.3, a locus that is often deleted in CLL (Calin et al., 2002). Through
gain- and loss-of-function experiments, it was established that miR-15/16
behave as tumor suppressors, blocking the function of Bcl2 (an anti-apoptotic
factor) (Cimmino et al., 2005). Expression of these two miRNAs was also
shown to be sufficient to induce apoptosis and a concomitant decrease in Bcl2
protein levels in various cancer cells.
Perhaps one of the most important findings in the tumor suppressor field
came when it was shown that miR-34 family members possess the two major
functions of p53 (namely growth arrest and apoptosis) and are activated by p53.
They have been shown to be important in various types of cancers, including
colon and lung cancers. Their genomic locations, 1p36 (miR-34a) and 11q23
(miR-34b/c), frequently undergo heterozygous deletions (Calin et al., 2004;
Versteeg et al., 1995). In support of these findings, it was shown that the anti-
apoptotic protein Bcl2 and many cell cycle regulators such as CDK4, CDK6,
cyclin E2, and E2F3 are targets of miR-34 (Bommer et al., 2007).
In many cancers, including breast cancer, gliomas, prostate cancers, and cho-
langiocarcinomas, miR-21 levels have been shown to be overexpressed, and one of
the most prominent targets of miR-21 is PTEN, a negative regulator of PI3K
signaling. Multiple functions known to be important for tumor formation and
progression, such as proliferation, anti-apoptotic activity, increased mobility, and
invasiveness (Meng et al., 2007; Si et al., 2007; Zhu et al., 2008), can be attributed to
aberrant miR-21 functions (Chan et al., 2005; Iorio et al., 2005; Meng et al., 2007).
