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(CAGRs). A close inspection of these regions revealed that many miRNA genes
are frequently associated with them (Rossi et al., 2008). Almost half of the
human miRNA genes (known at the time of study) have been found near FRAs
and CAGRs, suggesting that mechanisms such as deletion and amplification or
other genetic modifications could also be important for miRNA-mediated
malignancies (Calin et al., 2004). One such region, where the HOX genes or
HOX gene family members are clustered along with various miRNA genes, has
been shown to be critical for normal development and is frequently altered in
cancers (Calin et al., 2004; Cillo et al., 1999; Owens and Hawley, 2002; Pollard
and Holland, 2000).
Array comparative genomic hybridization (aCGH) analysis of various can-
cer samples suggests that copy number abnormality in regions with miRNAs is
partly responsible for the progression of cancer (Greshock et al., 2004).
Furthermore, these copy number abnormalities have been shown to be asso-
ciated with expression levels of resident miRNAs in cancer samples, and about
73%of the miRNA genes showed expression reflective of copy numbers (Zhang
et al., 2006). Thus, copy number variation may be a critical factor in the
abnormal expression pattern of miRNAs in cancers. Simultaneously, a similar
alteration in the copy number of genes responsible for miRNA processing and
maturation may affect the expression of miRNAs in human cancers. Expression
levels of miRNAs have also been shown to be correlated with the cell prolifera-
tion index, and miRNA is linked to abnormal cell proliferation, a hallmark of
tumorigenesis (Gaur et al., 2007).
5.1.3 miRNA Processing
Precursor miRNA molecules undergo a series of maturation steps, which
include processing by Drosha and Dicer and interactions with Argonaute
family members (as described in Sect. 2). Any defects due to mutation of
genes in these processing factors have been shown to affect normal development
and cancer (Carmell et al., 2002; Hutvagner and Zamore, 2002). Often, poorly
differentiated non-small cell lung cancer has a lowered expression level of Dicer,
and lower Dicer expression/function is a prognostic indicator for surgically
treated NSCLC (Karube et al., 2005).
5.2 Specific miRNAs in Cancer
MiRNAs seem to regulate various aspects of development and cellular home-
ostasis, but the mechanistic details for their functions in many aspects of
biology remain elusive. Our understanding of miRNA function is limited
because multiple miRNAs can regulate a specific mRNA, and a specific
miRNA may have multiple targets. There is evidence that miRNA-mRNA
pairs can be cell-type or context dependent (Cheng et al., 2005a; Scott et al.,
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