The Application of MicroRNAs in Cancer Diagnostics - RNA Interference from Biology to Therapeutics - page 258

13.1.3 Mechanisms of miRNA Deregulation in Cancer

Precise control of miRNA levels is essential for maintaining normal cellular
homeostasis. Although the biogenesis of miRNAs is often described in a simplified
linear manner, many of the steps in the processing of a given miRNA can be
performed in multiple ways, since miRNAs are under precise control of develop-
mental and/or tissue-specific signaling. Therefore, there are multiple ways by which
something can go wrong [ 66 ]. This section describes major mechanisms known to
be involved in miRNA deregulation in cancer.
Genetic, epigenetic, transcriptional, and posttranscriptional mechanisms have all
been found to contribute to changes in miRNA expression in cancer (Fig. 13.1 ).
Genetic mechanisms include primarily chromosomal abnormalities that can lead to
genomic deletion, amplification, translocation, or mutation of miRNA genes. It has
been reported that more than half of all human miRNAs are located at fragile sites
or in genomic regions that are frequently involved in chromosomal alterations in
multiple types of cancer [ 67 ]. Likewise, it has been shown that oncomiRs are often
located in regions amplified in cancer, while tumor suppressor miRNAs are located
mainly in regions of genomic loss [ 68 ]. miRNAs have a high overall conservation,
consistent with the finding that miRNA genes have lower single nucleotide poly-
morphism (SNP) density than their neighboring regions [ 68 ] . Somatic mutations in
the mature miRNA seed sequence seem rare events. Several studies have shown that
so-called miRSNPs, i.e., SNPs present at or near a miRNA binding site in a func-
tional gene, affect the interaction of miRNAs with their target mRNA, and that this
mode of regulation is implicated in cancer [ 69- 71 ] .
Although not clearly understood, transcriptional regulation of miRNAs is known
to be controlled by a variety of factors, including transcription factors [ 8, 72- 74 ] .
Accordingly, overexpression or downregulation of a transcription factor at an inap-
propriate time or in the wrong tissue can lead to upregulation or silencing of a
miRNA, and hence may contribute to tumorigenesis. For example, in prostate can-
cer cell lines, the mutation and consequent loss of function of the tumor suppressor
TP53 have been connected to downregulation of miR-145 [ 75 ] . Other mechanisms
influencing the regulation of transcription are heritable changes in gene activity,
which are independent of changes in the primary DNA sequence, i.e., epigenetic
mechanisms. There are three main epigenetic events regulating cancer-associated
genes: abnormal hypermethylation of CpG islands associated with the promoter
region of tumor suppressor genes, global DNA hypomethylation, and activating/
repressive posttranslational modifications of histone proteins [ 44, 76 ] . Bioinformatic
analyses have shown that around half of all human miRNA genes have a promoter-
associated CpG island [ 77, 78 ], potentially exposing these miRNA genes to the
regulatory control of epigenetic modifications. An example of this is miR-127,
which is downregulated in bladder cancer cells. The silencing of miR-127 has been
shown to be mediated by epigenetic mechanisms and miR-127 is significantly
induced in bladder cancer cell lines upon treatment with activating chromatin-
modifying drugs [ 79 ] .