The Application of MicroRNAs in Cancer Diagnostics - RNA Interference from Biology to Therapeutics - page 255

13.1 Introduction to MicroRNA and Cancer

13.1.1 Biological Roles of MicroRNAs in Cancer

MicroRNAs (miRNAs) are endogenous small non-coding RNA molecules of
approximately 22 nucleotides (nt) in length that control cellular processes. miRNA
are initially transcribed into long hairpin-containing primary miRNAs (pri-miR-
NAs). These are processed to approximately 70-nt precursor miRNAs (pre-miR-
NAs), which are exported to the cytoplasm and cleaved to mature miRNAs that bind
to perfect or near-perfect complementary target sequences in messenger RNA
(mRNA), leading to mRNA degradation and/or translational inhibition [ 1 ] . Highly
complex cellular and signal transduction pathways can be controlled by targeting
and controlling the level of mRNAs and their translation.
Since their discovery in 1993 [ 2 ], miRNAs have been shown to play fundamental
roles in a wide range of biological processes, and aberrant miRNA expression has
been connected to several human pathologies, including cancer [ 3 ] . The fi rst evi-
dence linking miRNAs to cancer was presented in 2002 by Calin and coworkers,
who reported the genomic loss of a pair of neighboring miRNAs, the miR-15a and
miR-16-1 cluster, in a majority of chronic lymphocytic leukemias (CLLs) [ 4 ] . During
the past decade, this finding has prompted a new and exciting field of miRNA studies
in cancer research. Today, almost 5,000 publications (including ~1,000 reviews)
have linked miRNAs with cancer. Deregulated miRNA expression is believed to
contribute to the pathogenesis of most if not all human malignancies [ 1 ] .
Several reports have shown that miRNAs directly regulate well-known onco-
genes and tumor suppressor genes, including, e.g., tumor protein p53 (TP53) [ 5 ] ,
B-cell CLL/lymphoma 2 (BCL2) [ 6 ], and v-myc myelocytomatosis viral oncogene
homolog (MYC) [ 7 ]. Thus, depending on their mRNA target, miRNAs can act as
tumor suppressors or oncogenes themselves [ 8- 10 ]. miRNAs that are upregulated
in cancer may be considered oncogenes and have been termed “oncomiRs.”
OncomiRs advance tumor development and/or progression by targeting and inhibit-
ing tumor suppressor genes and genes that control, e.g., apoptosis or cell differentia-
tion. Likewise, miRNAs with decreased expression in cancer cells may be considered
potential tumor suppressor miRNAs and generally prevent tumor development and/
or progression by targeting and inhibiting oncogenes, proliferation-related genes or
genes that control apoptosis [ 11 ]. In addition to the direct regulation of target genes,
miRNAs can affect the expression of tumor suppressors and oncogenes indirectly.
This is exemplified by the observation that members of the miR-29 family directly
target de novo DNA methyltransferases 3A and 3B (DNMT3A/B), causing changes
in DNA methylation (and hence transcriptional activity) of multiple genes in lung
cancer [ 12 ] .
miRNAs have been shown to regulate all known processes involved in cancer,
including apoptosis, cell cycle regulation, stress response, differentiation, survival,
migration, adhesion, and invasion [ 13 ]. Thus, miRNAs are involved in both the