The Application of MicroRNAs in Cancer Diagnostics - RNA Interference from Biology to Therapeutics - page 256

initiation and the progression of cancer. The regulatory roles of miRNAs in cancer
can be highly complex and are not covered in detail here. For example, a single
miRNA may target tens or hundreds of different mRNAs, and the expression of a
certain miRNA can change according to individual steps of tumorigenesis [ 10 ] .
Several aspects remain to be uncovered regarding the functional roles of miRNAs in
human cells and their potential importance in the fight against cancer, e.g., their
potential as therapeutic targets and/or therapeutic drugs.

13.1.2 Commonly Deregulated miRNAs in Cancer

Since the first cancer-related miRNAs were discovered in 2002, the list of miRNAs
that function as either tumor suppressors or oncomiRs in different cancer types has
continually expanded. The expression level of several of these miRNAs has been
found to be deregulated in multiple human malignancies (Table 13.1 ) and hence
such miRNAs may have potential as new cancer biomarkers (molecular mecha-
nisms responsible for aberrant miRNA expression in cancer cells are described
below in Sect. 13.1.3 ). For instance, loss of miR-15a and miR-16-1 as seen in CLL
patients has also been observed in patients suffering from, e.g., prostate cancer [ 21 ] ,
pancreatic cancer [ 22 ] , and multiple myeloma [ 13 ] . Likewise, overexpression of
miR-155 has been found in high-risk CLL [ 32 ], acute myeloid leukemia (AML)
[ 33 ] , breast cancer [ 14 ] , and lung cancer [ 25 ]. The fact that the expression level of
some miRNAs is changed not only in one but also in many types of cancer suggests
that these miRNAs may be downstream targets of commonly deregulated pathways
in cancer [ 26 ] .
When describing a specific miRNA as an oncomiR or tumor suppressor, it is
necessary to specify the cell and tissue type in which the miRNA functions. miRNA
expression patterns are highly cell specific, and a given miRNA can control differ-
ent functions depending on the cellular context, and which targets and pathways that
are affected in different types of cells. An example is the miR-221 and miR-222
cluster. This cluster is upregulated in CLL, glioblastoma, liver cancer, and thyroid
carcinoma, and targets at least four important tumor suppressors: cyclin-dependent
kinase inhibitor 1B (CDKN1B; p27/Kip1) [ 59 ] , cyclin-dependent kinase inhibitor
1C (CDKN1C; p57/Kip2) [ 60 ], phosphatase and tensin homolog (PTEN), and tis-
sue inhibitor of metalloproteinases 3 (TIMP3) [ 61 ], and hence are considered as
oncomiRs in these malignancies. In contrast, the downregulation of miR-221 and
miR-222 in erythroblastic leukemia, where they target the oncogene KIT (v-kit
Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog KIT), defines miR-221
and miR-222 as tumor suppressor miRNAs in this type of cancer [ 62 ] . Thus, it is
worth noting that some miRNAs have dual tumor suppressive and oncogenic roles
in cancer, that is dependent on the cell type and pattern of gene expression. Attempts
to understand the complex biological roles of miRNAs in cancer are further compli-
cated by the many ways in which a given miRNA can be deregulated.