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protein levels. Moreover, miR-21 was highly overexpressed in hepatocellular
carcinoma (HCC) and cell lines [
20
]. Inhibition of miR-21 in cultured HCC cells
increased expression of the phosphatase and tensin homolog (PTEN) tumor sup-
pressor and decreased tumor cell proliferation, migration, and invasion. In contrast,
enhanced miR-21 expression by transfection with precursor miR-21 increased
tumor cell proliferation, migration, and invasion. Moreover, an increase in cell
migration was observed in normal human hepatocytes transfected with precursor
miR-21. PTEN was shown to be a direct target of miR-21 and to contribute to miR-
21 effects on cell invasion. Aberrant expression of miR-21 can contribute to HCC
growth and metastatic spread by modulating PTEN expression and PTEN-dependent
pathways involved in mediating the phenotypic characteristics of cancer cells, such
as cell growth, migration, and invasion.
The definition of oncogenic miRNAs and tumor-suppressive miRNAs is deter-
mined by their expression and function in cancer cells; however, designation to a
particular subset varies dependent on the cell type or the microenvironment. For
instance, let-7 induces translation and upregulation of target mRNAs upon cell cycle
arrest, yet represses translation in proliferating cells [
21
] . Knowing the precise
mechanisms of miRNA regulation and the cellular function of miRNAs is critical
for the design and choice of miRNA-mediated therapy.
14.2
Therapeutic Control of miRNA
14.2.1
Overproduction of miRNA Can Be Suppressed
by Antisense Oligonucleotides
Single-strand antisense oligonucleotides (ASOs) are an attractive approach to inhibit
the function of miRNAs (Fig.
14.1
). Previously, ASOs were used as inhibitors of
mRNA expression; however, after the discovery of RNA interference (RNAi), small
interfering RNA (siRNA) has become the preferred method for gene silencing.
ASOs against miRNAs are referred to as either anti-miRs, antagomirs, or anti-
miRNA oligonucleotides (AMOs). There are several types of antisense nucleotide
inhibiting miRNAs in the cells. The difference in these molecules depends on the
chemical modification or the structure of nucleic acid constructs.
Antagomirs are 2¢ -
O
-methyl oligonucleotides with a cholesterol terminus and a
few phosphorothioates complementary to the miRNA [
22
] . In addition, 2 ¢ -
O
-methyl
oligonucleotide is used with a full phosphorothioate backbone [
23
] . The 2 ¢ -
O
-methyl-
group (OMe) is one of the most classical and most often used modifications to oli-
gonucleotides [
24
]. The methyl group contributes a limited amount of nuclease
resistance and improves binding affinity to RNA compared to unmodified oligonu-
cleotides. Furthermore, 2¢ -
O
-methoxyethyl (MOE)-modi fi ed oligonucleotides have
higher affinity and specificity to RNA than their OMe analogs [
24
] . Locked nucleic
acid (LNA)-modified oligonucleotides are distinctive 2¢ -
O
-modi fi ed RNA in which
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