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Fig. 12
Therapeutic relevance of miRNA biogenesis inhibitors. A tumor mouse
model was treated with either polylysine (PLL) or trypafl avine (TPF), which were
previously found to inhibit miRNA function/maturation. Only drug-treated mice
exhibited a reduction in tumor growth demonstrating the in vivo effi cacy of the
small-molecule inhibitors. Image adapted with permission from Watashi K et al.
(2010) J Biol Chem
the mature miRNAs, resulting in a loss-of-function phenotype.
While this does not directly affect miRNA maturation, its preva-
lence within the fi eld is worth noting.
Early studies employed 2
-O-methyl oligonucleotides directed
against let-7 miRNA and demonstrated effi cient and irreversible
base pairing to the miRNA guide strand within RISC [
23
].
Additionally, they helped elucidate key protein components of
RISC within
C. elegans
and suggested the ability of these miRNA-
targeting oligonucleotides to achieve a let-7 loss-of-function phe-
notype within a model organism by simple injection into the larvae.
Finally, the antisense oligonucleotides were able to show that RISC
function was signifi cantly more impacted by antisense binding to
RISC rather than binding to the complementary mRNA sequence,
suggesting an active mechanism of gene silencing by RISC.
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