Are miRNAs Suitable Targets for Cancer Therapy? - Therapeutic Strategies in Cancer Biology and Pathology - page 19

tumour angiogenesis in vivo . Let-7-f, miRNA-27b and miRNA-130a are believed
to be pro-angiogenic in vitro (Kuehbacher et al., 2008, Urbich et al., 2008). The
role of miRNA-27b requires further study. Fang et al. (2011) found that this miRNA
inhibited angiogenesis. Their work has indicated that miRNA-29b directly tar-
geted MMP-2. Fang et al. (2011) have reported that experimental tumours derived
from HCC expressing miRNA-29b showed reduced tumour associated microves-
sel density. Davis et al. (2009) noticed that miRNA-221 occurred in parallel with
downregulation of c-Kit, which is normally linked with induction of angiogenesis.
Certain miRNAs, for example miRNAs-17-92 and miRNA-378, might show spe-
cific association with tumour angiogenesis. Of note would be the association of
miRNA-223 which is inducible by the bHLH transcription factor Twist, itself linked
with EMT and embryonic differentiation and which has been deeply correlated with
angiogenesis.
The mTOR signalling pathway is closely involved in growth factor receptors func-
tion ( Figure 3.2 ). The PI3K/Akt activation leads to the phosphorylation of mTOR,
which then phosphorylate the downstream targets p70S6K and 4EBP leading in turn to
cell proliferation. Angiogenesis might be regulated by mTOR signalling as Grundmann
et al. (2011) have shown. MiRNA-100 regulated mTOR expression in vitro and
in vivo . It targeted mTOR in vascular cells and downregulated its expression and inhib-
ited endothelial cell proliferation and so attributed with anti-angiogenic properties
( Figure 3.3 ).
Hypoxia is another major regulator of angiogenesis. HIF-1α (hypoxia-inducible
factor-1α) is a transcription regulator in hypoxia. Signals transduced via RTK/PI3K/
Akt into PDK1/PKC or mTOR and downstream to the phosphorylation of S6K1/
EBP1 can lead to HIF-1α protein expression. HIF-1α is recognised and degraded by
VHL (von Hippel-Lindau tumour-suppressor protein), which is a component of the
E3 ubiquitin ligase complex. In hypoxic situations VHL is inactivated and HIF-1α is
stabilised and accumulates. This then can activate VEGF to induce angiogenesis and
TGF-α and promotes cell survival (Pantuck et al., 2003). Hypoxia involves miRNAs
Figure 3.2 A general notion of the instigation by miRNAs of the regulation of cell
proliferation via RTKs, GPCRs and the nuclear ER. Also shown is the involvement of
p53 in controlling cell proliferation by activating the apoptotic pathway, which is also
modulated by miRNAs. It ought to be borne in mind here that some miRNAs may promote
apoptosis. This is not shown in this figure. Further details of the signalling systems are
provided in Figures 3.3-3.7 and described in the text.