Are miRNAs Suitable Targets for Cancer Therapy? - Therapeutic Strategies in Cancer Biology and Pathology - page 18

miRNAs. Upregulating the expression of miRNA-199a-3p has been found to target
c-met and reduce invasion ability of HCC cells (Fornari et al., 2010).
Modulations in cell mobility and the acquisition of invasive potential are an inevi-
table consequence of alterations in intercellular adhesion and the transduction of sig-
nals imparted by cell membrane associated adhesion molecules to the cytoskeletal
system. As referred to above, miRNAs have been shown to alter the expression of
cadherins. E-cadherin is an established suppressor of cell motility and invasion. It is
downregulated in cancers and this correlates with acquisition of invasive ability and
metastatic spread. Equally, miRNAs can target molecules such as Ezrin, the prod-
uct of the Vil2 gene. Ezrin links up with the actin cytoskeleton and by virtue of this
participates in cell motility, morphogenesis and intercellular adhesion. When over-
expressed it promotes anchorage-independent growth in vitro , and motility and inva-
sion. Downstream it regulates signalling pathways of PI3K/Akt/MAPK and ERK1/2,
and so its function has clear implications for apoptosis and cell proliferation.
Therefore the targeting of Ezrin by miRNAs is of some considerable significance to
the life of the cell and its biological behaviour. Lowery et al. (2010) found miRNA-
183, which is downregulated in breast cancer, targets Ezrin. In vitro also overexpres-
sion of miRNA-183 has led to the downregulation of Ezrin.
MiRNAs do affect other adhesion molecules such as CADM1 and EPB41L3 (see
pp. 134-135), which interact downstream with actin elements to regulate cell motil-
ity. MiRNAs are known to modulate the expression of ECM components and regu-
late adhesion mediated processes including EMT, and cell motility and invasion. As
stated on many previous occasions the transcription factor Snail 1 promotes the acti-
vation of EMT. Vetter et al. (2010) have suggested that this process involves down-
regulation of another immunoglobulin-like adhesion molecule Nectin-1 through
the upregulation of miRNA-661 (Vetter et al., 2010). VCAM-1 mediates leucocyte
adhesion and is possibly involved in this way in diapedesis across endothelia and
also known to influence the processes of metastasis. This is another adhesion mol-
ecule which is also regulated by miRNAs. VCAM-1 expression in endothelial cells is
regulated by miRNA-126. Overexpression of miRNA-126 has been correlated with
increased expression of VCAM-1, whilst TNF-α-stimulated VCAM-1 expression is
inhibited in endothelial cells transfected with anti-sense miRNA-126 (Harris et al.,
2008).
Finally, the hyaluronate receptor glycoprotein CD44 which participates in cell
adhesion and of which the splice variant CD44v6 participates also in metastasis
(Lakshmi and Sherbet, 1997) is directly targeted by miRNA-34a (Liu et al., 2011a).
miRNAs and Tumour Angiogenesis
Angiogenesis is another essential requirement for tumour growth and spread.
MiRNA-221 and 222 have been implicated in the inhibition of angiogenesis on
the basis that they block endothelial cell migration, proliferation and angiogenesis
in vitro , either by targeting the SCF receptor c-Kit or by altering the expression
of endothelial nitric oxide synthase; whilst in contrast, miRNA-17-92 promotes