Are miRNAs Suitable Targets for Cancer Therapy? - Therapeutic Strategies in Cancer Biology and Pathology - page 16

angiogenesis and metastasis associated genes are targeted by miRNAs. Invasion is a
prerequisite for the secondary spread of cancer. Some of the tumour promoter miR-
NAs have been found to enhance cell motility. Li et al. (2011c) have claimed that
cell lines derived from metastatic gastric cancers overexpressed miRNA-223 and
indeed stimulated non-metastatic gastric cancer cells to migrate and invade. This is
highly significant given that miRNAs can accentuate and augment angiogenic signal-
ling, as discussed earlier.
MiRNAs actively influence EMT. Indirect support is also adduced by the fact that
miRNA-223 is inducible by the basic helix-loop-helix (bHLH) transcription factor
Twist which is associated with EMT and embryonic differentiation and which has been
deeply correlated with regulation of genes associated with metastasis. The transcription
factors Twist, Snail, ZEBs, etc. are negative regulators of E-cadherin expression. Loss
of E-cadherin expression initiates EMT. Downregulation of Twist has led to the inhi-
bition of EMT (Yu et al., 2011). The miRNA Let-7d expression inversely correlated
with the expression of Twist and Snail in oral squamous cell carcinoma cell lines and
inhibited EMT (Chang et al., 2011a). MiRNA-21 seems to be involved in the induction
of EMT by TGF-β. It is often upregulated in cancers and promotes TGF-β-mediated
activation of EMT (Zavadil et al., 2001). Forced downregulation of miRNA-21 has
been shown to promote apoptosis and inhibit cell motility of ovarian carcinoma cells
in vitro (Lou et al., 2011). This could quite possibly involve p53, although not dem-
onstrated to be the case here. Some miRNAs are regulated by p53; p53 can and does
upregulate miRNA-200c and inhibit EMT (Chang et al., 2011b). P53 also upregulates
miRNA-34a. Upon being induced to re-express in human pancreatic cancer stem cells
(CSCs) and in human pancreatic cancer cell lines miRNA-34a inhibited cell prolifera-
tion, cell cycle progression, EMT and invasion (Nalls et al., 2011). Enforced expres-
sion of miRNA-34c in breast cancer cell lines has been shown to inhibit the activation
of EMT (Yu et al., 2012a). Others such as miRNA-200 and miRNA-205 are said to
be downregulated in EMT stimulated by TGF-β. MiRNA-200 can transcriptionally
upregulate E-cadherin by ZEB1 repression and apparently in this way inhibit the EMT
phenotype (Tryndyak et al., 2010). The Snail-mediated regulation of EMT activa-
tion seems to involve miRNA-661. Vetter et al. (2010) have suggested that this pro-
cess involves downregulation of the immunoglobulin-like adhesion molecule Nectin-1
through the upregulation of miRNA-661. The expression of Let-7f is reduced in gastric
cancers, and upon transfection into cell lines significantly suppressed cell invasion and
the transfected cells also showed reduced ability to form tumours when xenografted
into immune-compromised mice (Liang et al., 2011b). These authors state that Let-7f
directly targets and binds to the 3′UTR of MYH9 (myosin-9 also known as cellular
myosin heavy chain, type A) gene. It should be noted here many functions that could
impinge upon cell motility and invasion have been attributed to MYH9 such as the
reorganisation of the actin cytoskeleton. So the targeting of MYH9 could be important.
MiRNA-335 has been found to be able to upregulate BRCA1 expression (Heyn et al.,
2011). This is in agreement with the view that miRNA-335 is an inhibitor of metas-
tasis. MiRNA-335 is said to suppress cell migration and lung colonisation in the less
than ideal assay for metastasis upon tail vein injection. This in fact seems to occur by
inhibiting SOX4, an activator of EMT (Zhang et al., 2012c).