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Some years ago, Yang et al. (2004) demonstrated the involvement of Twist in
EMT as indicated by the expression of EMT markers together with alterations in
E-cadherin and acquisition of cell motility. Further definitive evidence is now avail-
able implicating Twist in EMT. Twist overexpression is accompanied in parallel by
increased cell motility and alteration in the expression of E-cadherin, N-cadherin
and MMP-9 expression (Yu et al., 2012b). Jouppila-Matto et al. (2011) examined a
series of pharyngeal carcinomas and noted that Twist and Snail expression was asso-
ciated with stromal component of higher grade tumours, and these recurred more fre-
quently. They also noted that Twist and Snail negative tumours reflected favourable
prognosis. Similar relationship was reflected in gastric and renal cancers also (Ru
et al., 2011; Mikami et al., 2011).
We now know that besides Twist, the transcription factors such as Snail (SNAI1
Snail 1 Drosophila homologue), Slug, ZEB and Sip1 are also involved in EMT.
MiRNA-205 has been reported to suppress EMT by inhibiting transcription factors
ZEB1 and ZEB2, which are known to promote EMT. MiRNA-138, which is capable
of inhibiting EMT, has been shown to target ZEB2 and regulate E-cadherin expres-
sion (Liu et al., 2011e). The miRNA-200s and miRNA-205 block the repression of
E-cadherin expression (Burk et al., 2008; Gregory et al., 2008; Korpal et al., 2008;
Park et al., 2008). MiRNA-200 family can transcriptionally upregulate E-cadherin
accompanied by ZEB1 repression and inhibit EMT generating a less aggressive
phenotype (Tryndyak et al., 2010). Not only this, Twist induces the expression of
Snail and this is essential for Twist-mediated activation of EMT (Casas et al., 2011).
PDGF overexpression in PC3 cells has been found to activate EMT. This seems to
result from the suppression of miRNA-200s. This leads to the upregulation of ZEB1,
ZEB2 and Snail2, with consequent repression of E-cadherin transcription (Kong
et al., 2008, 2009). ZEB1 recruits the co-repressor BRG1 (Sánchez-Tilló et al.,
2010). Blocking this interaction induces the expression of E-cadherin and inhib-
its EMT. Logistically this membrane associated disposition of the ZEB1/BRG1
complex and E-cadherin could be a mechanism linking EMT with tumour inva-
sion. Whist in many cell types miRNA-200 suppresses EMT by upregulation of
E-cadherin expression, it is the overexpression of miRNA-375 that inhibits migra-
tion in gastric cancer cells. This seems to occur by a different route via inhibition of
JAK2 (Ding et al., 2010). MiRNA-194 has been shown to inhibit EMT by upregu-
lating the expression of E-cadherin and downregulating that of Vimentin. MiRNA-
194 suppresses the transcriptional repressor BMI-1, a Polycomb group (PcG) gene
by directly binding to its 3′-UTR (Dong et al., 2011). Thus miRNAs might achieve
the same phenotypic effect by targeting different genes, possibly through the func-
tion of different transcription factors. It should also be borne in mind in this context
that many miRNAs are downregulated and others upregulated (Angeles et al., 2011),
but whether they induce the expression of specific transcription factors needs to be
fully understood. Twist expression shows marked correlation with tumour associated
microvascular density in HCCs (Che et al., 2011), which indeed adds another twist,
to use a well-worn cliché, to the argument. Snail expression has been linked with
choroidal neovascularisation (Hirasawa et al., 2011). One should include a comment
here that the c-met receptor of HGF/scatter factor is also known to be targeted by
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