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Equally one has to consider other mechanism by which TXNIP might suppress
angiogenesis. As discussed above, TXNIP is known to inhibit the Akt signalling
pathway. Now in invasive ductal breast cancers, VEGF-A and -C isoforms show
enhanced expression upon activation of Akt and this correlated with microvessel
density (Tsutsui et al., 2010). Possibly then TXNIP could inhibit angiogenesis by
suppressing Akt mediated upregulation of VEGFs. TXNIP also inhibits NF-κB path-
way. VEGF expression is also enhanced by NF-κB induced Akt activation.
In Ras environment, TXNIP is upregulated leading to the inhibition of thiore-
doxin and increase in ROS and the induction of endothelial cell proliferation
and tubule formation (Piao et al., 2009). But it is noteworthy that Ras upregulates
VEGF expression as well as proteolytic systems such as MMPs and uPA which aid
in the release of ECM-associated VEGF and in this way promotes angiogenesis.
Hypoxia mediates the induction of VEGF; this also requires activated Ras signalling.
Furthermore, Ras controls the function of the anti-angiogenic TSPs (Kranenburg
et al., 2004). As noted earlier, RAGE upregulates TXNIP and interestingly RAGE
can also upregulate the expression of VEGF (Ma et al., 2007). So an accurate defi-
nition of the molecular environment is most essential in ruling in or ruling out the
function of TXNIP in the angiogenic process.
Finally equally important in terms of TXNIP participation in pathogenesis is that
glucose can upregulate its transcription and expression. Minn et al. (2005) identi-
fied a distinct carbohydrate response element in the human TXNIP promoter of two
E-box sequences and more precisely the effects of glucose are mediated via a region
at −341 to −324 bp upstream of the translational starting point of the TXNIP gene
(Pang et al., 2009).
miRNAs in TXNIP Function
The ubiquitous miRNAs have also been implicated in TXNIP suppressor function. Yan
et al. (2011) claim that it is a direct target of miRNA-373, one of several putative can-
didates, and possibly route the signal to achieve E-cadherin expression as noted earlier.
Equally, a target site has been provisionally identified in the promoter of E-cadherin that
binds this miRNA-373. Binding of the miRNA has been found to induce E-cadherin
expression (Place et al., 2008). This should result in the suppression of EMT and inva-
sive behaviour. These findings are important whether they occur independently or in a
TXNIP-dependent manner. However, recently totally contradictory results have been
reported in respect of the effects of miRNA-373. The Wnt pathway, of which aber-
rant activation leads to E-cadherin inactivation and activation of EMT, has also been
shown to be targeted by miRNA-371-373. The expression of these miRNAs has shown
positive correlation of Wnt/β-catenin signalling in many human cancer cell lines. TCF/
Lef1-binding elements occur in the promoter region required for Wnt-dependent
activation of miRNA-371-373 and conversely miRNA-37-373 activate Wnt/β-catenin
signalling and also target elements in the cascade (Zhou et al., 2012a).
Voorhoeve et al. (2006) believe that miRNA-372 and miRNA-373 function as
oncogenes in testicular germ cell tumours and probably collaborate with Ras in
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