S100A4 as a Potential Target - Therapeutic Strategies in Cancer Biology and Pathology - page 66

S100A4 using interference RNA upregulates the expression of PRDM2 and VASH1
(Tabata et al., 2009). Saito et al. (2011) injected VASH1 intravenously using an
adenovirus vector into diabetic mice and noticed suppression of VEGF induction
together with increase in expression of P-cadherin. Interestingly they also noticed
the suppression of S100A4 expression and of Slug/Snail. This might suggest that
VASH1 might be effective in suppressing the activation of EMT. These observations
support the attribution to S100A4 with the ability to promote angiogenesis.
S100A2 Suppressor Gene and S100A4 Function
S100A2 has long been regarded as a tumour suppressor, despite some dissenting find-
ings. It shows diminished or loss of expression in many forms of cancer and the loss of
expression has been linked with cancer progression and prognosis. A few investigations
have revealed an inverse relationship between expression of S100A2 and S100A4. Loss
of expression of the gene is mainly due to hypermethylation of its promoter.
Many S100 family proteins both tumour suppressor and promoters interact with
members of the cell cycle regulator p53 family and in that way exert their influence
on cell proliferation. Tetramerisation is required for p53 function, including binding
to DNA, interaction with other proteins function and its degradation. P53 occurs in a
monomeric form and tetramerisation is preceded by an intermediate state of dimeri-
sation which is believed to be a rate-limiting step in achieving tetramerisation. S100
proteins bind different tetramerisation domains of p53 proteins and with differing
affinities. Also different S100 proteins seem to bind different oligomeric forms of
p53. Since they bind p53 in both monomeric and tetrameric state, it has been sug-
gested that binding to the monomer is inhibitory whilst binding to the tetramer has an
activating effect. These contrasting effects depend upon the degree of expression of
the proteins (Van Dieck et al., 2009, 2010). Equally, S100A4 is said to bind preferen-
tially to the p53 tetramerisation domain in its lower state of oligomerisation and effec-
tively disrupt the tetramerisation and function of p53 (Fernandez-Fernandez et al.,
2005). This would be expected to inactivate the cell cycle regulatory function of p53.
The involvement of RAGE is a shared feature in the functioning of S100 proteins.
As noted earlier, S100P promotes cell proliferation and survival by activating ERK
and NF-κB signalling. These effects can be prevented by inhibiting RAGE activa-
tion. S1004 activates NF-κB via RAGE. The induction of cell migration by S100A4
is inhibited by the inhibition of RAGE. RAGE functioning has been implicated in the
suppression of cell motility by S100A2. An inverse relationship was noticed between
RAGE expression and that of S100A2 (Nagy et al., 2001). Subsequent investiga-
tions by the same group encountered RAGE expression in many human cancers.
In breast and lung cancers, that expression of S100A4 and S100A6 correlated with
RAGE (Hsieh et al., 2003). However, doublestaining for S100A4 and RAGE does
not appear to have been carried out; hence it is difficult to state with confidence
that S100A4 expression and RAGE were related. But quite obviously there is a link
between S100A4, not S100A2, and activation of NF-κB and this is aided by RAGE
(Haase-Kohn et al., 2011).