S100A4 as a Potential Target - Therapeutic Strategies in Cancer Biology and Pathology - page 62

Osteopontin function can itself be suppressed by targeting its receptors or
its downstream signalling components. One of the surface molecules of inter-
est is CD44. Osteopontin and its 45 kDa fragment contain the RGD (Arg-Gly-Asp)
sequence which binds to a number of cell surface integrins. Notably, osteopontin
binds to α5β1, α v β3 and α v β5, and this determines its ability to promote intercellular
adhesion and cells spreading (Yokosaki et al., 2005). Ovarian clear cell carcinomas
strongly express osteopontin. Osteopontin upregulates integrin receptor expression in
ovarian clear cell carcinoma cell lines, RMG-1 and TOV-21 G and increases in vitro
cell motility. These effects are suppressed by Simvastatin (Matsuura et al., 2010).
Osteopontin interaction with CD44 has been suggested as a putative route to the acti-
vation of c-met and so lead to cell invasion (Yoo et al., 2011).
One would recall here that the RAN (Ras-related nuclear) GTPase occurs at
greatly increased levels in human clear cell renal carcinoma as compared with nor-
mal tissue and further enhanced expression was associated with tumour grade and
has correlated with invasion and metastasis (Abe et al., 2008a). Transfection and
forced expression of osteopontin in the non-invasive Rama37 cell line transforms
them into an invasive and metastatic phenotype. These cells also show enhanced
expression of the RAN GTPase. Furthermore, transfection of an expression vector
for RAN GTPase is also able to generate the invasive phenotype of Rama37. Taken
together these observations have been interpreted as suggesting that RAN GTPase
is induced by osteopontin leading to the manifestation of invasive and metastasising
ability (Kurisetty et al., 2008).
With the current sharp focus on miRNA in the biological behaviour of cells, one
should note that transfection of miRNA-96 into HCC cells has markedly enhanced
the expression of osteopontin in HCC cells. Reducing miRNA-96 expression using
anti-miRNA-96 oligonucleotides led to reduced migration and osteopontin expres-
sion (Chen et al., 2012a).
The clear influence of Wnt signalling on S100A4 expression together with the
perceived involvement of both signalling systems in EMT and the function of osteo-
pontin as an intermediary in S100A4 coheres these courses of signalling to seek and
formulate a form of focus for therapy. Wnt pathway has been implicated in the regu-
lation of osteopontin expression. In Wnt signalling β-catenin, the transcriptional fac-
tors Lef-1, TCF-4 and other HMGs function in collusion and these are known to be
differentially expressed in some tumours. Osteopontin is activated by Wnt signalling
and indeed the transcription factor TCF-4 not only can activate osteopontin expres-
sion but also promote cell motility (Ravindranath et al., 2011). The osteopontin
promoter is responsive to β-catenin/Lef and the response is enhanced by Ets family
transcription factors. Indeed osteopontin transcription is regulated by a complex that
includes Ets, PEA3 of the Ets-domain transcription factor subfamily and β-catenin/
TCF-4 (El-Tanani et al., 2004).
Osteopontin has been implicated in loss of the suppressor protein, Merlin encoded
by NF2, the neurofibromatosis 2 gene on chromosome 22q12. Merlin is an ERM
protein, which in an under-phosphorylated form functions as a suppressor gene and
regulates many downstream signalling systems. It is able to link transmembrane
proteins with the actin cytoskeleton and modulate cell behaviour. Merlin regulates