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2012). RKIP showed downregulated expression in a small proportion of gliomas.
Loss of expression was not related to histological type or malignancy grades, that
is grade II and grade III/IV gliomas. The loss of expression has been claimed to be
related to prognosis (Martinho et al., 2012).
The degree of downregulation seems to relate to the extent of differentiation or his-
tological grade and stage in some tumour types. RKIP is downregulated in expression
in the highly metastatic derivative cell line as compared with the parent LNCaP prostate
cancer cell line with relatively low metastatic potential. Of further significance is that
RKIP protein expression was lower in metastatic tumour than in the primary (Keller,
2004). This has been confirmed in a study of breast cancer, where RKIP expression was
high in normal breast epithelia and expressed also in primary breast tumours. However,
significantly RKIP expression was greatly reduced or absent in lymph node metastases
(Hagan et al., 2005). Reduced RKIP expression was reported in 90% of metastatic pros-
tate tumours as compared with 48% of primary tumours (Fu et al., 2006).
This suggests the RKIP negative component cells might show a greater propensity
to metastasise. A most telling commentary on the importance of RKIP in progno-
sis is provided by the study of colorectal cancer with hepatic metastasis. RKIP loss
was seen in 24.5% (12/49) of colorectal cancer without metastases, 47.1% (32/68)
of colorectal cancers with metastases and 68% of hepatic metastases. There was
a marked reduction in the median survival of patients with reduced RKIP expres-
sion as compared with RKIP positive patients (Kim et al., 2012a). It has also been
claimed that restoration of RKIP expression reduced metastasis of prostate cancer
C4-2B cells upon xenografting. In pancreatic carcinoma, loss of RKIP is related
to metastasis to regional nodes and to distant sites. Also loss of RKIP correlated
with poorer disease-free survival (Kim et al., 2010). So also an inverse relationship
between RKIP expression and prognosis has been recorded for gliomas (Martinho
et al., 2012) and oesophageal cancers (Birner et al., 2012). In some tumours, RKIP
loss occurs only in a small proportion of specimens. Whether these subsets of
tumours are more prone to aggressive behaviour is a moot point.
EMT is an important feature of neoplastic transformation. Several markers of
EMT are currently available. As shown in
Figures 22.2 and 22.3
, suppression of
RKIP is conducive to EMT. RKIP inhibits the transcription factor Snail, a negative
regulator of E-cadherin and a consequence of this is EMT inhibition (also see below
for a more detailed discussion). NPI-0052 induces RKIP expression and can upregu-
late E-cadherin expression by inhibiting Snail expression and EMT at the phenotypic
level (Baritaki et al., 2009).
Pathways of RKIP Signalling
In the pre-eminent position occupied by MAPK and Ras/Raf signalling in cancer
pathology, it is unsurprising that attention was focused on RKIP. RKIP is a member
of the phosphatidylethanolamine-binding protein family. It has a functionally flexible
pocket which can interact with and integrate the functions of the signalling ligand,
Raf-1 and kinases that phosphorylate RKIP. Phosphorylation of RKIP disables binding
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