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correlated with clinical stage and lymphatic invasion and poor prognosis, in total
contradiction to the report by Ren et al. (2010a). Gastric carcinoma cell lines have
also shown upregulation of 14-3-3σ (Kuramitsu et al., 2010). No relationship sub-
sisted between 14-3-3σ and various clinical parameters of tumour stage, grade and
response to therapy or overall survival or disease-free survival in patients with ovar-
ian epithelial carcinoma (Mhawech-Fauceglia et al., 2009).
Naidoo et al. (2012) detected 14-3-3σ in a majority of pancreatic ductal adeno-
carcinoma. Metastatic epithelia showed upregulated expression in the cytoplasm.
Interestingly, even the metastatic tissue of primary tumours not expressing the
protein showed upregulated expression. This work involved immunohistochemi-
cal assessment of expression and the reliability of the scoring system of summing
up intensity and frequency of staining requires much scrutiny. One ought to query
the rationale for choosing 14-3-3σ, a postulated suppressor protein but excluding
14-3-3γ and 14-3-3θ which have been reported to promote tumorigenesis and pos-
sibly metastatic progression. Also it is somewhat intriguing that suppressor proteins
such as NDRG1 and Raf kinase inhibitor protein (RKIP) which have been linked
with the progression of pancreatic tumours to the metastatic stage do not occur in the
list of differentially expressed proteins.
An important point that has lapsed in many investigations is that very little atten-
tion is paid to regulation of expression at the translational levels. Most studies have
concentrated upon measuring mRNA or protein expression. Holm et al. (2009) found
no relationship between 14-3-3σ mRNA levels and protein levels. This empha-
sises the difficulties inherent in attempting correlative relationship between protein
expression and clinical features and prognostic outcome.
Nakamura et al. (2012) found 14-3-3σ in about a third of breast cancer specimens
examined. Expression of 14-3-3σ negatively correlated with resistance to paclitaxel/
5-FU/epirubicin/cyclophosphamide therapy. 14-3-3σ may regulate p53 and stabilise
its expression by suppressing its ubiquitination. It has also been shown to promote
p53 oligomerisation and increase its transcription activity (Yang, 2003b). A specific
loss of function mutations of p53 has been attributed with the ability to confer multi-
drug resistance on cells. Mutant p53 can transactivate the mdr-1 gene and this is
accompanied by increased P-glycoprotein levels (Chan and Lung, 2004). This could
be an isolated finding. However, Nakamura et al. (2012) found no correlation of drug
resistance with wild-type or mutated p53. But as noted in a later section, 14-3-3 pro-
teins are known to be induced by p53 in response to DNA damage. This suggests that
they might be involved with DNA repair and therefore can be implicated in inducing
drug resistance. This has been discussed in the following section.
How Do Other 14-3-3 Isoforms Perform in the
Clinical Settting?
In pleasant contrast, one detects much agreement regarding the effects of other iso-
forms of 14-3-3. The isoforms 14-3-3ζ, β, ε, θ, τ and γ have all been linked with
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