14-3-3 Proteins in Normal and Tumour Cell Biology - Therapeutic Strategies in Cancer Biology and Pathology - page 81

lung cancer cells with siRNA directed against 14-3-3σ and demonstrated that inhibi-
tion of 14-3-3σ increased in vitro invasion. Promoter methylation has been found in
around a third of nasopharyngeal carcinomas (Chan et al., 2010). The promoter was
more frequently partially methylated in node positive than in node negative tumours
(Yi et al., 2009), but in the latter study there was little of interest in respect of cor-
relation with distant metastases. It was downregulated in oesophageal squamous cell
carcinomas and indeed reduced expression was related to invasion and lymphatic and
distant metastatic spread and reduced 5-year survival (Ren et al., 2010a).
A most telling link between 14-3-3σ expression and metastasis may have been
established by Schultz et al. (2009) with the demonstration of enhanced methyla-
tion of the gene in lymph node and cutaneous metastases of melanoma than in pri-
mary tumours, with attendant decrease in mRNA expression potentially indicating
a clonal link of the metastases with subpopulations of the primary lesion. Ling et al.
(2012) used another approach. They demonstrated that loss of one or both alleles of
the 14-3-3σ gene leads to increased cell motility in vitro , tumour growth and metas-
tasis and further that with the loss of 14-3-3σ MAPK but not PI3K/Akt signalling
is activated together with increase in proliferation but without any changes in apop-
tosis. Finally, Ling et al. (2012) show that loss of 14-3-3σ increases both invasion
and metastatic ability. However, in respect of the last parameter, only the lungs of
tumour-bearing animals were checked for metastases.
It is needless to say there are sharp disagreements too. Shiba-Ishii et al. (2011)
found higher expression of 14-3-3σ in invasive than in in situ adenocarcinoma of the
lung. Okumura et al. (2010) studying a large group of patients with oesophageal squa-
mous cell carcinomas concluded that nuclear, rather than cytoplasmic, 14-3-3σ cor-
related with clinical stage and lymphatic invasion and poor prognosis. The latter study
employed immunohistochemical methods to assess the expression. It is needless to
reiterate the problems intrinsic to this form of assessment of degree of expression.
Although methylation frequency was higher in sporadic breast cancer than in hyper-
plastic lesions, methylation status was unrelated to 5-year survival (Luo et al., 2010).
Further disagreements and divergence in views have surfaced recently in rela-
tion to the expression status of 14-3-3σ. Contrary to expectation, augmented expres-
sion has been reported in many tumour types. As stated below, 14-3-3σ expression
in cholangiocarcinomas directly correlated with lymph node involvement (Wu et al.,
2012a). 14-3-3σ expression was greater and more frequently encountered in gas-
tric cancers and furthermore, high expression correlated with disease progression
and poorer prognosis with poorer overall survival and progression-free survival
(Zhou et al., 2011b). Radhakrishnan et al. (2011a) found higher levels of 14-3-3σ
in NSCLC with attendant hypomethylation of the gene and they also emphasise that
there were no alterations in gene copy numbers or mutations that could account for
higher or aberrant expression of 14-3-3σ. In oral squamous cell carcinoma exfolia-
tive cells, the 14-3-3σ gene was hypermethylated in patients as well as in control
subjects (Cordeiro-Silva et al., 2011). There was no obvious correlation between
14-3-3σ and p53 in oesophageal squamous cell carcinoma. In fact from a study of
a large group of patients, Okumura et al. (2010) concluded that nuclear 14-3-3σ