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invasion might involve PI3K/Akt signalling with regulation by PTEN. Overexpression
of PDCD4 is associated with enhanced PTEN expression and reduced Akt (Wei et al.,
2012a). As discussed later in this section, both PI3K/Akt/mTOR and MAPK/ERK
pathways are probably operational in the inhibition of angiogenesis by PDCD4.
PDCD4 is targeted and regulated by miRNA-21, as noted earlier in connection
with the discussion of cell proliferation and metastasis. It is downregulated or inac-
tivated in expression in many tumours. Early studies with miRNA-21 has generated
much interest because it was found to be markedly upregulated and expressed in
relation to grade in breast cancer (Iorio et al., 2005; Volinia et al., 2006). MiRNA-
21 is anti-apoptotic (Carletti et al., 2010; Chan et al., 2005) and induces cell pro-
liferation (Asangani et al., 2008; Roldo et al., 2006; Si et al., 2007). MiRNA-21
is said to be able to inhibit the tumour suppressor PDCD4 (Asangani et al., 2008;
Frankel et al., 2008; Li et al., 2010d). The anti-apoptotic effect might also result
from its ability to inhibit PTEN, which negatively regulates Akt and Fas/FasL sig-
nalling (Yang et al., 2011a; Zhang et al., 2012a). In fact, Zhang et al. (2012a) found
that miRNA-21 is overexpressed in gastric carcinoma tissues and suppression of its
expression levels correlates with upregulated expression of PTEN.
MiRNA-21 seems to regulate PDCD4 levels as evidenced by the fact that inhibi-
tion of miRNA-21 lead to approximately 3.5-fold upregulation of PDCD4 expression
(Frankel et al., 2008). Suppression of miRNA-21 has led to reduction of invasion of
MDA-MB-231
in vitro
and reduced lung metastases in animal models (Zhu et al.,
2008b). Interestingly these authors also reported that the expression of miRNA-21
inversely correlated with that of PDCD4 and Maspin (a putative metastasis inhibi-
tor) in breast cancer specimens. Unfortunately this is a study limited to breast cancer
specimens and corresponding normal tissues. No clinical information on the speci-
mens is available. Glioblastomas also show an inverse relationship. Downregulation
of miRNA-21 correlated with enhanced expression of PDCD4, together with reduced
cell proliferation and increased apoptosis (Gaur et al., 2011). Experimentally alter-
ing the levels of miRNA-21 of malignant peripheral nerve sheath tumour cells by
transfection the cells with miRNA-21 inhibitor suppressed cell proliferation with
induction of apoptosis. This was accompanied by enhanced PDCD4 expression
(Itani et al., 2012). Horiuchi et al. (2012) investigated a large series of colorec-
tal cancer patients. Levels of PDCD4 were negatively related to Dukes grade. Low
PDCD4 levels correlated with poor prognosis in each of Dukes' stages B, C and
D. Furthermore, PDCD4 mRNA expression was negatively related to miRNA-21
(Horiuchi et al., 2012). This is a clear example of progression-related downregula-
tion of PDCD4 with parallel enhanced miRNA-21 expression. Nonetheless, dis-
senting voices are heard. For instance, Torres et al. (2011) have reported marked
upregulation of miRNA-21 in endometrial cancers, but Maspin also showed con-
siderably increased expression. PDCD4 expression was not altered. None of them
showed any correlation with FIGO stage. Other possibilities also need to be reck-
oned with. As discussed in another location, miRNA-21 can regulate the PI3K/Akt/
mTOR pathway albeit operating via PDCD4 (see below). It can also promote pro-
liferation and invasion by downregulating p12 (CDK2-AP1), which suppresses cell
proliferation by inhibiting cdk2 and G1-S transition. MiRNA-21 has also been asso-
ciated with the induction of EMT by TGF-β.
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