Are miRNAs Suitable Targets for Cancer Therapy? - Therapeutic Strategies in Cancer Biology and Pathology - page 10

Growth factors
hormones, cytokines

Wnt

RTK Receptors

Ras

PI3K

PTEN GSK3

Akt

mTORC2
G β L-mTOR-Rictor

mTORC1
G β L-mTOR-Raptor

Rho/Rac
Actin dynamics Cell proliferation HIF-1 / VEGF

Figure 3.1 An abbreviated and simplified representation of the mTOR signalling pathway.
The PI3K/Akt/mTOR pathway is the predominant pathway activated by growth factors
and other biological behaviour modulators to bring about in cellular proliferation, growth,
apoptosis and cell motility. Activation of mTOR signalling involves the formation of ternary
complexes mTORC1 and mTORC2; mTORC1 in association with Raptor and GβL (G-protein
beta-subunit-like protein) (MLST8 in HUGO [Human Genome Organisation] nomenclature),
whereas the second complex mTORC2 contains GβL and Rictor (Rapamycin insensitive
companion of mTOR). Both mTOR complexes negatively regulate Deptor. As shown in the
figure, mTORC1 can activate VEGF signalling. This has been attributed with the ability to
modulate actin dynamics through Rho/Rac and so might modulate cell invasion. The figure
also shows how Wnt signalling might modulate cell behaviour by mTOR signalling.
This representation is based on references that are cited in the text (Sarbassov et al., 2005;
Efeyan and Sabatini, 2010; Sherbet, 2011a).

RECK is a negative regulator of MMPs. MiRNA-21 might influence MMPs by this
means. Suppression of RECK would confer oncogenic properties on miRNA-21.
Downregulation of its expression using anti-sense strategy has led to inhibition of
glioma cell proliferation and to the induction of caspase-mediated apoptosis (Zhou
et al., 2010b). MiRNA-21 can inhibit PTEN/Akt pathway and the pro-apoptosis Fas/
FasL signalling. Also downregulation of miRNA-21 can upregulate FasL and PTEN
and activation of Akt reverses this effect (Sayed et al., 2010). Foley et al. (2010) have
demonstrated by some elegant experimentation that miRNA-184 is a pro-apoptosis
miRNA that targets and inhibits Akt. They showed that N-myc inhibited miRNA-
184 and increased Akt levels. They then co-transfected miRNA-184 with a vector
carrying active Akt that lacked the miRNA-184 target site and found that this elimi-
nated the pro-apoptosis effects of the miRNA. The recourse to PTEN signalling is
also evident from the effects of miRNA-9 in oral/pharyngeal carcinomas. MiRNA-9
is suppressed by methylation in tumour tissue and 5-aza-deoxycytidine enhanced
its expression. Furthermore, when it was transfected into tumour cell lines, PTEN
expression was upregulated (Minor et al., 2012).