Are miRNAs Suitable Targets for Cancer Therapy? - Therapeutic Strategies in Cancer Biology and Pathology - page 12

Another potential mode of miRNA function in promoting tumour progression has
emerged from some recent studies, which show interaction between miRNAs and
growth factor signalling. Several growth factor signalling pathways have been identi-
fied as being able to interact with miRNAs. Of considerable interest in this respect
are the EGFR family. Of these EGFR and HER2 (human EGFR 2) signalling has
received some attention. EGFR is highly expressed in a proportion of breast cancers,
which also tend to be ER negative. Wang et al. (2012c) have addressed the question
of the interaction of miRNAs in EGFR-mediated signalling via the PTEN/Akt sig-
nalling system in the pathogenesis of gliomas. Investigating the role of miRNA-143
in prostate cancer cells and tumour tissues, other studies have not only shown the
involvement of PTEN/Akt system but also that PTEN mediation inactivates mTOR
and its downstream effectors in response to the presence of certain miRNAs. For
instance, Fornari et al. (2010) have suggested that miRNA-199a-3p might inhibit
mTOR to generate its phenotypic effects. Indeed according to Uesugi et al. (2011)
in oral squamous cell carcinomas, miRNA-218 and miRNA-585 are often silenced
by methylation. But in experimental systems forced expression of miRNA-218 was
found to inhibit mTOR.
Xu et al. (2011a) describe an inverse correlation of expression between miRNA-
143 and K-Ras protein expression and further state that overexpression of the
miRNA inhibited cell proliferation and migration by inactivating the EGFR/Ras/
MAPK pathway. Downregulation of miRNA-181a is frequently encountered in oral
squamous cell carcinoma cells. Forced expression of the miRNA inhibits cell prolif-
eration and anchorage-independent growth. In this system miRNA-181a decreased
the expression of K-Ras (Shin et al., 2011). MiRNAs are also known to modulate
signalling by JAK/STAT/Akt and MEK/ERK signalling to effect cell proliferation.
The membrane TRK c-Kit receptor for the cytokine stem cell factor (SCF), the kit
receptor ligand, is involved with the regulation of cell survival and proliferation,
mast cell biology and haematopoiesis, etc. and transduces signals via the PI3K and
MAPK/ERK pathway to STAT transcription factors. MiRNA-193a was found to be
downregulated by promoter hypermethylation in acute myeloid leukaemia (AML)
cell lines and primary AML blasts; levels of expression of the miRNA showed a neg-
ative correlation with c-Kit receptor expression in leukaemia cell lines and primary
AML (Gao et al., 2011). Liu et al. (2011b) found miRNA-125b frequently downreg-
ulated in osteosarcoma samples and human osteosarcoma cell lines. In the cell lines
cell growth was suppressed and in vitro cell motility was inhibited when levels of the
miRNA were restored. They also showed that STAT3 was a direct downstream target
of miRNA-125b. On the other hand, in a feedback loop STAT3 itself seemed capable
of regulating transcription and regulating the levels of miRNA-125b.
The GPCRs are an important family of transmembrane receptors which are
known to co-ordinate and mediate several pathways of signalling, for exam-
ple through the RTK/PLC/PKC and PKA systems leading to genetic transcription
and promotion of cell proliferation. GPCR also regulates cell survival or apopto-
sis through PI3K, with the mediation of genes such as apoptosis-inducing Bax and
inhibitory Bcl2 genes (Sherbet, 2011a). GPCRs are able to function with EGFR
to promote cell proliferation and migration. G-proteins convey GPCR signals by