Are miRNAs Suitable Targets for Cancer Therapy? - Therapeutic Strategies in Cancer Biology and Pathology - page 21

capable of enhancing in vitro invasion. Furthermore, inhibition of ADAM-17 leads
to reduced expression of VEGF and MMP-2 activation. Several ADAM proteins
have been identified with chronic inflammation and cancer. The ADAM proteins,
ADAM-9, ADAM-12, ADAM-15 and ADAM-17, have been implicated in tumour
development. ADAM-17 is overexpressed in primary and metastatic colonic cancers
compared with normal colonic mucosa. Inhibition of EGFR using RTK inhibitors
and inhibition of ADAM-17 and effectively blocking EGFR activation and down-
stream signalling, suppresses cell proliferation, invasion and angiogenesis (Sherbet,
2011a). According to the findings of Tsai et al. (2009) miRNA-122 is downregu-
lated in liver cancers with intrahepatic metastasis, but when present at normal levels
miRNA-122 suppresses cell migration and invasion and in vivo suppresses angiogen-
esis. The import of the significance of ADAM-17 is accentuated as it turns out to be
a target of miRNA-122. Nonetheless, these are presented as parallel findings and no
causal link has emerged. Further study into the biological outcome of targeting of
ADAM-17 is warranted.
miRNAs, Tumour Growth, Invasion and Metastasis
The Influence of miRNAs on Metastasis Suppressors
With the identification of many metastasis suppressor and promoter genes, efforts
have been directed towards determining whether any of these genes might be tar-
geted by miRNAs. Several miRNAs that generate their phenotypic effects by influ-
encing suppressor gene function have been identified. There are many reports
relating to the effects of miRNAs on putative tumour-suppressor genes, nota-
bly BRCA1 and BRCA2, BRMS1, PDCD4 (programmed cell death 4), Maspin,
EPB41L3, CADM1 among others. These exert their suppressor effects by different
mechanisms and the association of miRNAs with suppressor with diverse modes of
function reiterates the multiplicity of targeting by miRNAs. The suppressor function
of BRCA1 is induced and modulated by miRNAs through the mediation of other
genes and signalling elements such as ID4, ERα, IGF-1R, and Sp1 that can exert
exemplary effects cell growth and behaviour. BRMS1 is another example of a sup-
pressor gene that is regulated by miRNAs. PDCD4 is a suppressor gene that is tar-
geted and regulated by miRNA. So are Maspin, EPB41L3 and CADM1 modulated
by miRNAs. The specifics of suppressor gene regulation by miRNAs and vice versa
are discussed in detail in their respective locations. Conversely suppressor genes
such as the ING can manipulate the expression of miRNAs. The contention here sim-
ply is that there is overwhelming evidence that tumour- and metastasis-suppressor
genes and signalling systems are greatly influenced and impelled into regulating
their biological functions. Some important and classical suppressor genes do not
appear to have been investigated for potential regulation by miRNAs; possibly they
were and no miRNAs might have been involved. There is a prevalent view, erroneous
one, that negative results may not be worthy or publications.