Are miRNAs Suitable Targets for Cancer Therapy? - Therapeutic Strategies in Cancer Biology and Pathology - page 23

markers. In vivo let-7d inhibition was associated with increased S100A4 expres-
sion (Pandit et al., 2010). Reading between the lines, the change of cell morphology
could be linked with let7-d-mediated effects of S100A4.
miRNAs and Chemo/Radiosensitivity of Tumours
The pronounced effects on cell proliferation and growth of tumours has inevitably
led to examining the influence of miRNAs on the modulation of chemo/radiosensi-
tivity of tumours since active proliferation makes cells susceptible to the action of
cytotoxic agents and to radiation. Several miRNAs have been identified to be able to
modulate tumour sensitivity.
A large number of miRNAs have been linked with chemo- and radiosensitivity
( Table 3.1 ). Some miRNAs have been reported to directly correlate with drug sensitiv-
ity, whilst others might be inversely related. No specific associations have appeared,
although some have received more attention than others. This would be due to accident
than by design in the sense that some miRNAs have been focused upon because of
their occurrence in and relationship to cancer and the biological behaviour of cancer
cells. In the light of this more attention is devoted here to the possible mechanisms and
modes of perceived link with drug resistance and sensitivity to radiation.
The question for determining the state of therapeutic resistance has prompted
investigations into the mechanisms by which miRNAs might confer drug resist-
ance or radio/drug sensitivity to tumours. Among the lines of investigation are
(a) the modes of regulation of miRNA expression by natural and integral inhibitors,
(b) effects of miRNAs on links in signalling systems and (3) the intrinsic modes of
cell defence against stress and environmental insults, including drugs (see Table 3.1 ).
Many miRNAs can determine the state of drug resistance or sensitivity of
tumours. Instances are not many where the effects exerted by miRNA effects on
tumours is controlled or regulated by endogenous or natural inhibitors. The expres-
sion of the composite Lin28-let7 does offer an illustration of this. Overexpression
of let-7a and inhibition of its negative regulator Lin28 reduce K-ras expression
and radiosensitise A549 cells (Oh et al., 2010). The mode of action of miRNAs in
chemoresistance is yet to be elucidated.
MiRNAs are known to markedly modulate the expression of a family of pro-
teins called regulators of G-protein signalling (RGS) proteins, which modulate the
function of heterotrimeric G-proteins. RGS proteins activate GTPase function lead-
ing to the hydrolysis of G-protein alpha subunits, which inactivates the G-protein
and G-protein-coupled signalling pathways (De Vries et al., 2000) and so regarded
as negative regulators of G-protein-dependent signalling. GPCRs use G-protein as
intermediary in their signalling function of activating several important systems such
as Src, Ras, MAPK and JAK/STAT pathways. GPCRs co-operate with EGF and
PDGF in mitogenic function and possibly also with VEGF. Their mediation may be
seen in the functions of some cytokines, including interleukins and TNF. It may be
relevant also to recall here that certain miRNAs are known to regulate the activation
by TNF-α of apoptosis signalling (Sherbet, 2011a).