Are miRNAs Suitable Targets for Cancer Therapy? - Therapeutic Strategies in Cancer Biology and Pathology - page 25

MiRNA-22 is able to regulate the expression of RGS2 (Muinos-Gimeno et al.,
2011). Several RGSs are expressed at lower levels in cells resistant to chemother-
apy. Cytotoxic agents downregulate RGS10 and RGS17 expression. Inhibition of
these RGSs by siRNA reduces cytotoxicity of the agents suggesting the possibility
that cytotoxic agents could be inhibiting specific miRNAs leading to the develop-
ment of chemoresistance. Both RGSs inhibited the Akt pathway (Hooks et al., 2010).
However, miRNA-22 suppresses PTEN and would lead to activation of Akt signal-
ling and in a self-regulatory loop Akt seems able to upregulate miRNA-22. So valu-
able it would be to consider that several miRNAs can and do influence Akt signalling
in either direction to modulate cell migration and apoptosis.
It would be worthwhile examining the possible effects in such a system of the
expression of miRNAs. However, it would also be worthy of note that RGS pro-
tein are not expressed at levels consistent with neoplastic status. Jiang et al. (2010)
reported not only that RGS2 expression was lower in recurrent colorectal cancer as
well as in cell lines derived from metastatic tumour but also the lower levels cor-
related with poor prognosis. Hurst et al. (2009) noted that whilst RGS2 occurred at
lower levels in ovarian cancer cells as compared with immortalised epithelial cells
and RGS19 showed similar levels of expression in both. In contrast, RGS4 and
RGS6 were occurred at a magnitude higher in epithelial cells as compared with can-
cer cells. Perhaps levels of RGS are not relevant to chemoresistance, but it begs the
question whether RGSs differ in respect of their chemoresistance potential. This is
not to be construed as a total denial of their significance. But the possibility that
miRNAs might function independently of the RGSs has to be envisaged.
Genetic changes have been detected in RGSs. Dai et al. (2011a) found single
nucleotide polymorphisms (SNPs) in NSCLC that significantly correlated with poor
prognosis. The situation is complicated further by claims that RGS2 might indeed
promote angiogenesis albeit by an unrelated mechanism (Boelte et al., 2011). So this
topic has to rest at present.
The MDR (multidrug resistance) genes (mdr1 and mdr2) and the mdr1 encoded
P-glycoprotein (p170) form an intrinsic cellular system for dealing with efflux of
cytotoxic substances from the cell. P-glycoprotein mediates efflux of chemothera-
peutic agents from the intracellular sites thus produce drug resistance. It seems that
miRNAs might be involved in P-glycoprotein-mediated drug resistance or sensitiv-
ity. Zhang et al. (2010b) found that downregulation of miRNA-27a might decrease
the expression of P-glycoprotein. In parallel they noticed downregulation of the
apoptosis family Bcl-2 and upregulation of Bax. These genes also function down-
stream of p53 and since miRNAs can and do modulate p53 expression, it may be
that these effects have resulted from parallel signalling by the p53 pathway ( Figure
3.7 ). Indeed, miRNAs - 15b and miRNA-16 target Bcl-2 in human gastric cancer
cells (Xia et al., 2008), whilst others, for example miRNA-27a and miRNA-451,
have been shown to regulate mdr1/P-glycoprotein expression (Zhu et al., 2008a).
Also the PTEN/Akt pathway might be operating here. These various interactive sig-
nalling systems have to be taken into account while assessing the role of miRNAs
in drug resistance. Li et al. (2010g) found upregulation of expression of miRNA-
27a and P-glycoprotein in paclitaxel-resistant ovarian cancer cells. According to