Are miRNAs Suitable Targets for Cancer Therapy? - Therapeutic Strategies in Cancer Biology and Pathology - page 13

dissociating into subunits. GNAI2 (guanine nucleotide-binding protein alpha inhib-
iting activity polypeptide 2) is said to be targeted by miRNA-30d. The enhanced
expression of this miRNA in hepatocellular carcinoma (HCC) is said to correlate
with greater cell migration in vitro and with incidence of liver metastases (Yao et al.,
2010). Most of these findings are interesting per se , but they need to be followed up
further to elucidate how and which signalling systems the miRNA modulates.
HER2 is highly expressed in a major proportion of human breast cancer and
these receptors have been targeted by Herceptin (humanised antibodies against
HER2) in breast cancer treatment. From this view point it is significant that
miRNAs should interact with and influence HER2 signalling. Lin28 which inhibits the
suppressor function of Let-7 miRNA seems able to upregulate the expression of HER2
and in this way promote cell proliferation and tumour growth. This is compatible
with the fact that Lin28 correlated with poor prognosis of breast cancer (Feng et al.,
2012). High expression of Lin28 is related to highly aggressive oesophageal cancer
and also with poor prognosis (Hamano et al., 2012). Huang et al. (2009) reported that
the expression of miRNA-21 correlated with HER2 upregulation. Furthermore, activa-
tion of HER2 and the MAPK (ERK1/2) pathway upregulated miRNA-21. In differ-
ent mode, the miRNA downregulated PDCD4, the suppressor called the programmed
cell death protein, in HER2+ cells. Thus miRNA-21 might promote tumour pro-
gression by HER2-mediated stimulation of invasion and by preventing induction of
apoptosis by PDCD4 (also refer to discussion on pp. 209-212). The upregulation of
HER2 should make tumours sensitive to Trastuzumab (Herceptin). On the contrary,
upregulation of miRNA-21 has been shown to lead to the development of resistance
to Trastuzumab therapy of breast cancer (Gong et al., 2011). Possibly, this is a con-
sequence of lack of saturation binding of HER2 by Trastuzumab. High miRNA-21
could be counteracting the blockage of EGFR by Trastuzumab by activating EGFR/
STAT signalling with apparent increase of resistance to Trastuzumab. In gastric cancer
reduced expression of miRNA-125a-5p has been linked with larger tumours, enhanced
invasion and metastasis to liver and poor prognosis. The miRNA appeared to suppress
cell proliferation in vitro by directly targeting HER2. This inhibitory effect was com-
pounded by Trastuzumab (Nishida et al., 2011).
MiRNA-21 seems to be able to control growth and apoptosis of glioblastoma
cells. Ren et al. (2010b) tested the effects of miRNA-21 inhibition in glioblastoma
U251 (PTEN-mutant) and LN229 (PTEN wild-type) cells. Inhibition of miRNA-21
rendered both cell types sensitive to Taxol. Also both cell types showed enhanced
apoptosis. Therefore the authors have suggested that the miRNA inhibitor might be
inhibiting EGFR/STAT3 signalling and diminishing the anti-apoptotic effect of the
miRNA and apparently in this way render the cells sensitive to Taxol quite indepen-
dently of PTEN function (Ren et al., 2010b). Also in the loop are ER and PR which
not only regulate growth of tumours, but in breast cancer in the absence of ER a pro-
portion of tumours seem to engage EGFR signalling. ERα is required for oestrogen-
dependent growth and ERα positivity correlates with enhanced proliferation. Many
miRNAs have been found to downregulate the expression of ERα, among them are
miR-18a and b, miR-302, miR-193b, miR-22, and miR221/222 as well as miR-206
which have target sites in ERα 3′UTR and inhibit the promotion of proliferation by