Are miRNAs Suitable Targets for Cancer Therapy? - Therapeutic Strategies in Cancer Biology and Pathology - page 22

miRNAs and Tumour/Metastasis Promoter Genes
Far less attention has been received by tumour promoter genes with regard to pos-
sible association with miRNAs and their function. Li et al. (2010f) found that the
expression of miRNA-146a in pancreatic cancer cells was lower than in correspond-
ing normal epithelium. In vitro , induced overexpression of the miRNA inhibited
the invasive capacity. These changes occurred in parallel with the downregulation
of EGFR, NF-κB and the tumour promoter MTA (metastasis associated antigen)-2.
One would recall here the MTA family genes are a well-studied family of metastasis
associated proteins. They are repressors of transcription by virtue of their function in
histone deacetylation and are a component of the NuRD (nucleosome remodelling
and deacetylating) complex.
MTA2 is believed to interact with p53 and interfere with its cell cycle regulatory
function and apoptosis pathway. At the level of cell behaviour, MTAs are involved in
cancer cell migration by regulation of cell adhesion proteins in consort with cytoskel-
etal proteins such as ezrin. MTA1 can repress ERα activation by chromatin deacet-
ylation of the ER-response element of responsive genes (Toh and Nicolson, 2009).
However, given that ERα promotes and ERβ inhibits cell proliferation, it may be that
the effects of MTA are partly attributable to the suppression of ERβ (see pp. 77-79.).
S100 family proteins exert marked negative or positive effects on tumour pro-
gression. S100A4, which actively promotes metastasis and counters the suppressive
effects of nm23, appears to produce a >fourfold increase in expression in EMT-
mediated aggressive behaviour engendered by miRNAs. Besides, the expression of
several other genes possibly associated with EMT and promotion of metastasis was
also influenced by miRNA (Lopez-Lago et al., 2010). No specific miRNAs have
been ascribed with these changes. However, Fassina et al. (2012) recently demon-
strated that miRNA-205 is downregulated with EMT in malignant mesotheliomas
and in parallel there was increased expression of S100A4 and the conventional EMT
markers. Further they showed that forced expression of miRNA-205 inhibited EMT
as indicted by the suppression of ZEB1 and ZEB2 and enhanced E-cadherin expres-
sion. In contrast, higher levels of miRNA-196a have been reported in oesophageal
carcinoma and Barrett's oesophagus (BE) and dysplastic lesions than normal squa-
mous mucosa, and in high-grade dysplasia than in BE and low-grade dysplasia.
Also miRNA-196a expression showed an inverse with its molecular targets among
them S100A9. Experimentally enhancing the levels of miRNA-196a in carcinoma
cell lines resulted in the suppression of transcription of S100A9 (Maru et al., 2009).
These findings are compatible with the well-established relationship between
S100A9 and tumour progression. S100A9 is highly expressed in many tumours and
higher S100A9 levels have correlated with enhanced cell proliferation and greater
invasive potential.
Idiopathic pulmonary fibrosis (IPF) is an age-related condition wherein activated
alveolar epithelial cells induce mesenchymal cell proliferation and stimulate EMT
(see King et al., 2011). Several miRNAs are downregulated in IPF, among them is
let-7d, which is targeted and downregulated by TGF-β via the downstream effector
Smad3 binding to the let-7d promoter. This results in the expression of some EMT