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Feng et  al. (2011a) miRNA-331-5p and miRNA-27a expressions inversely cor-
related with P-glycoprotein expression in doxorubicin-resistant cells, and besides
when transfected into doxorubicin-resistant K562 and HL60 cells, these miRNAs
increased the sensitivity of the cells to the drug. Quite clearly the P-glycoprotein
pathway of drug resistance is mediated by miRNAs. Another protein associated
with multidrug resistant, namely MCP (monocyte chemoattractant protein)-1 is also
influenced by miRNA-326 as Liang et al. (2010b) have reported. Downregulation of
miRNA-326 was inversely related to MCP-1 expression in advanced breast cancers.
When expressed at high levels miRNA-326 not only downregulated MCP-1 expres-
sion but also sensitised these cells to VP-16 and doxorubicin.
Potential operation of mTOR signalling and its attenuation by miRNAs have
been adduced as another means by which drug resistance might be modulated.
When miRNA-100 occurs in a downregulated state, mTOR shows parallel upregu-
lation. In agreement with this, when overexpressed miRNA-100 inhibits mTOR
signalling (Nagaraja et  al., 2010), a clear indication that the miRNA-100 targets
mTOR. The work of Fornari et al. (2010) has suggested the possibility that miRNA-
199a-3p might also be inhibiting mTOR signalling and increase doxorubicin sensi-
tivity. Inhibitors of mTOR are known to be able to reverse doxorubicin resistance
(Grünwald et al., 2002).
ABC (ATP-binding cassette) transporters are another family of proteins impli-
cated in drug resistance in tumour cells. There is evidence that miRNAs are also
involved in the regulation of these. Borel et  al. (2011) reported the upregulation of
five ABC genes by 13 cellular miRNAs in human HCC samples. ABC2 was down-
regulated by miRNA-379 (Haenisch et  al., 2011). These may offer themselves as
suitable therapeutic targets in the light of their acknowledged drug resistance func-
tion and having been linked with targeting of the relevant miRNAs. Equally, one
should not lose sight of the possibility that drugs can induce the expression of
miRNAs, some of which might be able to activate signalling systems for cell survival
and or proliferation and growth.
Massive amounts of data have accumulated concerning the role of miRNAs
in conferring drug resistance or sensitivity; nonetheless no specific patterns of
response, specific attributions of induction or alleviation of drug resistance, or any
tumour or tissue specificity have emerged from these data.
The Therapeutic Potential of miRNAs
The potentialities of miRNAs as therapeutic tools have been largely appreciated in
the light of their ability to inhibit, influence or modulate a number of features of cell
behaviour that are relevant in the contexts of cancer development and spread. It is
patently obvious that they affect cell proliferation, apoptosis, invasion and angiogen-
esis and in this way might be expected to have a major bearing on metastatic spread
of cancer. As depicted in Figures 3.4-3.7 , several miRNAs have been identified to
be able to affect these phenotypic features (see also Table 2.1). Also in many cases
their molecular targets have been identified and their functional involvement with
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