Association of miRNAs with Pathogenesis - Therapeutic Strategies in Cancer Biology and Pathology - page 7

attributed with resistance to induction of apoptosis by anticancer agents (Taniguchi
et al., 2012). Indeed overexpression has been linked with multidrug resistance.
Enhanced expression of GLO1 increases cell survival. It takes part in the cellular
detoxification of reactive carbonyl compounds. The precise mode of its phenotypic
effects is still unclear. De Hemptinne et al. (2007) have reported the involvement
of GLO1. Indeed, De Hemptinne et al. (2009) showed that GLO1 is a substrate for
CaMKII (calcium/calmodulin-dependent protein kinase II). GLO1 also undergoes
nitric-oxide-induced post-translational modification. These changes seem to be able
to suppress TNF/NF-κB inducible target genes. This could be one of the mecha-
nisms adopted by GLO1 in promoting cell viability survival. Some of NF-κB respon-
sive genes might have relevance to the formation of osteolytic metastasis. GLO1 is
possibly a requirement for the generation of osteoclasts and appropriate inhibitors
have been identified (Kawatani et al., 2008). For example, inhibition of the regula-
tory component IKK (IκB kinase) of NF-κB has been found to inhibit the osteoclast
activity of NF-κB and inhibit osteolytic metastasis of breast cancer (Sherbet, 2011a).
So inhibition of GLO1 could be helpful in preventing osteolytic metastasis. GLO1
is a downstream effector in the functional route of miRNAs and therefore can be
targeted by inhibitors. Some miRNAs may counteract and suppress AGE (advanced
glycation end product)-induced cell survival. Li et al. (2011b) have identified many
miRNAs of rice (Oryza sativa indica) which have been projected to target mRNAs
for important protein kinases, peroxidases and glyoxalases. They found that MiRNA-
3981 is an exonic miRNA of the first exon of the putative glyoxalase gene and have
proposed that its biogenesis pathway might be involved in the post-translational reg-
ulation of glyoxalase expression.
An indirect approach to targeted inhibition might be offered by the finding that
miRNA-22 can regulate the expression of RGS2 (regulator of G-protein signalling
protein) (Muinos-Gimeno et al., 2011), which itself can regulate the function of
GLO1. RGS2 seems to regulate GLO1 by activating p38 MAPK and protein kinase
C (PKC) signalling systems (Salim et al., 2011).
An exploration of potential inhibitors seems justified by findings that GLO1
expression is altered in many human neoplasms. However the status of expres-
sion seems uncertain at present. GLO1 is said to be downregulated in renal cell
carcinoma (Cabello et al., 2010), but higher levels of GLO1 transcripts have been
reported in primary prostate cancer (Romanuik et al., 2009). Bair et al. (2010)
reported a marked upregulation of GLO1 expression in human melanoma (stages
III and IV). Inhibition by siRNA of GLO1 expression in A375 and G361 melanoma
cells led to inhibition of proliferation and induction of apoptosis. There are also other
suggestions subject to the provision of further confirmation that GLO1 polymor-
phism is associated with breast cancer (Antognelli et al., 2009).