Biology Reference
In-Depth Information
A further thought is that certain miRNAs might be downstream targets of RKIP.
MiRNAs have been strongly implicated in cancer pathogenesis, as discussed in
detail in another location in this topic. Many species of miRNA have been regarded
as tumour suppressors. MiRNA Let-7 species are downregulated in tumours, which
is compatible with their ability to inhibit the activation of EMT. Let-7d inhibits EMT
and its expression is inversely related to Twist and Snail which are negative regulators
of E-cadherin expression. Dangi-Garimella et al. (2009) showed that RKIP mediated
suppression of MAPK signalling decreases Lin-28B transcription by Myc and leads
to enhanced let-7 processing in breast cancer cells. Let-7 in turn inhibits HMGA2,
an activator of the transcription factor Snail. These changes in Lin28/Let-7 suppress
bone metastasis. In C5 molecular subtype of high grade serous ovarian cancer, marked
changes have been reported in the expression of N-myc, Lin-28B, Let-7 and the high
mobility group HMGA2. Characteristic amplification and overexpression of N-myc
and overexpression of its targets Lin-28B together with loss of Let-7 expression and
amplification and overexpression of HMGA2 were encountered (Helland et al., 2011).
Among other targets of Let-7 that RKIP inhibits is Bach1. HMGA2 and Bach1 upregu-
late MMP1 conducive to invasion and metastasis as well as osteopontin and CXCR4
both implicated in bone metastasis (Yun et al., 2011) (Figures 3.4 and 3.5).
The transcription factor YY1 (Yin Yang 1) belonging to the Gli-Kruppel class of zinc
finger proteins has been attributed with ability to repress and activate a diverse number of
promoters by directing histone deacetylases and histone acetyltransferases to the promot-
ers (
www.ncbi.nlm.nih.gov/gene/7528
)
. In hepatocellular carcinoma, YY1 and RKIP are
inversely related (Notarbartolo et al., 2011). Induction of NF-κB increased YY1 expres-
sion and ablation of the RelA/p65 subunit of NF-κB reduced YY1 expression (Wang
et al., 2007) again emphasising a close-knit relationship of RKIP with the NF-κB sur-
vival pathway. CD20, the B-lymphocyte antigen, is putatively linked with the regulation
of B-cell activation and proliferation. Cross linking of CD20 with anti-CD20 antibod-
ies induces apoptosis and probably also inhibits the cell cycle traverse. CD20 signalling
does induce Src family kinases (Deans et al., 1995). ERK activation is a requisite for the
induction of B-cell receptor mediated apoptosis and SAPK also a downstream effector
of an arm of MAPK signalling might provide mitogenic signals (Healy and Goodnow,
1998). Quite compatibly, Jazirehi et al. (2005) showed that the anti-CD20 antibody
Rituximab significantly increased RKIP expression and inhibited NF-κB signalling path-
way. Vega et al. (2009) have broadly confirmed this using another humanised antibody
which upregulated RKIP expression and inhibited constitutively activated NF-κB and
p38 MAPK pathways.
Effects of Re-expression of RKIP on Metastatic Spread
Inhibition of NF-
κ
B Signalling
In line with conventional wisdom, attempts have been made to reinstate RKIP
expression. Many potential opportunities can be identified with RKIP operating by
inhibiting Raf-MEK-ERK, GPCR kinase and NF-κB signalling. Upregulation of
Search WWH ::
Custom Search