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The NF-κB survival pathway has also been implicated in the functioning of
ING4. Klironomos et al. (2010) found that ING4 is downregulated in association
with grade in astrocytomas. They also noticed that the expression of p65 (RelA) sub-
unit of NF-κB was higher in grade IV astrocytomas than in grade I/II tumours.
The suppressive effects of ING on cell proliferation and induction of apopto-
sis may be compounded by their ability to inhibit neovascularisation in their over-
all ability to suppress tumour progression. Ovarian cancers not only showed ING3
downregulation, but this was also associated with enhanced microvessel density (Liu
et al., 2012h). Earlier Li et al. (2010i) showed that ING4 was able to suppress the
density of microvessels associated with tumours formed by MDA-MB-231 cells
implanted
in vivo
.
Allelic loss of all members of the family (ING1-5) occurs at high frequency in
tumours. The frequency of LOH of ING2 correlated with progression of head and
neck squamous cell carcinoma (Borkosky et al., 2009, 2010). A point mutation has
been reported in ING4 and this can conceivably lead to functional inactivation of
the protein (Moreno et al., 2010). ING5 mutations together with the downregulation
of ING5 mRNA have been reported in oral squamous cell carcinoma (Cengiz et al.,
2010). Splice variants potentially differing in function have been found in human
gastric adenocarcinoma (Li et al., 2009e).
The ING isoforms seem to have well-defined suppressor functions, but Unoki
et al. (2009) state that ING2 is overexpressed in colorectal cancer and supports inva-
sion via the MMP route. They also found that the presence of ING2a and ING2b
inhibited cell cycle arrest and apoptosis, and some ING proteins might indeed be
oncogenic, contrary to the accepted view in relation to a majority of the ING pro-
teins. ING2 levels in colon cancer were twice as high as in normal mucosa, and
this enhanced expression was seen in nearly half of the cancer tissues examined.
Besides, ING2 bound NK-κB and this could have led to increased invasive behav-
iour encountered in this study. Also encountered was increased MMP 13 expression
seemingly mediated by NF-κB (Kumamoto et al., 2009). MMPs are an activation
target of NK-κB (see Table 9.2). Allelic loss of 4q35.1, the ING2 locus, occurred
in head and neck squamous cell carcinomas and this was associated with advanced
stage tumours (Borkosky et al., 2009). By implication, the loss of ING2 could be
occurring late in progression rather than initiate progression. The topographical
aspect of distribution is an important factor here. ING2 bears significant sequence
homology to ING1b and loss of ING2 function could result from being restricted to
the cytoplasmic compartment. Indeed ING1b seems to be inactive because of local-
isation in the cytoplasm (Gong et al., 2011). One ought to note that other reports
that have supported a suppressor function for ING2. It occurred at lower in HCCs as
compared with matched normal liver tissue. Loss of ING2 was also related to poor
prognosis (Zhang et al., 2008a). ING2 expression is lost in melanoma progression
too as Lu et al. (2006) reported some time ago.
ING1 suppresses the expression of many genes. Among them of interest in the
present context of the inhibitory effects of ING proteins on cell proliferation is
the tumour suppressor and cell cycle regulator p53, which has been implicated in the
induction of apoptosis by ING. Another gene directly affected by ING is DGCR8,
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