HIC1 Suppressor Gene - Therapeutic Strategies in Cancer Biology and Pathology - page 150

high Bmi-1 expression also to breast cancer tumorigenesis. However in the light of
doubts being expressed about the suppression of ARFs by Bmi-1 (Chiba et al., 2008;
Xu et al., 2009), one has to look at other lines of evidence for ARF involvement in
CSC and tumorigenesis. In glioblastoma multiforme, Bmi-1 is expressed in CD133+
cells (Abdouh et al., 2009), suggesting a close relationship between Bmi-1 and the
capacity of stem cells for self-renewal. Indeed Zheng et al. (2008) have implicated
Myc/p53/PTEN axis in the regulation of stem cell self-renewal and tumorigenesis of
glioblastomas. In the absence of other oncogenic signals, Bmi-1 probably acts only
partially in an ARF-dependent manner as Dovey et al. (2008) have put it. As stated at
the outset, ARFs are involved with both p53 and Rb signalling. With deletion of ARF
leading to the restoration of Bmi-1 function, one can conclude that modulation of
p32/Rb function and suppression of ARF could achieve the faculty of self-renewal.
As alluded to in the introductory chapter, metastatic progression has to be viewed
as a stem cell clone with specialised ability of invasion and dissemination. The find-
ing of Mihic-Probst et al. (2007) that Bmi-1 shows greater expression in metastatic
lesions of melanomas that in corresponding primary tumours is of prodigiously sig-
nificant in this context.
ARF Function and p53 Activity
ARFs are often found to function as a tumour suppressor. ARF was shown some
time ago to induce apoptosis by recourse to the mitochondrial pathway. ARF acti-
vates caspases. ARF also modulates the expression of Bcl-2 family genes and this
occurs either dependent upon or independently of p53. Du et al. (2011) transfected
a cell line lacking p53 with an inducible p14ARF construct and showed that induc-
tion of p14ARF activated p21 and ERK1/2 in the transfectants cells and initiated
G1 arrest. ARF is said to downregulate anti-apoptosis Bcl-2 in a p53-dependent
manner but upregulate the pro-apoptotsis Bax/Bim via a p53-independent pathway
(Nakazawa et al., 2003). Indeed induction of apoptosis by ARF may require differ-
ent pro-apoptosis genes in genetic environment with or without p53 (Hemmati et al.,
2006). In other words, p53-dependent or independent function of ARF is related to
which pro-apoptosis genes of the Bcl-2 family are engaged.
ARF Interactions with CtBP
As noted earlier, HIC1 engages the co-repressor CtBP. CtBPs have been strongly
implicated in promoting EMT and tumour progression, inhibition of tumour sup-
pressor genes and suppression of apoptosis. Hence the antagonistic interac-
tion between CtBP and ARF has been focused upon by several investigators. A
marked inverse correlation of expression of CtBP and ARF has been reported in
adenocarcinoma of the colon (Kovi et al., 2010; Straza et al., 2010). The suppres-
sion of p19ARF increases in vitro invasion by an HCC cell line increases invasion