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to promote cell proliferation and survival. Sp1 is highly expressed in many tumours
and has been linked with the regulation of cell-cycle-related genes, growth factor
signalling, apoptosis and it is also said to regulate tumour suppressor genes (Culver
et al., 2011; Li and Davie, 2010; Sankpal et al., 2011). Sp1 is markedly associated
with induction of cell proliferation and inhibition of apoptosis. Many cell cycle and
apoptosis-related genes such as p53, cyclins and IκB are degraded by the ubiquitin-
proteasome pathway. NFY induces proteasome gene expression and knockdown of
the same inhibits the proteasome pathway and proteasome genes (Xu et al., 2012).
The FOXO family transcription factors regulate many biological processes
such as apoptosis and cell cycle arrest. They inhibit cell proliferation and promote
apoptosis via activation of pro-apoptosis genes of the Bcl family or by enhancing
the expression of FasL death receptor ligands and TRAIL or by inducing cell cycle
arrest. In this way FOXO transcription factors function as tumour suppressors. In
fact, loss of FOXO function with the accompaniment of increased cell survival has
been reported in many human cancers.
Akt kinase inhibits FOXO and promotes cell survival. FOXO1 is downregulated
in Hodgkin's (but not in non-Hodgkin's lymphoma) (Xie et al., 2012). FOXO3 is
inactivated in mantle cell lymphoma cells (Obrador-Hevia et al., 2012). It is worth
noting that the VEGF gene is a target of and repressed by FOXO3a. VEGF and
FOXO3a show inverse correlation in breast cancer tissues (Karadedou et al., 2012).
Loss of expression would be conducive to the progression of aggressive disease.
But the function of FOXO3 has been controversial. For, it has been attributed with
promotion of invasion. Furthermore FOXO3a might activate the NF-κB survival
pathway (Li et al., 2012e). Largely this is incongruous in some ways, for LKB1 tran-
scription is enhanced by these transcription factors. As noted, many genes are tar-
geted by these transcription factors and one has to guard against overinterpretation
of their part in LKB1 expression. Equally LKB1 might activate Akt signalling and
promote cell survival. Akt phosphorylated and repressed FOXO3a in LKB1 wild-
type but not null cells. Also depletion of LKB1 in wild-type cells reduced FOXO3
phosphorylation. This suggests LKB1-activated Akt led to suppression of FOXO3a
and cell survival (Zhong et al., 2008). Nevertheless, as discussed below, expression
of LKB1 does indeed suppress angiogenesis as well as invasion.
LKB1 Suppresses Invasion and Metastasis
Genetic alterations as homozygous deletions or LOH and loss of expression by epi-
genetic mechanisms of LKB1 are not infrequently reported in many tumours. In
fact, loss of LKB1 expression might be conducive to invasion and metastasis. LKB1
(−/+) female mice develop endometrial adenocarcinomas highly invasive into the
myometrium. LKB1 (L/L homozygous floxed allele) mice were injected intrauterine
with Ad-Cre recombinase to excise the floxed alleles to achieve endometrium-spe-
cific deletion of LKB1. This produced highly invasive endometrial adenocarcinomas.
In human endometrial cancers, loss of LKB1 correlated with tumour progression
more aggressive disease (Contreras et al., 2008).
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