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LKB1 suppression also suppressed miRNA-200a/c expression (Roy et al., 2010) and
inversely correlated with that of ZEB1 in cell clones with suppressed LKB1.
Another path to suppression of EMT by PTEN is via upregulation of PTEN
leading to the upregulation NDRG1 (see pp. 111-112); the latter would eventually
inhibit EMT. This builds up a complex scenario of LKB1 interaction with PTEN
which is known to be an LKB1 interacting protein and a substrate of the kinase
(Mehenni et al., 2005).
LKB1 and Stem Cell Survival and Pluripotency
The suppression of EMT by LKB1 has inevitably led to investigations of its effects
on formation and maintenance of CSCs subpopulations in tumours and acquisition
of EMT. Indeed, apart from the conventional features associated with tumour sup-
pressors, LKB1 has to be accorded with prominence because there are indications
of its potential involvement in stem cell perpetuation. It may be recalled here that
cell clones carrying CD44+CD24+ESA+ markers are regarded as putative stem and
these clones might be expanded and the tumour enriched in respect of this subpopu-
lation that is capable of not only initiating the tumour development and possibly also
related to progression of tumours to an aggressive state (see pp. 35, 214-215). Liu
et al. (2012e) found that forced inactivation of LKB1 activity in the presence of acti-
vated oncogenic Ras, probably also in the backdrop of loss of p53 led to the expan-
sion of CD24+ cell population which could represent CSCs. Activation of AMPK, a
direct target of LKB1, can prevent the transcriptional activation of Oct4 (Vazquez-
Martin et al., 2012). Metformin, also an AMPK activator, inhibited Oct4 expression.
Although reduced Oct4 transcription would suggest AMPK-initiated regulation of
stem cell programming, no stem cell marker expression was assessed here.
The opposite view has been expounded by other reports. Reduced LKB1 expres-
sion has been correlated with upregulated expression of genes associated with pluri-
potency in human embryonic stem cells. The transcription factors Oct4, Nanog and
Sox2 are said to be expressed at higher levels in the absence of LKB1 expression
and this is accompanied by the downregulation of differentiation markers, for exam-
ple Runx1, AFP, GATA, Brachyury, Sox17 and Nestin (Lai et al., 2012). It would be
interesting to see if miRNAs operate in this. Let-7miRNAs suppress stem cell pluri-
potency and oppose the effects of the miRNA-290 cluster that promote pluripotency.
This functional disparity is due to the ability of miRNA-290 to maintain the expres-
sion of Lin28 which inhibits the maturation of Let-7. The pluripotency factors Oct4,
Sox2, REX1 and Nanog induce miRNAs that promote pluripotency and cell survival,
whilst Let-7s inhibit pluripotency (Li and He, 2012). Notwithstanding the disagree-
ments, it is quite obvious from the limited resources at hand that deregulation of
LKB1 signalling can lead to defects in differentiation, stem cell perpetuation and
activation of EMT encountered in tumorigenesis, both PJS-associated and not asso-
ciated with PJS. The extensive interactions of LKB1 with proliferation, cell adhe-
sion linked features of motility and invasion-related signalling pathways together
with cross talk with those operating in differentiating system lend themselves to
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