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associated with tumorigenesis, so also alterations in gene expression consequent
upon promoter methylation. As mentioned before, the incidence of mutations of
LKB1 in sporadic tumour is not remarkable. Somatic mutations were recorded in
around a third of lung adenocarcinomas (Ji et al., 2007; Weir et al., 2007), but Suzuki
et al. (2012) found mutations in only 14% of samples. A small proportion of NSCLC
carry altered LKB1 (Strazisar et al., 2009), but interestingly they add the rider that
changes occurred mainly in advanced stage tumours. Okuda et al. (2011) found
LKB1 mutated only in 5/174 patients. Mutations have been reported in four of seven
sporadic non-PJS mucinous bronchioalveolar carcinomas. Allelic loss and mutations
occurred in 70% of cases, but percentages do not reflect much when the patient num-
bers are small (Osoegawa et al., 2011). Mutations were even less frequent in cervical
cancer (Forbes et al., 2011; Wingo et al., 2009) and melanoma (Forbes et al., 2011;
Guldberg et al., 1999; Rowan et al., 1999). A recent study of acinar cell carcinoma
of the pancreas has revealed no mutations, deletions or promoter hypermethylation
of LKB1, nor alterations in its expression (De Wilde et al., 2011), but a caveat to be
attached to this finding is that only five sporadic carcinomas were studied here.
A familiar approach to the loss of expression by methylation of LKB1 as a cause
of tumorigenesis has led to early reports of hypermethylation of the gene in many
forms of human cancer. Some early investigations reported hypermethylation of the
gene in a small number of tumour cell lines and also methylation was not encoun-
tered too frequently in tumour tissues. It ought to be mentioned that small numbers
of tumour samples were used in this study. Nonetheless, hypermethylation also
occurred in tumours from PJS patients (Esteller et al., 2000). Loss of expression of
LKB1 is not remarkable in invasive ductal carcinoma of the breast. However, a pro-
portion of
in situ
and invasive carcinomas with loss of LKB1 expression have turned
out to be high grade tumours; also in some of the invasive tumours LKB1 was meth-
ylated (Fenton et al., 2006). No significant methylation of the promoter was found in
sporadic colon adenocarcinomas, but LOH showed some association with advanced
stage tumours (Trojan et al., 2000). Overall, the evidence is not overwhelming
that promoter methylation is a mechanism for the silencing of LKB1 in tumours.
However, inactivation of LKB1 by homozygous deletion or LOH at the LKB1 locus
has been noted in a vast majority of NSCLC (Gill et al., 2011).
Other molecular and mechanistic modes than heritable and somatic mutations
and epigenetic modifications of modulation of LKB1 can be envisaged. Regulation
of transcription of the gene is an alternative mode of modulating gene expression.
LKB1 possesses four cis-acting elements in its promoter, which are able to bind to
transcription factors such as Sp1, NFY (nuclear transcription factor Y) and FOXO3
(forkhead box O) and FOXO4. LKB1 promoter activity is greatly enhanced when
these transcription factors are overexpressed (Luetzner et al., 2012).
NF-κB and Sp1 activation seems to be closely integrated. Sp1 can activate or
repress genetic transcription dependent upon the signalling ligand. It is involved in
biological processes of cell differentiation, proliferation and apoptosis and immune
responses. Sp1 regulates both RelA (NF-κB p65 subunit) and p50 (NF-κB1) subu-
nits of NF-κB. RelA binds to the zinc finger region of Sp1 in a specific interaction.
Significantly, there are indications that NF-κB can induces Sp1 and they co-operate
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