Biology Reference
In-Depth Information
11
Metastasis Suppressor nm23 and
Manipulation of its Expression
The nm23 gene is now unquestionably established as a metastasis suppressor. Allelic
loss of nm23 is an important feature of many forms of tumour. Loss of the normal
regulatory function of nm23 by methylation has been linked with tumour progression.
The overriding influence of the gene is unmistakable and patently obvious from its
ability to counteract the influence metastasis promoter genes, interfere with growth
factor receptor signalling, regulate cell proliferation and modulate cell membrane
components that function as determinants of cell motility and invasion. Nm23 was
originally identified as an NDPK (nucleoside diphosphate kinase). Histidine kinase
activity has been putatively associated with its function in the suppression of motility.
Nm23 was recognised as a metastasis suppressor on account of its differential expres-
sion in tumour with high and low metastasising abilities and positively demonstrated
as a suppressor by gene transfer studies. The human nm23 family is composed of
nm23-H1, nm23-H2, DR-nm23, nm23-H4 and nm23-H5 genes, which play impor-
tant roles in cell proliferation, differentiation and in tumour development and metas-
tasis. Of these, nm23-H1 has been persuasively and clearly linked with many human
cancers. Nm23-H1 and nm23-H2 encode NDP kinase subunits. Nm23-H1 has been
implicated in monitoring the integrity of DNA repair and replication.
Metastasis suppression by nm23 is well established in many tumour types but is
unproven in some forms of cancer. But this has to be gauged in the background of
activity of promoters of tumour growth and metastatic spread. The downregulation
of expression of nm23 and of E-cadherin correlates with invasion and the presence
of nodal metastasis. Besides, nm23 is a growth suppressor and possibly annuls the
abrogation of cell cycle checkpoint control mechanisms by metastasis promoter gene
such as S100A4. Oestrogen and progesterone do influence nm23 expression and do
bring about changes in cell motility and invasion. Thus oestrogen appears to down-
regulate nm23-HI expression together with promotion of cell migration and inva-
sion by activating the PI3K/Akt pathway, whilst progesterone opposes this effect.
Furthermore,
in vitro
oestrogen enhances and progesterone decreases cell motility
(Hua et al., 2006; Sherbet, 2011a).
Oestrogen exerts its physiological effects via ERα and ERβ mediation. Both the
receptors bind 17β-oestradiol with high affinity and in similar if not identical man-
ner to the oestrogen response elements (EREs). But there are major differences:
17β-oestradiol has selective affinity for ERα, but 17α-epiestriol is an ERβ selective
agonist. Besides they differ in respect of their transcriptional activities (Barkham
et al., 1998; Dechering et al., 2000). Possibly as a consequence of this, ERα and
ERβ modulate the expression of different genes and exert different effects on cell
proliferation and invasion. Whereas ERα promotes cell motility and invasion, ERβ
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