Biology Reference
In-Depth Information
Oestrogens do function by activating GPCRs (Sherbet, 2011a). Nonetheless, the
importance of MTAs in tumour promotion and dissemination is amply supported by
the finding that they are also capable of inducing the expression of neoangiogenic
agents. Increased VEGF expression has been reported in conjunction with MTA pro-
teins in many tumours but lack of accessibility of the reports has prevented full dis-
cussion of the results here.
Modulation/Inhibition of MTA Expression
The significant biological effects exerted by MTAs have prompted investigations
designed to inhibit or modulate their expression. Among notable regulators of MTA
is miRNA-146a. According to Li et al. (2010f), the expression of this miRNA is
reduced in pancreatic cancer cells and experimental enhancement expression lev-
els by treating the cells with 3,3′-diindolylmethane (DIM) or isoflavone has been
found to inhibit cell invasion
in vitro
. In parallel the treatment downregulated EGFR,
MTA2, IRAK-1 (interleukin-1 receptor-associated kinase 1) and NF-κB resulting
in inhibition of pancreatic cancer cell invasion. This suggests possible interaction
of MTA signalling with EGFR and NF-κB signalling pathways. Inhibition of MTA
gene in neuroblastoma cells by using siRNA stimulates neurite extension (Singh
et al., 2008). In B16F10 cells, inhibition of the MTA1 expression has been shown to
reduce cell migration
in vitro
and lung colonisation upon introduction of the cells via
the tail vein (Qian et al., 2007a).
MTA Signalling Intercalates with Wnt/Notch/Hh Signalling
The massive phenotypic changes occurring in the wake of MTA activation in terms
of enhanced cell migration and aggressive behaviour of tumours have implicated a
positive role for MTA1 in EMT activation. Whilst MTA1 induces a more aggressive
phenotype, MTA3 exerts an opposite effect. It is able to inhibit the transcription fac-
tor Snail and lead to an upregulated expression of E-cadherin and inhibition of EMT.
In contrasting function, MTA1 activates Snail and downregulates E-cadherin to bring
about the expression of an aggressive cancer phenotype. It is becoming increasingly
apparent that MTA3 influences the Wnt signalling following upon the finding that
MTA3 directly represses Wnt4 transcription (Zhang et al., 2006a). MTA3 could be
countermanding Snail activation induced by Wnt. At the biological levels, there is
a solitary report of its downregulation in cancer. MTA3 occurred at reduced expres-
sion in endometrial adenocarcinomas and levels of expression were inversely related
to tumour grade and lower in poorly differentiated tumours (Bruning et al., 2010).
There are a couple of reports that suggest possible tumorigenic and EMT promoter
effects of MTA3. However, the paucity of evidence does not allow a consensus.
The developmental pathways of Wnt, Notch and Hh signalling are often acti-
vated in cancer and have been directly or indirectly linked with EMT. A highly
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