EGFR Signalling in EMT - Therapeutic Strategies in Cancer Biology and Pathology - page 55

prevent internalisation of EGFR upon ligand binding. In other words, inhibition of
E-cadherin or its stabilisation at the membrane might have similar outcomes in terms
of EMT activation and the associated alterations in marker expression upon EGFR
signalling. Indeed Zhao et al. (2010) showed that E-cadherin expression is reduced
via EGFR/ERK signalling.
EGFR and TGF- β Signalling Pathways Interact in EMT
EGFR might function with several other cellular factors. Not least among them is
TGF-β1, which itself is capable of initiating EMT. EGFR has also been shown to
engage in cross talk with TGF-β1/Smad canonical signalling in activating EMT.
TGF-β1 could not induce EMT when EGFR was inhibited (Kang et al., 2012a),
possibly indicating a regulatory role (see below). Cell subpopulations overexpress-
ing EGFR and expressing the ZEB negative regulators of E-cadherin appear to be
more prone to undergo EMT in response to TGF-β stimulation; also this competence
for EMT was augmented by the presence of p53 mutations (Ohashi et al., 2010).
Further, Kang et al. (2012a) showed that TGF-β signals by the canonical route
involving Smad to activate EGFR function. They found that activation of EGFR is
required for TGF-β to induce EMT.
Supplementary evidence of TGF-β/EGFR cross talk comes from the demonstra-
tion that the transmembrane 4 L6 family member 5 (TM4SF5) might be implicated
in the induction of EMT. TM4SF5 is highly expressed in HCC with attendant acti-
vation of EMT. Inhibition of TM4SF5 seems to suppress EMT. The involvement of
TGF-β and EGF signalling in this process has been emphasised by their ability to
induce TM4SF5 (Kang et al., 2012b). As noted before, TGF-β can indeed do that
in different ways, canonical and non-canonical pathways together with other modes
of signalling. Nonetheless, in the hepatocellular carcinoma model, it is clear that
EGFR is an en route requirement for induction of EMT by TGF-β. This view dif-
fers markedly from the one expressed earlier by Murillo et al. (2005) who found that
whilst TGF-β was capable of activating EGFR and Akt signalling, TGF-β mediation
of EGFR activation may involve the proteinase ADAM 17 inhibition of which sup-
presses Akt activation. EGFR involvement did not appear to be essential component
in the induction of EMT by TGF-β. However, this dissension does not detract from
the convincing demonstration of the role of EGFR in activating EMT.
Finally, it would be relevant to mention here the considerable role that miRNAs
play in the regulation of cell proliferation and apoptosis and growth factor signal-
ling, discussed in an earlier location (see pp. 5-18 and Figures 3.4-3.7). MiRNAs
target and influence the function of several genes such as p53, Bcl-2 family mem-
bers, and myc and so regulate cell cycle progression and cell proliferation and
apoptosis. MiRNAs also influence signalling by growth factors and growth factor
receptors, for example the EGFR signalling to EMT. They have been seen to func-
tion by interacting with and modulating the signalling pathways that are activated by
growth factors.