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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 J+Exp+Clin+Cancer+Res
2018 ; 37
(1
): 146
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Simultaneous E-cadherin and PLEKHA7 expression negatively affects E-cadherin/EGFR
mediated ovarian cancer cell growth
#MMPMID29996940
Rea K
; Roggiani F
; De Cecco L
; Raspagliesi F
; Carcangiu ML
; Nair-Menon J
; Bagnoli M
; Bortolomai I
; Mezzanzanica D
; Canevari S
; Kourtidis A
; Anastasiadis PZ
; Tomassetti A
J Exp Clin Cancer Res
2018[Jul]; 37
(1
): 146
PMID29996940
show ga
BACKGROUND: The disruption of E-cadherin-mediated adhesion is considered an
important driver of tumor progression. Nevertheless, numerous studies have
demonstrated that E-cadherin promotes growth- or invasion-related signaling,
contrary to the prevailing notion. During tumor progression, epithelial ovarian
cancer (EOC) maintains E-cadherin expression and can positively affect EOC cell
growth by contributing to PI3K/AKT activation. In polarized epithelia PLEKHA7, a
regulator of the zonula adherens integrity, impinges E-cadherin functionality,
but its role in EOCs has been never studied. METHODS: Ex-vivo EOC cells and cell
lines were used to study E-cadherin contribution to growth and EGFR activation.
The expression of the proteins involved was assessed by real time RT-PCR,
immunohistochemistry and western blotting. Cells growth and drug susceptibility
was monitored in different 3-dimensional (3D) systems. Recombinant
lentivirus-mediated gene expression, western blotting, immunoprecipitation and
confocal microscopy were applied to investigate the biological impact of PLEKHA7
on E-cadherin behaviour. The clinical impact of PLEKHA7 was determined in
publicly available datasets. RESULTS: We show that E-cadherin expression
contributes to growth of EOC cells and forms a complex with EGFR thus positively
affecting ligand-dependent EGFR/CDK5 signaling. Accordingly, 3D cultures of
E-cadherin-expressing EOC cells are sensitive to the CDK5 inhibitor roscovitine
combined with cisplatin. We determined that PLEKHA7 overexpression reduces the
formation of E-cadherin-EGFR complex, EGFR activation and cell tumorigenicity.
Clinically, PLEKHA7 mRNA is statistically decreased in high grade EOCs respect to
low malignant potential and low grade EOCs and correlates with better EOC patient
outcome. CONCLUSIONS: These data represent a significant step towards untangling
the role of E-cadherin in EOCs by assessing its positive effects on EGFR/CDK5
signaling and its contribution to cell growth. Hence, the inhibition of this
signaling using a CDK5 inhibitor exerts a synergistic effect with cisplatin
prompting on the design of new therapeutic strategies to inhibit growth of EOC
cells. We assessed for the first time in EOC cells that PLEKHA7 induces changes
in the asset of E-cadherin-containing cell-cell contacts thus inhibiting
E-cadherin/EGFR crosstalk and leading to a less aggressive tumor phenotype.
Accordingly, PLEKHA7 levels are lower in high grade EOC patient tumors and EOC
patients with better outcomes display higher PLEKHA7 levels.
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