Simultaneous E-cadherin and PLEKHA7 expression negatively affects E-cadherin/EGFR mediated ovarian cancer cell growth

Katia Rea, Francesca Roggiani, Loris De Cecco, Francesco Raspagliesi, Maria Luisa Carcangiu, Joyce Nair-Menon, Marina Bagnoli, Ileana Bortolomai, Delia Mezzanzanica, Silvana Canevari, Antonis Kourtidis, Panagiotis Z Anastasiadis, Antonella Tomassetti

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Article number146
JournalJournal of Experimental and Clinical Cancer Research
Volume37
Issue number1
DOIs
StatePublished - Jul 11 2018

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Cadherins
Ovarian Neoplasms
Growth
Cisplatin
Neoplasms
Western Blotting
Ovarian epithelial cancer
Adherens Junctions
Lentivirus
Phosphatidylinositol 3-Kinases
Immunoprecipitation
Confocal Microscopy
Real-Time Polymerase Chain Reaction
Epithelium
Immunohistochemistry
Ligands
Phenotype
Gene Expression
Cell Line

Keywords

  • CDK5
  • E-cadherin
  • EGFR
  • Epithelial ovarian cancer
  • PLEKHA7

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Simultaneous E-cadherin and PLEKHA7 expression negatively affects E-cadherin/EGFR mediated ovarian cancer cell growth. / Rea, Katia; Roggiani, Francesca; De Cecco, Loris; Raspagliesi, Francesco; Carcangiu, Maria Luisa; Nair-Menon, Joyce; Bagnoli, Marina; Bortolomai, Ileana; Mezzanzanica, Delia; Canevari, Silvana; Kourtidis, Antonis; Anastasiadis, Panagiotis Z; Tomassetti, Antonella.

In: Journal of Experimental and Clinical Cancer Research, Vol. 37, No. 1, 146, 11.07.2018.

Research output: Contribution to journalArticle

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 2018, 'Simultaneous E-cadherin and PLEKHA7 expression negatively affects E-cadherin/EGFR mediated ovarian cancer cell growth', Journal of Experimental and Clinical Cancer Research, vol. 37, no. 1, 146. https://doi.org/10.1186/s13046-018-0796-1
Rea, Katia ; Roggiani, Francesca ; De Cecco, Loris ; Raspagliesi, Francesco ; Carcangiu, Maria Luisa ; Nair-Menon, Joyce ; Bagnoli, Marina ; Bortolomai, Ileana ; Mezzanzanica, Delia ; Canevari, Silvana ; Kourtidis, Antonis ; Anastasiadis, Panagiotis Z ; Tomassetti, Antonella. / Simultaneous E-cadherin and PLEKHA7 expression negatively affects E-cadherin/EGFR mediated ovarian cancer cell growth. In: Journal of Experimental and Clinical Cancer Research. 2018 ; Vol. 37, No. 1.
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T1 - Simultaneous E-cadherin and PLEKHA7 expression negatively affects E-cadherin/EGFR mediated ovarian cancer cell growth

AU - Rea, Katia

AU - Roggiani, Francesca

AU - De Cecco, Loris

AU - Raspagliesi, Francesco

AU - Carcangiu, Maria Luisa

AU - Nair-Menon, Joyce

AU - Bagnoli, Marina

AU - Bortolomai, Ileana

AU - Mezzanzanica, Delia

AU - Canevari, Silvana

AU - Kourtidis, Antonis

AU - Anastasiadis, Panagiotis Z

AU - Tomassetti, Antonella

PY - 2018/7/11

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N2 - 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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KW - CDK5

KW - E-cadherin

KW - EGFR

KW - Epithelial ovarian cancer

KW - PLEKHA7

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