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CAR Co-Operates With Integrins to Promote Lung Cancer Cell Adhesion and Invasion

The coxsackie and adenovirus receptor (CAR) is a member of the junctional adhesion molecule (JAM) family of adhesion receptors and is localised to epithelial cell tight and adherens junctions. CAR has been shown to be highly expressed in lung cancer where it is proposed to promote tumor growth and r...

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Autores principales: Owczarek, Claudia, Ortiz-Zapater, Elena, Kim, Jana, Papaevangelou, Efthymia, Santis, George, Parsons, Maddy
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8889575/
https://www.ncbi.nlm.nih.gov/pubmed/35252000
http://dx.doi.org/10.3389/fonc.2022.829313
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author Owczarek, Claudia
Ortiz-Zapater, Elena
Kim, Jana
Papaevangelou, Efthymia
Santis, George
Parsons, Maddy
author_facet Owczarek, Claudia
Ortiz-Zapater, Elena
Kim, Jana
Papaevangelou, Efthymia
Santis, George
Parsons, Maddy
author_sort Owczarek, Claudia
collection PubMed
description The coxsackie and adenovirus receptor (CAR) is a member of the junctional adhesion molecule (JAM) family of adhesion receptors and is localised to epithelial cell tight and adherens junctions. CAR has been shown to be highly expressed in lung cancer where it is proposed to promote tumor growth and regulate epithelial mesenchymal transition (EMT), however the potential role of CAR in lung cancer metastasis remains poorly understood. To better understand the role of this receptor in tumor progression, we manipulated CAR expression in both epithelial-like and mesenchymal-like lung cancer cells. In both cases, CAR overexpression promoted tumor growth in vivo in immunocompetent mice and increased cell adhesion in the lung after intravenous injection without altering the EMT properties of each cell line. Overexpression of WTCAR resulted in increased invasion in 3D models and enhanced β1 integrin activity in both cell lines, and this was dependent on phosphorylation of the CAR cytoplasmic tail. Furthermore, phosphorylation of CAR was enhanced by substrate stiffness in vitro, and CAR expression increased at the boundary of solid tumors in vivo. Moreover, CAR formed a complex with the focal adhesion proteins Src, Focal Adhesion Kinase (FAK) and paxillin and promoted activation of the Guanine Triphosphate (GTP)-ase Ras-related Protein 1 (Rap1), which in turn mediated enhanced integrin activation. Taken together, our data demonstrate that CAR contributes to lung cancer metastasis via promotion of cell-matrix adhesion, providing new insight into co-operation between cell-cell and cell-matrix proteins that regulate different steps of tumorigenesis.
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spelling pubmed-88895752022-03-03 CAR Co-Operates With Integrins to Promote Lung Cancer Cell Adhesion and Invasion Owczarek, Claudia Ortiz-Zapater, Elena Kim, Jana Papaevangelou, Efthymia Santis, George Parsons, Maddy Front Oncol Oncology The coxsackie and adenovirus receptor (CAR) is a member of the junctional adhesion molecule (JAM) family of adhesion receptors and is localised to epithelial cell tight and adherens junctions. CAR has been shown to be highly expressed in lung cancer where it is proposed to promote tumor growth and regulate epithelial mesenchymal transition (EMT), however the potential role of CAR in lung cancer metastasis remains poorly understood. To better understand the role of this receptor in tumor progression, we manipulated CAR expression in both epithelial-like and mesenchymal-like lung cancer cells. In both cases, CAR overexpression promoted tumor growth in vivo in immunocompetent mice and increased cell adhesion in the lung after intravenous injection without altering the EMT properties of each cell line. Overexpression of WTCAR resulted in increased invasion in 3D models and enhanced β1 integrin activity in both cell lines, and this was dependent on phosphorylation of the CAR cytoplasmic tail. Furthermore, phosphorylation of CAR was enhanced by substrate stiffness in vitro, and CAR expression increased at the boundary of solid tumors in vivo. Moreover, CAR formed a complex with the focal adhesion proteins Src, Focal Adhesion Kinase (FAK) and paxillin and promoted activation of the Guanine Triphosphate (GTP)-ase Ras-related Protein 1 (Rap1), which in turn mediated enhanced integrin activation. Taken together, our data demonstrate that CAR contributes to lung cancer metastasis via promotion of cell-matrix adhesion, providing new insight into co-operation between cell-cell and cell-matrix proteins that regulate different steps of tumorigenesis. Frontiers Media S.A. 2022-02-14 /pmc/articles/PMC8889575/ /pubmed/35252000 http://dx.doi.org/10.3389/fonc.2022.829313 Text en Copyright © 2022 Owczarek, Ortiz-Zapater, Kim, Papaevangelou, Santis and Parsons https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Owczarek, Claudia
Ortiz-Zapater, Elena
Kim, Jana
Papaevangelou, Efthymia
Santis, George
Parsons, Maddy
CAR Co-Operates With Integrins to Promote Lung Cancer Cell Adhesion and Invasion
title CAR Co-Operates With Integrins to Promote Lung Cancer Cell Adhesion and Invasion
title_full CAR Co-Operates With Integrins to Promote Lung Cancer Cell Adhesion and Invasion
title_fullStr CAR Co-Operates With Integrins to Promote Lung Cancer Cell Adhesion and Invasion
title_full_unstemmed CAR Co-Operates With Integrins to Promote Lung Cancer Cell Adhesion and Invasion
title_short CAR Co-Operates With Integrins to Promote Lung Cancer Cell Adhesion and Invasion
title_sort car co-operates with integrins to promote lung cancer cell adhesion and invasion
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8889575/
https://www.ncbi.nlm.nih.gov/pubmed/35252000
http://dx.doi.org/10.3389/fonc.2022.829313
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