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Overexpression of the Ubiquitin Specific Proteases USP43, USP41, USP27x and USP6 in Osteosarcoma Cell Lines: Inhibition of Osteosarcoma Tumor Growth and Lung Metastasis Development by the USP Antagonist PR619

Osteosarcoma (OS) is the most common malignant bone tumor in children and teenagers. In many cases, such as poor response to treatment or the presence of metastases at diagnosis, the survival rate of patients remains very low. Although in the literature, more and more studies are emerging on the rol...

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Autores principales: Lavaud, Mélanie, Mullard, Mathilde, Tesfaye, Robel, Amiaud, Jérôme, Legrand, Mélanie, Danieau, Geoffroy, Brion, Régis, Morice, Sarah, Regnier, Laura, Dupuy, Maryne, Brounais-Le Royer, Bénédicte, Lamoureux, François, Ory, Benjamin, Rédini, Françoise, Verrecchia, Franck
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8464711/
https://www.ncbi.nlm.nih.gov/pubmed/34571917
http://dx.doi.org/10.3390/cells10092268
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author Lavaud, Mélanie
Mullard, Mathilde
Tesfaye, Robel
Amiaud, Jérôme
Legrand, Mélanie
Danieau, Geoffroy
Brion, Régis
Morice, Sarah
Regnier, Laura
Dupuy, Maryne
Brounais-Le Royer, Bénédicte
Lamoureux, François
Ory, Benjamin
Rédini, Françoise
Verrecchia, Franck
author_facet Lavaud, Mélanie
Mullard, Mathilde
Tesfaye, Robel
Amiaud, Jérôme
Legrand, Mélanie
Danieau, Geoffroy
Brion, Régis
Morice, Sarah
Regnier, Laura
Dupuy, Maryne
Brounais-Le Royer, Bénédicte
Lamoureux, François
Ory, Benjamin
Rédini, Françoise
Verrecchia, Franck
author_sort Lavaud, Mélanie
collection PubMed
description Osteosarcoma (OS) is the most common malignant bone tumor in children and teenagers. In many cases, such as poor response to treatment or the presence of metastases at diagnosis, the survival rate of patients remains very low. Although in the literature, more and more studies are emerging on the role of Ubiquitin-Specific Proteases (USPs) in the development of many cancers, few data exist regarding OS. In this context, RNA-sequencing analysis of OS cells and mesenchymal stem cells differentiated or not differentiated into osteoblasts reveals increased expression of four USPs in OS tumor cells: USP6, USP27x, USP41 and USP43. Tissue microarray analysis of patient biopsies demonstrates the nucleic and/or cytoplasmic expression of these four USPs at the protein level. Interestingly, Kaplan–Meyer analysis shows that the expression of two USPs, USP6 and USP41, is correlated with patient survival. In vivo experiments using a preclinical OS model, finally demonstrate that PR619, a USP inhibitor able to enhance protein ubiquitination in OS cell lines, reduces primary OS tumor growth and the development of lung metastases. In this context, in vitro experiments show that PR619 decreases the viability of OS cells, mainly by inducing a caspase3/7-dependent cell apoptosis. Overall, these results demonstrate the relevance of targeting USPs in OS.
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spelling pubmed-84647112021-09-27 Overexpression of the Ubiquitin Specific Proteases USP43, USP41, USP27x and USP6 in Osteosarcoma Cell Lines: Inhibition of Osteosarcoma Tumor Growth and Lung Metastasis Development by the USP Antagonist PR619 Lavaud, Mélanie Mullard, Mathilde Tesfaye, Robel Amiaud, Jérôme Legrand, Mélanie Danieau, Geoffroy Brion, Régis Morice, Sarah Regnier, Laura Dupuy, Maryne Brounais-Le Royer, Bénédicte Lamoureux, François Ory, Benjamin Rédini, Françoise Verrecchia, Franck Cells Article Osteosarcoma (OS) is the most common malignant bone tumor in children and teenagers. In many cases, such as poor response to treatment or the presence of metastases at diagnosis, the survival rate of patients remains very low. Although in the literature, more and more studies are emerging on the role of Ubiquitin-Specific Proteases (USPs) in the development of many cancers, few data exist regarding OS. In this context, RNA-sequencing analysis of OS cells and mesenchymal stem cells differentiated or not differentiated into osteoblasts reveals increased expression of four USPs in OS tumor cells: USP6, USP27x, USP41 and USP43. Tissue microarray analysis of patient biopsies demonstrates the nucleic and/or cytoplasmic expression of these four USPs at the protein level. Interestingly, Kaplan–Meyer analysis shows that the expression of two USPs, USP6 and USP41, is correlated with patient survival. In vivo experiments using a preclinical OS model, finally demonstrate that PR619, a USP inhibitor able to enhance protein ubiquitination in OS cell lines, reduces primary OS tumor growth and the development of lung metastases. In this context, in vitro experiments show that PR619 decreases the viability of OS cells, mainly by inducing a caspase3/7-dependent cell apoptosis. Overall, these results demonstrate the relevance of targeting USPs in OS. MDPI 2021-08-31 /pmc/articles/PMC8464711/ /pubmed/34571917 http://dx.doi.org/10.3390/cells10092268 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lavaud, Mélanie
Mullard, Mathilde
Tesfaye, Robel
Amiaud, Jérôme
Legrand, Mélanie
Danieau, Geoffroy
Brion, Régis
Morice, Sarah
Regnier, Laura
Dupuy, Maryne
Brounais-Le Royer, Bénédicte
Lamoureux, François
Ory, Benjamin
Rédini, Françoise
Verrecchia, Franck
Overexpression of the Ubiquitin Specific Proteases USP43, USP41, USP27x and USP6 in Osteosarcoma Cell Lines: Inhibition of Osteosarcoma Tumor Growth and Lung Metastasis Development by the USP Antagonist PR619
title Overexpression of the Ubiquitin Specific Proteases USP43, USP41, USP27x and USP6 in Osteosarcoma Cell Lines: Inhibition of Osteosarcoma Tumor Growth and Lung Metastasis Development by the USP Antagonist PR619
title_full Overexpression of the Ubiquitin Specific Proteases USP43, USP41, USP27x and USP6 in Osteosarcoma Cell Lines: Inhibition of Osteosarcoma Tumor Growth and Lung Metastasis Development by the USP Antagonist PR619
title_fullStr Overexpression of the Ubiquitin Specific Proteases USP43, USP41, USP27x and USP6 in Osteosarcoma Cell Lines: Inhibition of Osteosarcoma Tumor Growth and Lung Metastasis Development by the USP Antagonist PR619
title_full_unstemmed Overexpression of the Ubiquitin Specific Proteases USP43, USP41, USP27x and USP6 in Osteosarcoma Cell Lines: Inhibition of Osteosarcoma Tumor Growth and Lung Metastasis Development by the USP Antagonist PR619
title_short Overexpression of the Ubiquitin Specific Proteases USP43, USP41, USP27x and USP6 in Osteosarcoma Cell Lines: Inhibition of Osteosarcoma Tumor Growth and Lung Metastasis Development by the USP Antagonist PR619
title_sort overexpression of the ubiquitin specific proteases usp43, usp41, usp27x and usp6 in osteosarcoma cell lines: inhibition of osteosarcoma tumor growth and lung metastasis development by the usp antagonist pr619
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8464711/
https://www.ncbi.nlm.nih.gov/pubmed/34571917
http://dx.doi.org/10.3390/cells10092268
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