USP19 modulates cancer cell migration and invasion and acts as a novel prognostic marker in patients with early breast cancer

Autores
Rossi, Fabiana Alejandra; Enriqué Steinberg, Juliana Haydeé; Calvo Roitberg, Ezequiel Hernán; Joshi, Molishree Umesh; Pandey, Ahwan; Abba, Martín Carlos; Dufrusine, Beatrice; Buglioni, Simonetta; De Laurenzi, Vincenzo; Sala, Gianluca; Lattanzio, Rossano; Espinosa, Joaquín Maximiliano; Rossi, Mario
Año de publicación
2021
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Tumor cell dissemination in cancer patients is associated with a significant reduction in their survival and quality of life. The ubiquitination pathway plays a fundamental role in the maintenance of protein homeostasis both in normal and stressed conditions and its dysregulation has been associated with malignant transformation and invasive potential of tumor cells, thus highlighting its value as a potential therapeutic target. In order to identify novel molecular targets of tumor cell migration and invasion we performed a genetic screen with an shRNA library against ubiquitination pathway-related genes. To this end, we set up a protocol to specifically enrich positive migration regulator candidates. We identified the deubiquitinase USP19 and demonstrated that its silencing reduces the migratory and invasive potential of highly invasive breast cancer cell lines. We extended our investigation in vivo and confirmed that mice injected with USP19 depleted cells display increased tumor-free survival, as well as a delay in the onset of the tumor formation and a significant reduction in the appearance of metastatic foci, indicating that tumor cell invasion and dissemination is impaired. In contrast, overexpression of USP19 increased cell invasiveness both in vitro and in vivo, further validating our findings. More importantly, we demonstrated that USP19 catalytic activity is important for the control of tumor cell migration and invasion, and that its molecular mechanism of action involves LRP6, a Wnt co-receptor. Finally, we showed that USP19 overexpression is a surrogate prognostic marker of distant relapse in patients with early breast cancer. Altogether, these findings demonstrate that USP19 might represent a novel therapeutic target in breast cancer.
Fil: Rossi, Fabiana Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina
Fil: Enriqué Steinberg, Juliana Haydeé. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina
Fil: Calvo Roitberg, Ezequiel Hernán. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina
Fil: Joshi, Molishree Umesh. University of Colorado; Estados Unidos
Fil: Pandey, Ahwan. No especifíca;
Fil: Abba, Martín Carlos. Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Inmunológicas Básicas y Aplicadas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Dufrusine, Beatrice. University of Chieti-Pescara; Italia
Fil: Buglioni, Simonetta. Regina Elena Cancer Institute; Italia
Fil: De Laurenzi, Vincenzo. University of Chieti-Pescara; Italia
Fil: Sala, Gianluca. University of Chieti-Pescara; Italia
Fil: Lattanzio, Rossano. University of Chieti-Pescara; Italia
Fil: Espinosa, Joaquín Maximiliano. University of Colorado; Estados Unidos
Fil: Rossi, Mario. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina
Materia
USP19
BREAST CANCER
INVASION
MIGRATION
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/184293
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/184293
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling USP19 modulates cancer cell migration and invasion and acts as a novel prognostic marker in patients with early breast cancerRossi, Fabiana AlejandraEnriqué Steinberg, Juliana HaydeéCalvo Roitberg, Ezequiel HernánJoshi, Molishree UmeshPandey, AhwanAbba, Martín CarlosDufrusine, BeatriceBuglioni, SimonettaDe Laurenzi, VincenzoSala, GianlucaLattanzio, RossanoEspinosa, Joaquín MaximilianoRossi, MarioUSP19BREAST CANCERINVASIONMIGRATIONhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Tumor cell dissemination in cancer patients is associated with a significant reduction in their survival and quality of life. The ubiquitination pathway plays a fundamental role in the maintenance of protein homeostasis both in normal and stressed conditions and its dysregulation has been associated with malignant transformation and invasive potential of tumor cells, thus highlighting its value as a potential therapeutic target. In order to identify novel molecular targets of tumor cell migration and invasion we performed a genetic screen with an shRNA library against ubiquitination pathway-related genes. To this end, we set up a protocol to specifically enrich positive migration regulator candidates. We identified the deubiquitinase USP19 and demonstrated that its silencing reduces the migratory and invasive potential of highly invasive breast cancer cell lines. We extended our investigation in vivo and confirmed that mice injected with USP19 depleted cells display increased tumor-free survival, as well as a delay in the onset of the tumor formation and a significant reduction in the appearance of metastatic foci, indicating that tumor cell invasion and dissemination is impaired. In contrast, overexpression of USP19 increased cell invasiveness both in vitro and in vivo, further validating our findings. More importantly, we demonstrated that USP19 catalytic activity is important for the control of tumor cell migration and invasion, and that its molecular mechanism of action involves LRP6, a Wnt co-receptor. Finally, we showed that USP19 overexpression is a surrogate prognostic marker of distant relapse in patients with early breast cancer. Altogether, these findings demonstrate that USP19 might represent a novel therapeutic target in breast cancer.Fil: Rossi, Fabiana Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; ArgentinaFil: Enriqué Steinberg, Juliana Haydeé. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; ArgentinaFil: Calvo Roitberg, Ezequiel Hernán. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Joshi, Molishree Umesh. University of Colorado; Estados UnidosFil: Pandey, Ahwan. No especifíca;Fil: Abba, Martín Carlos. Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Inmunológicas Básicas y Aplicadas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Dufrusine, Beatrice. University of Chieti-Pescara; ItaliaFil: Buglioni, Simonetta. Regina Elena Cancer Institute; ItaliaFil: De Laurenzi, Vincenzo. University of Chieti-Pescara; ItaliaFil: Sala, Gianluca. University of Chieti-Pescara; ItaliaFil: Lattanzio, Rossano. University of Chieti-Pescara; ItaliaFil: Espinosa, Joaquín Maximiliano. University of Colorado; Estados UnidosFil: Rossi, Mario. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; ArgentinaNature Publishing Group2021-03info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/184293Rossi, Fabiana Alejandra; Enriqué Steinberg, Juliana Haydeé; Calvo Roitberg, Ezequiel Hernán; Joshi, Molishree Umesh; Pandey, Ahwan; et al.; USP19 modulates cancer cell migration and invasion and acts as a novel prognostic marker in patients with early breast cancer; Nature Publishing Group; Oncogenesis; 10; 3; 3-2021; 1-152157-9024CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://www.nature.com/articles/s41389-021-00318-xinfo:eu-repo/semantics/altIdentifier/doi/10.1038/s41389-021-00318-xinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-11-12T09:40:00Zoai:ri.conicet.gov.ar:11336/184293instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-11-12 09:40:00.53CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv USP19 modulates cancer cell migration and invasion and acts as a novel prognostic marker in patients with early breast cancer
title USP19 modulates cancer cell migration and invasion and acts as a novel prognostic marker in patients with early breast cancer
spellingShingle USP19 modulates cancer cell migration and invasion and acts as a novel prognostic marker in patients with early breast cancer
Rossi, Fabiana Alejandra
USP19
BREAST CANCER
INVASION
MIGRATION
title_short USP19 modulates cancer cell migration and invasion and acts as a novel prognostic marker in patients with early breast cancer
title_full USP19 modulates cancer cell migration and invasion and acts as a novel prognostic marker in patients with early breast cancer
title_fullStr USP19 modulates cancer cell migration and invasion and acts as a novel prognostic marker in patients with early breast cancer
title_full_unstemmed USP19 modulates cancer cell migration and invasion and acts as a novel prognostic marker in patients with early breast cancer
title_sort USP19 modulates cancer cell migration and invasion and acts as a novel prognostic marker in patients with early breast cancer
dc.creator.none.fl_str_mv Rossi, Fabiana Alejandra
Enriqué Steinberg, Juliana Haydeé
Calvo Roitberg, Ezequiel Hernán
Joshi, Molishree Umesh
Pandey, Ahwan
Abba, Martín Carlos
Dufrusine, Beatrice
Buglioni, Simonetta
De Laurenzi, Vincenzo
Sala, Gianluca
Lattanzio, Rossano
Espinosa, Joaquín Maximiliano
Rossi, Mario
author Rossi, Fabiana Alejandra
author_facet Rossi, Fabiana Alejandra
Enriqué Steinberg, Juliana Haydeé
Calvo Roitberg, Ezequiel Hernán
Joshi, Molishree Umesh
Pandey, Ahwan
Abba, Martín Carlos
Dufrusine, Beatrice
Buglioni, Simonetta
De Laurenzi, Vincenzo
Sala, Gianluca
Lattanzio, Rossano
Espinosa, Joaquín Maximiliano
Rossi, Mario
author_role author
author2 Enriqué Steinberg, Juliana Haydeé
Calvo Roitberg, Ezequiel Hernán
Joshi, Molishree Umesh
Pandey, Ahwan
Abba, Martín Carlos
Dufrusine, Beatrice
Buglioni, Simonetta
De Laurenzi, Vincenzo
Sala, Gianluca
Lattanzio, Rossano
Espinosa, Joaquín Maximiliano
Rossi, Mario
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv USP19
BREAST CANCER
INVASION
MIGRATION
topic USP19
BREAST CANCER
INVASION
MIGRATION
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Tumor cell dissemination in cancer patients is associated with a significant reduction in their survival and quality of life. The ubiquitination pathway plays a fundamental role in the maintenance of protein homeostasis both in normal and stressed conditions and its dysregulation has been associated with malignant transformation and invasive potential of tumor cells, thus highlighting its value as a potential therapeutic target. In order to identify novel molecular targets of tumor cell migration and invasion we performed a genetic screen with an shRNA library against ubiquitination pathway-related genes. To this end, we set up a protocol to specifically enrich positive migration regulator candidates. We identified the deubiquitinase USP19 and demonstrated that its silencing reduces the migratory and invasive potential of highly invasive breast cancer cell lines. We extended our investigation in vivo and confirmed that mice injected with USP19 depleted cells display increased tumor-free survival, as well as a delay in the onset of the tumor formation and a significant reduction in the appearance of metastatic foci, indicating that tumor cell invasion and dissemination is impaired. In contrast, overexpression of USP19 increased cell invasiveness both in vitro and in vivo, further validating our findings. More importantly, we demonstrated that USP19 catalytic activity is important for the control of tumor cell migration and invasion, and that its molecular mechanism of action involves LRP6, a Wnt co-receptor. Finally, we showed that USP19 overexpression is a surrogate prognostic marker of distant relapse in patients with early breast cancer. Altogether, these findings demonstrate that USP19 might represent a novel therapeutic target in breast cancer.
Fil: Rossi, Fabiana Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina
Fil: Enriqué Steinberg, Juliana Haydeé. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina
Fil: Calvo Roitberg, Ezequiel Hernán. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina
Fil: Joshi, Molishree Umesh. University of Colorado; Estados Unidos
Fil: Pandey, Ahwan. No especifíca;
Fil: Abba, Martín Carlos. Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Inmunológicas Básicas y Aplicadas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Dufrusine, Beatrice. University of Chieti-Pescara; Italia
Fil: Buglioni, Simonetta. Regina Elena Cancer Institute; Italia
Fil: De Laurenzi, Vincenzo. University of Chieti-Pescara; Italia
Fil: Sala, Gianluca. University of Chieti-Pescara; Italia
Fil: Lattanzio, Rossano. University of Chieti-Pescara; Italia
Fil: Espinosa, Joaquín Maximiliano. University of Colorado; Estados Unidos
Fil: Rossi, Mario. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina
description Tumor cell dissemination in cancer patients is associated with a significant reduction in their survival and quality of life. The ubiquitination pathway plays a fundamental role in the maintenance of protein homeostasis both in normal and stressed conditions and its dysregulation has been associated with malignant transformation and invasive potential of tumor cells, thus highlighting its value as a potential therapeutic target. In order to identify novel molecular targets of tumor cell migration and invasion we performed a genetic screen with an shRNA library against ubiquitination pathway-related genes. To this end, we set up a protocol to specifically enrich positive migration regulator candidates. We identified the deubiquitinase USP19 and demonstrated that its silencing reduces the migratory and invasive potential of highly invasive breast cancer cell lines. We extended our investigation in vivo and confirmed that mice injected with USP19 depleted cells display increased tumor-free survival, as well as a delay in the onset of the tumor formation and a significant reduction in the appearance of metastatic foci, indicating that tumor cell invasion and dissemination is impaired. In contrast, overexpression of USP19 increased cell invasiveness both in vitro and in vivo, further validating our findings. More importantly, we demonstrated that USP19 catalytic activity is important for the control of tumor cell migration and invasion, and that its molecular mechanism of action involves LRP6, a Wnt co-receptor. Finally, we showed that USP19 overexpression is a surrogate prognostic marker of distant relapse in patients with early breast cancer. Altogether, these findings demonstrate that USP19 might represent a novel therapeutic target in breast cancer.
publishDate 2021
dc.date.none.fl_str_mv 2021-03
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/184293
Rossi, Fabiana Alejandra; Enriqué Steinberg, Juliana Haydeé; Calvo Roitberg, Ezequiel Hernán; Joshi, Molishree Umesh; Pandey, Ahwan; et al.; USP19 modulates cancer cell migration and invasion and acts as a novel prognostic marker in patients with early breast cancer; Nature Publishing Group; Oncogenesis; 10; 3; 3-2021; 1-15
2157-9024
CONICET Digital
CONICET
url http://hdl.handle.net/11336/184293
identifier_str_mv Rossi, Fabiana Alejandra; Enriqué Steinberg, Juliana Haydeé; Calvo Roitberg, Ezequiel Hernán; Joshi, Molishree Umesh; Pandey, Ahwan; et al.; USP19 modulates cancer cell migration and invasion and acts as a novel prognostic marker in patients with early breast cancer; Nature Publishing Group; Oncogenesis; 10; 3; 3-2021; 1-15
2157-9024
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
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info:eu-repo/semantics/altIdentifier/doi/10.1038/s41389-021-00318-x
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
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instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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