C3G is upregulated in hepatocarcinoma, contributing to tumor growth and progression and to HGF/MET pathway activation

[EN]The complexity of hepatocellular carcinoma (HCC) challenges the identification of disease-relevant signals. C3G, a guanine nucleotide exchange factor for Rap and other Ras proteins, plays a dual role in cancer acting as either a tumor suppressor or promoter depending on tumor type and stage. The...

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Autores: Sequera, Celia, Bragado, Paloma, Manzano, Sara, Arechederra, Maria, Richelme, Sylvie, Gutiérrez-Uzquiza, Alvaro, Sánchez, Aránzazu, Maina, Flavio, Guerrero Arroyo, María Carmen, Porras, Almudena
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2020
País:España
Institución:Universidad de Salamanca (USAL)
Repositorio:GREDOS. Repositorio Institucional de la Universidad de Salamanca
OAI Identifier:oai:gredos.usal.es:10366/148931
Acceso en línea:http://hdl.handle.net/10366/148931
Access Level:acceso abierto
Palabra clave:C3G
Hepatocarcinoma
Cancer
MET
Cell signaling
Carcinoma, Hepatocellular
3207.13 Oncología
2415 Biología Molecular
3207.08 Hematología
carcinoma hepatocelular
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oai_identifier_str oai:gredos.usal.es:10366/148931
network_acronym_str ES
network_name_str España
repository_id_str
spelling C3G is upregulated in hepatocarcinoma, contributing to tumor growth and progression and to HGF/MET pathway activationSequera, CeliaBragado, PalomaManzano, SaraArechederra, MariaRichelme, SylvieGutiérrez-Uzquiza, AlvaroSánchez, AránzazuMaina, FlavioGuerrero Arroyo, María CarmenPorras, AlmudenaC3GHepatocarcinomaCancerMETCell signalingCarcinoma, Hepatocellular3207.13 Oncología2415 Biología Molecular3207.08 Hematologíacarcinoma hepatocelular[EN]The complexity of hepatocellular carcinoma (HCC) challenges the identification of disease-relevant signals. C3G, a guanine nucleotide exchange factor for Rap and other Ras proteins, plays a dual role in cancer acting as either a tumor suppressor or promoter depending on tumor type and stage. The potential relevance of C3G upregulation in HCC patients suggested by database analysis remains unknown. We have explored C3G function in HCC and the underlying mechanisms using public patient data and in vitro and in vivo human and mouse HCC models. We found that C3G is highly expressed in progenitor cells and neonatal hepatocytes, whilst being down-regulated in adult hepatocytes and re-expressed in human HCC patients, mouse HCC models and HCC cell lines. Moreover, high C3G mRNA levels correlate with tumor progression and a lower patient survival rate. C3G expression appears to be tightly modulated within the HCC program, influencing distinct cell biological properties. Hence, high C3G expression levels are necessary for cell tumorigenic properties, as illustrated by reduced colony formation in anchorage-dependent and -independent growth assays induced by permanent C3G silencing using shRNAs. Additionally, we demonstrate that C3G down-regulation interferes with primary HCC tumor formation in xenograft assays, increasing apoptosis and decreasing proliferation. In vitro assays also revealed that C3G down-regulation enhances the pro-migratory, invasive and metastatic properties of HCC cells through an epithelial-mesenchymal switch that favors the acquisition of a more mesenchymal phenotype. Consistently, a low C3G expression in HCC cells correlates with lung metastasis formation in mice. However, the subsequent restoration of C3G levels is associated with metastatic growth. Mechanistically, C3G down-regulation severely impairs HGF/MET signaling activation in HCC cells. Collectively, our results indicate that C3G is a key player in HCC. C3G promotes tumor growth and progression, and the modulation of its levels is essential to ensure distinct biological features of HCC cells throughout the oncogenic program. Furthermore, C3G requirement for HGF/MET signaling full activation provides mechanistic data on how it works, pointing out the relevance of assessing whether high C3G levels could identify HCC responders to MET inhibitors.202220222020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10366/148931reponame:GREDOS. Repositorio Institucional de la Universidad de Salamancainstname:Universidad de Salamanca (USAL)InglésMarie CurieAttribution-NonCommercial-NoDerivatives 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:gredos.usal.es:10366/1489312026-06-07T06:28:51Z
dc.title.none.fl_str_mv C3G is upregulated in hepatocarcinoma, contributing to tumor growth and progression and to HGF/MET pathway activation
title C3G is upregulated in hepatocarcinoma, contributing to tumor growth and progression and to HGF/MET pathway activation
spellingShingle C3G is upregulated in hepatocarcinoma, contributing to tumor growth and progression and to HGF/MET pathway activation
Sequera, Celia
C3G
Hepatocarcinoma
Cancer
MET
Cell signaling
Carcinoma, Hepatocellular
3207.13 Oncología
2415 Biología Molecular
3207.08 Hematología
carcinoma hepatocelular
title_short C3G is upregulated in hepatocarcinoma, contributing to tumor growth and progression and to HGF/MET pathway activation
title_full C3G is upregulated in hepatocarcinoma, contributing to tumor growth and progression and to HGF/MET pathway activation
title_fullStr C3G is upregulated in hepatocarcinoma, contributing to tumor growth and progression and to HGF/MET pathway activation
title_full_unstemmed C3G is upregulated in hepatocarcinoma, contributing to tumor growth and progression and to HGF/MET pathway activation
title_sort C3G is upregulated in hepatocarcinoma, contributing to tumor growth and progression and to HGF/MET pathway activation
dc.creator.none.fl_str_mv Sequera, Celia
Bragado, Paloma
Manzano, Sara
Arechederra, Maria
Richelme, Sylvie
Gutiérrez-Uzquiza, Alvaro
Sánchez, Aránzazu
Maina, Flavio
Guerrero Arroyo, María Carmen
Porras, Almudena
author Sequera, Celia
author_facet Sequera, Celia
Bragado, Paloma
Manzano, Sara
Arechederra, Maria
Richelme, Sylvie
Gutiérrez-Uzquiza, Alvaro
Sánchez, Aránzazu
Maina, Flavio
Guerrero Arroyo, María Carmen
Porras, Almudena
author_role author
author2 Bragado, Paloma
Manzano, Sara
Arechederra, Maria
Richelme, Sylvie
Gutiérrez-Uzquiza, Alvaro
Sánchez, Aránzazu
Maina, Flavio
Guerrero Arroyo, María Carmen
Porras, Almudena
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv C3G
Hepatocarcinoma
Cancer
MET
Cell signaling
Carcinoma, Hepatocellular
3207.13 Oncología
2415 Biología Molecular
3207.08 Hematología
carcinoma hepatocelular
topic C3G
Hepatocarcinoma
Cancer
MET
Cell signaling
Carcinoma, Hepatocellular
3207.13 Oncología
2415 Biología Molecular
3207.08 Hematología
carcinoma hepatocelular
description [EN]The complexity of hepatocellular carcinoma (HCC) challenges the identification of disease-relevant signals. C3G, a guanine nucleotide exchange factor for Rap and other Ras proteins, plays a dual role in cancer acting as either a tumor suppressor or promoter depending on tumor type and stage. The potential relevance of C3G upregulation in HCC patients suggested by database analysis remains unknown. We have explored C3G function in HCC and the underlying mechanisms using public patient data and in vitro and in vivo human and mouse HCC models. We found that C3G is highly expressed in progenitor cells and neonatal hepatocytes, whilst being down-regulated in adult hepatocytes and re-expressed in human HCC patients, mouse HCC models and HCC cell lines. Moreover, high C3G mRNA levels correlate with tumor progression and a lower patient survival rate. C3G expression appears to be tightly modulated within the HCC program, influencing distinct cell biological properties. Hence, high C3G expression levels are necessary for cell tumorigenic properties, as illustrated by reduced colony formation in anchorage-dependent and -independent growth assays induced by permanent C3G silencing using shRNAs. Additionally, we demonstrate that C3G down-regulation interferes with primary HCC tumor formation in xenograft assays, increasing apoptosis and decreasing proliferation. In vitro assays also revealed that C3G down-regulation enhances the pro-migratory, invasive and metastatic properties of HCC cells through an epithelial-mesenchymal switch that favors the acquisition of a more mesenchymal phenotype. Consistently, a low C3G expression in HCC cells correlates with lung metastasis formation in mice. However, the subsequent restoration of C3G levels is associated with metastatic growth. Mechanistically, C3G down-regulation severely impairs HGF/MET signaling activation in HCC cells. Collectively, our results indicate that C3G is a key player in HCC. C3G promotes tumor growth and progression, and the modulation of its levels is essential to ensure distinct biological features of HCC cells throughout the oncogenic program. Furthermore, C3G requirement for HGF/MET signaling full activation provides mechanistic data on how it works, pointing out the relevance of assessing whether high C3G levels could identify HCC responders to MET inhibitors.
publishDate 2020
dc.date.none.fl_str_mv 2020
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10366/148931
url http://hdl.handle.net/10366/148931
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Marie Curie
dc.rights.none.fl_str_mv Attribution-NonCommercial-NoDerivatives 4.0 Internacional
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv Attribution-NonCommercial-NoDerivatives 4.0 Internacional
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:GREDOS. Repositorio Institucional de la Universidad de Salamanca
instname:Universidad de Salamanca (USAL)
instname_str Universidad de Salamanca (USAL)
reponame_str GREDOS. Repositorio Institucional de la Universidad de Salamanca
collection GREDOS. Repositorio Institucional de la Universidad de Salamanca
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300724

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