C3G Is Upregulated in Hepatocarcinoma, Contributing to Tumor Growth and Progression and to HGF/MET Pathway Activation

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 pot...

Descripción completa

Detalles Bibliográficos
Autores: Sequera Hurtado, Celia, Bragado Domingo, Paloma, Manzano Figueroa, Sara, Arechederra, Maria, Richelme, Sylvie, Gutiérrez Uzquiza, Álvaro, Sánchez Muñoz, Aranzazu, Maina, Flavio, Guerrero, Carmen, Porras Gallo, María Almudena
Tipo de recurso: artículo
Fecha de publicación:2020
País:España
Institución:Universidad Complutense de Madrid (UCM)
Repositorio:Docta Complutense
Idioma:inglés
OAI Identifier:oai:docta.ucm.es:20.500.14352/8375
Acceso en línea:https://hdl.handle.net/20.500.14352/8375
Access Level:acceso abierto
Palabra clave:C3G
Hepatocarcinoma
Cancer
MET
Cell signaling
Gastroenterología y hepatología
Oncología
Biología molecular (Farmacia)
3205.03 Gastroenterología
3201.01 Oncología
id ES_130931fa32029cf97d875662de683305
oai_identifier_str oai:docta.ucm.es:20.500.14352/8375
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 Hurtado, CeliaBragado Domingo, PalomaManzano Figueroa, SaraArechederra, MariaRichelme, SylvieGutiérrez Uzquiza, ÁlvaroSánchez Muñoz, AranzazuMaina, FlavioGuerrero, CarmenPorras Gallo, María AlmudenaC3GHepatocarcinomaCancerMETCell signalingGastroenterología y hepatologíaOncologíaBiología molecular (Farmacia)3205.03 Gastroenterología3201.01 OncologíaThe 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.MDPIUniversidad Complutense de Madrid20202020-08-1420202020-08-14journal articlehttp://purl.org/coar/resource_type/c_6501info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/20.500.14352/8375reponame:Docta Complutenseinstname:Universidad Complutense de Madrid (UCM)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Atribución 3.0 Españahttps://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:docta.ucm.es:20.500.14352/83752026-06-02T12:44:21Z
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 Hurtado, Celia
C3G
Hepatocarcinoma
Cancer
MET
Cell signaling
Gastroenterología y hepatología
Oncología
Biología molecular (Farmacia)
3205.03 Gastroenterología
3201.01 Oncología
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 Hurtado, Celia
Bragado Domingo, Paloma
Manzano Figueroa, Sara
Arechederra, Maria
Richelme, Sylvie
Gutiérrez Uzquiza, Álvaro
Sánchez Muñoz, Aranzazu
Maina, Flavio
Guerrero, Carmen
Porras Gallo, María Almudena
author Sequera Hurtado, Celia
author_facet Sequera Hurtado, Celia
Bragado Domingo, Paloma
Manzano Figueroa, Sara
Arechederra, Maria
Richelme, Sylvie
Gutiérrez Uzquiza, Álvaro
Sánchez Muñoz, Aranzazu
Maina, Flavio
Guerrero, Carmen
Porras Gallo, María Almudena
author_role author
author2 Bragado Domingo, Paloma
Manzano Figueroa, Sara
Arechederra, Maria
Richelme, Sylvie
Gutiérrez Uzquiza, Álvaro
Sánchez Muñoz, Aranzazu
Maina, Flavio
Guerrero, Carmen
Porras Gallo, María Almudena
author2_role author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universidad Complutense de Madrid
dc.subject.none.fl_str_mv C3G
Hepatocarcinoma
Cancer
MET
Cell signaling
Gastroenterología y hepatología
Oncología
Biología molecular (Farmacia)
3205.03 Gastroenterología
3201.01 Oncología
topic C3G
Hepatocarcinoma
Cancer
MET
Cell signaling
Gastroenterología y hepatología
Oncología
Biología molecular (Farmacia)
3205.03 Gastroenterología
3201.01 Oncología
description 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
2020-08-14
2020
2020-08-14
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/20.500.14352/8375
url https://hdl.handle.net/20.500.14352/8375
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución 3.0 España
https://creativecommons.org/licenses/by/3.0/es/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución 3.0 España
https://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv reponame:Docta Complutense
instname:Universidad Complutense de Madrid (UCM)
instname_str Universidad Complutense de Madrid (UCM)
reponame_str Docta Complutense
collection Docta Complutense
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869403652691591168
score 15,300724

Similares en LA Referencia