Neuroblastoma RAS viral oncogene homolog (N-RAS) deficiency aggravates liver injury and fibrosis

Zheng, Kang; Hao, Fengjie; Medrano-Garcia, Sandra; chaobo, chen; Guo, Feifei; Morán-Blanco, Laura; Ciudin Mihai, Andreea; Rivera-Esteban, Jesús; Pericas, Juan M

Neuroblastoma RAS viral oncogene homolog (N-RAS) deficiency aggravates liver injury and fibrosis

Homeostasis; Pathogenesis

Detalles Bibliográficos
Autores:	Zheng, Kang, Hao, Fengjie, Medrano-Garcia, Sandra, chaobo, chen, Guo, Feifei, Morán-Blanco, Laura, Ciudin Mihai, Andreea, Rivera-Esteban, Jesús, Pericas, Juan M
Tipo de recurso:	artículo
Estado:	Versión publicada
Fecha de publicación:	2023
País:	España
Institución:	Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:	Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:	oai:recercat.cat:11351/10181
Acceso en línea:	https://hdl.handle.net/11351/10181 http://hdl.handle.net/11351/10181
Access Level:	acceso abierto
Palabra clave:	Neuroblastoma Fetge - Malalties - Tractament Oncogens DISEASES::Neoplasms::Neoplasms by Histologic Type::Neoplasms, Germ Cell and Embryonal::Neuroectodermal Tumors::Neoplasms, Neuroepithelial::Neuroectodermal Tumors, Primitive::Neuroectodermal Tumors, Primitive, Peripheral::Neuroblastoma PHENOMENA AND PROCESSES::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::Genes, Neoplasm::Oncogenes DISEASES::Digestive System Diseases::Liver Diseases Other subheadings::Other subheadings::Other subheadings::/drug therapy ENFERMEDADES::neoplasias::neoplasias por tipo histológico::neoplasias de células germinales y embrionarias::tumores neuroectodérmicos::neoplasias neuroepiteliales::tumores neuroectodérmicos primitivos::tumores neuroectodérmicos primitivos periféricos::neuroblastoma FENÓMENOS Y PROCESOS::fenómenos genéticos::estructuras genéticas::genoma::componentes genómicos::genes::genes de neoplasias::oncogenes ENFERMEDADES::enfermedades del sistema digestivo::enfermedades hepáticas Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia

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dc.title.none.fl_str_mv	Neuroblastoma RAS viral oncogene homolog (N-RAS) deficiency aggravates liver injury and fibrosis
title	Neuroblastoma RAS viral oncogene homolog (N-RAS) deficiency aggravates liver injury and fibrosis
spellingShingle	Neuroblastoma RAS viral oncogene homolog (N-RAS) deficiency aggravates liver injury and fibrosis Zheng, Kang Neuroblastoma Fetge - Malalties - Tractament Oncogens DISEASES::Neoplasms::Neoplasms by Histologic Type::Neoplasms, Germ Cell and Embryonal::Neuroectodermal Tumors::Neoplasms, Neuroepithelial::Neuroectodermal Tumors, Primitive::Neuroectodermal Tumors, Primitive, Peripheral::Neuroblastoma PHENOMENA AND PROCESSES::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::Genes, Neoplasm::Oncogenes DISEASES::Digestive System Diseases::Liver Diseases Other subheadings::Other subheadings::Other subheadings::/drug therapy ENFERMEDADES::neoplasias::neoplasias por tipo histológico::neoplasias de células germinales y embrionarias::tumores neuroectodérmicos::neoplasias neuroepiteliales::tumores neuroectodérmicos primitivos::tumores neuroectodérmicos primitivos periféricos::neuroblastoma FENÓMENOS Y PROCESOS::fenómenos genéticos::estructuras genéticas::genoma::componentes genómicos::genes::genes de neoplasias::oncogenes ENFERMEDADES::enfermedades del sistema digestivo::enfermedades hepáticas Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia
title_short	Neuroblastoma RAS viral oncogene homolog (N-RAS) deficiency aggravates liver injury and fibrosis
title_full	Neuroblastoma RAS viral oncogene homolog (N-RAS) deficiency aggravates liver injury and fibrosis
title_fullStr	Neuroblastoma RAS viral oncogene homolog (N-RAS) deficiency aggravates liver injury and fibrosis
title_full_unstemmed	Neuroblastoma RAS viral oncogene homolog (N-RAS) deficiency aggravates liver injury and fibrosis
title_sort	Neuroblastoma RAS viral oncogene homolog (N-RAS) deficiency aggravates liver injury and fibrosis
dc.creator.none.fl_str_mv	Zheng, Kang Hao, Fengjie Medrano-Garcia, Sandra chaobo, chen Guo, Feifei Morán-Blanco, Laura Ciudin Mihai, Andreea Rivera-Esteban, Jesús Pericas, Juan M
author	Zheng, Kang
author_facet	Zheng, Kang Hao, Fengjie Medrano-Garcia, Sandra chaobo, chen Guo, Feifei Morán-Blanco, Laura Ciudin Mihai, Andreea Rivera-Esteban, Jesús Pericas, Juan M
author_role	author
author2	Hao, Fengjie Medrano-Garcia, Sandra chaobo, chen Guo, Feifei Morán-Blanco, Laura Ciudin Mihai, Andreea Rivera-Esteban, Jesús Pericas, Juan M
author2_role	author author author author author author author author
dc.contributor.none.fl_str_mv	Institut Català de la Salut [Zheng K] Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, Madrid, Spain. 12 de Octubre Health Research Institute (imas12), Madrid, Spain. Department of Anesthesiology, Nanjing Pukou District Hospital of Chinese Medicine Central Laboratory affiliated to Nanjing University of Chinese Medicine, Nanjing, China. [Hao F] Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, Madrid, Spain. 12 de Octubre Health Research Institute (imas12), Madrid, Spain. Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai, China. [Medrano-Garcia S] Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, Madrid, Spain. 12 de Octubre Health Research Institute (imas12), Madrid, Spain. [Chen C] Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, Madrid, Spain. Department of General Surgery, Wuxi Xishan People’s Hospital, Wuxi, China. Department of General Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China. [Guo F] Department of Obstetrics and Gynaecology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China. [Morán-Blanco L] Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, Madrid, Spain. [Ciudin A] Servei d’Endocrinologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. [Rivera-Esteban J] Servei d’Hepatologia, Servei de Medicina Interna, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. [Pericàs JM] Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain. Servei d’Hepatologia, Servei de Medicina Interna, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain Vall d'Hebron Barcelona Hospital Campus
dc.subject.none.fl_str_mv	Neuroblastoma Fetge - Malalties - Tractament Oncogens DISEASES::Neoplasms::Neoplasms by Histologic Type::Neoplasms, Germ Cell and Embryonal::Neuroectodermal Tumors::Neoplasms, Neuroepithelial::Neuroectodermal Tumors, Primitive::Neuroectodermal Tumors, Primitive, Peripheral::Neuroblastoma PHENOMENA AND PROCESSES::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::Genes, Neoplasm::Oncogenes DISEASES::Digestive System Diseases::Liver Diseases Other subheadings::Other subheadings::Other subheadings::/drug therapy ENFERMEDADES::neoplasias::neoplasias por tipo histológico::neoplasias de células germinales y embrionarias::tumores neuroectodérmicos::neoplasias neuroepiteliales::tumores neuroectodérmicos primitivos::tumores neuroectodérmicos primitivos periféricos::neuroblastoma FENÓMENOS Y PROCESOS::fenómenos genéticos::estructuras genéticas::genoma::componentes genómicos::genes::genes de neoplasias::oncogenes ENFERMEDADES::enfermedades del sistema digestivo::enfermedades hepáticas Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia
topic	Neuroblastoma Fetge - Malalties - Tractament Oncogens DISEASES::Neoplasms::Neoplasms by Histologic Type::Neoplasms, Germ Cell and Embryonal::Neuroectodermal Tumors::Neoplasms, Neuroepithelial::Neuroectodermal Tumors, Primitive::Neuroectodermal Tumors, Primitive, Peripheral::Neuroblastoma PHENOMENA AND PROCESSES::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::Genes, Neoplasm::Oncogenes DISEASES::Digestive System Diseases::Liver Diseases Other subheadings::Other subheadings::Other subheadings::/drug therapy ENFERMEDADES::neoplasias::neoplasias por tipo histológico::neoplasias de células germinales y embrionarias::tumores neuroectodérmicos::neoplasias neuroepiteliales::tumores neuroectodérmicos primitivos::tumores neuroectodérmicos primitivos periféricos::neuroblastoma FENÓMENOS Y PROCESOS::fenómenos genéticos::estructuras genéticas::genoma::componentes genómicos::genes::genes de neoplasias::oncogenes ENFERMEDADES::enfermedades del sistema digestivo::enfermedades hepáticas Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia
description	Homeostasis; Pathogenesis
publishDate	2023
dc.date.none.fl_str_mv	2023 2023 2023
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	https://hdl.handle.net/11351/10181 http://hdl.handle.net/11351/10181
url	https://hdl.handle.net/11351/10181 http://hdl.handle.net/11351/10181
dc.language.none.fl_str_mv	Inglés
language_invalid_str_mv	Inglés
dc.relation.none.fl_str_mv	Cell Death & Disease;14(8) https://doi.org/10.1038/s41419-023-06029-y
dc.rights.none.fl_str_mv	Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess
rights_invalid_str_mv	Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv	openAccess
dc.format.none.fl_str_mv	application/pdf application/pdf application/pdf application/pdf
dc.publisher.none.fl_str_mv	Springer Nature
publisher.none.fl_str_mv	Springer Nature
dc.source.none.fl_str_mv	Scientia reponame:Recercat. Dipósit de la Recerca de Catalunya instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str	Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str	Recercat. Dipósit de la Recerca de Catalunya
collection	Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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spelling	Neuroblastoma RAS viral oncogene homolog (N-RAS) deficiency aggravates liver injury and fibrosisZheng, KangHao, FengjieMedrano-Garcia, Sandrachaobo, chenGuo, FeifeiMorán-Blanco, LauraCiudin Mihai, AndreeaRivera-Esteban, JesúsPericas, Juan MNeuroblastomaFetge - Malalties - TractamentOncogensDISEASES::Neoplasms::Neoplasms by Histologic Type::Neoplasms, Germ Cell and Embryonal::Neuroectodermal Tumors::Neoplasms, Neuroepithelial::Neuroectodermal Tumors, Primitive::Neuroectodermal Tumors, Primitive, Peripheral::NeuroblastomaPHENOMENA AND PROCESSES::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::Genes, Neoplasm::OncogenesDISEASES::Digestive System Diseases::Liver DiseasesOther subheadings::Other subheadings::Other subheadings::/drug therapyENFERMEDADES::neoplasias::neoplasias por tipo histológico::neoplasias de células germinales y embrionarias::tumores neuroectodérmicos::neoplasias neuroepiteliales::tumores neuroectodérmicos primitivos::tumores neuroectodérmicos primitivos periféricos::neuroblastomaFENÓMENOS Y PROCESOS::fenómenos genéticos::estructuras genéticas::genoma::componentes genómicos::genes::genes de neoplasias::oncogenesENFERMEDADES::enfermedades del sistema digestivo::enfermedades hepáticasOtros calificadores::Otros calificadores::Otros calificadores::/farmacoterapiaHomeostasis; PathogenesisHomeostasis; PatogénesisHomeòstasi; PatogènesiProgressive hepatic damage and fibrosis are major features of chronic liver diseases of different etiology, yet the underlying molecular mechanisms remain to be fully defined. N-RAS, a member of the RAS family of small guanine nucleotide-binding proteins also encompassing the highly homologous H-RAS and K-RAS isoforms, was previously reported to modulate cell death and renal fibrosis; however, its role in liver damage and fibrogenesis remains unknown. Here, we approached this question by using N-RAS deficient (N-RAS−/−) mice and two experimental models of liver injury and fibrosis, namely carbon tetrachloride (CCl4) intoxication and bile duct ligation (BDL). In wild-type (N-RAS+/+) mice both hepatotoxic procedures augmented N-RAS expression in the liver. Compared to N-RAS+/+ counterparts, N-RAS−/− mice subjected to either CCl4 or BDL showed exacerbated liver injury and fibrosis, which was associated with enhanced hepatic stellate cell (HSC) activation and leukocyte infiltration in the damaged liver. At the molecular level, after CCl4 or BDL, N-RAS−/− livers exhibited augmented expression of necroptotic death markers along with JNK1/2 hyperactivation. In line with this, N-RAS ablation in a human hepatocytic cell line resulted in enhanced activation of JNK and necroptosis mediators in response to cell death stimuli. Of note, loss of hepatic N-RAS expression was characteristic of chronic liver disease patients with fibrosis. Collectively, our study unveils a novel role for N-RAS as a negative controller of the progression of liver injury and fibrogenesis, by critically downregulating signaling pathways leading to hepatocyte necroptosis. Furthermore, it suggests that N-RAS may be of potential clinical value as prognostic biomarker of progressive fibrotic liver damage, or as a novel therapeutic target for the treatment of chronic liver disease.This work was supported by the MICINN Retos RTI2018-095673-B-I00, PID2020-11782RB-I00, PID2020-117941RB-I00, all of which were co-funded with FEDER funds, AMMF 2018/117, COST Action CA17112 and Comunidad de Madrid S2022/BMD-7409. This project has received funding from the European Horizon’s research and innovation program HORIZON-HLTH-2022-STAYHLTH-02 under agreement No. 101095679. The research group belongs to the validated Research Groups Ref. 970935 Liver Pathophysiology, 920631 Lymphocyte Immunobiology and IBL-6 (imas12-associated). KZ was supported by the China Scholarship Council. SM-G was supported by a predoctoral scholarship from Complutense University.Springer NatureInstitut Català de la Salut[Zheng K] Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, Madrid, Spain. 12 de Octubre Health Research Institute (imas12), Madrid, Spain. Department of Anesthesiology, Nanjing Pukou District Hospital of Chinese Medicine Central Laboratory affiliated to Nanjing University of Chinese Medicine, Nanjing, China. [Hao F] Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, Madrid, Spain. 12 de Octubre Health Research Institute (imas12), Madrid, Spain. Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai, China. [Medrano-Garcia S] Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, Madrid, Spain. 12 de Octubre Health Research Institute (imas12), Madrid, Spain. [Chen C] Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, Madrid, Spain. Department of General Surgery, Wuxi Xishan People’s Hospital, Wuxi, China. Department of General Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China. [Guo F] Department of Obstetrics and Gynaecology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China. [Morán-Blanco L] Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, Madrid, Spain. [Ciudin A] Servei d’Endocrinologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. [Rivera-Esteban J] Servei d’Hepatologia, Servei de Medicina Interna, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. [Pericàs JM] Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain. Servei d’Hepatologia, Servei de Medicina Interna, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, SpainVall d'Hebron Barcelona Hospital Campus202320232023info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttps://hdl.handle.net/11351/10181http://hdl.handle.net/11351/10181Scientiareponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésCell Death & Disease;14(8)https://doi.org/10.1038/s41419-023-06029-yAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:11351/101812026-05-29T05:05:01Z
score	15.81155

Neuroblastoma RAS viral oncogene homolog (N-RAS) deficiency aggravates liver injury and fibrosis

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