Inhibition of de novo NAD(+) synthesis by oncogenic URI causes liver tumorigenesis through DNA damage.

Molecular mechanisms responsible for hepatocellular carcinoma (HCC) remain largely unknown. Using genetically engineered mouse models, we show that hepatocyte-specific expression of unconventional prefoldin RPB5 interactor (URI) leads to a multistep process of HCC development, whereas its genetic re...

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Detalles Bibliográficos
Autores: Tummala, Krishna S, Gomes, Ana L, Yilmaz, Mahmut, Graña, Osvaldo, Bakiri, Latifa, Ruppen, Isabel, Ximénez-Embún, Pilar, Sheshappanavar, Vinayata, Rodriguez-Justo, Manuel, Pisano, David G, Wagner, Erwin F, Djouder, Nabil
Tipo de recurso: artículo
Fecha de publicación:2014
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/17547
Acceso en línea:http://hdl.handle.net/20.500.12105/17547
Access Level:acceso abierto
Palabra clave:DNA Damage
Animals
Carcinoma, Hepatocellular
Diethylnitrosamine
Gene Expression Regulation, Neoplastic
Hepatocytes
Humans
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spelling Inhibition of de novo NAD(+) synthesis by oncogenic URI causes liver tumorigenesis through DNA damage.Tummala, Krishna SGomes, Ana LYilmaz, MahmutGraña, OsvaldoBakiri, LatifaRuppen, IsabelXiménez-Embún, PilarSheshappanavar, VinayataRodriguez-Justo, ManuelPisano, David GWagner, Erwin FDjouder, NabilDNA DamageAnimalsCarcinoma, HepatocellularDiethylnitrosamineGene Expression Regulation, NeoplasticHepatocytesHumansMolecular mechanisms responsible for hepatocellular carcinoma (HCC) remain largely unknown. Using genetically engineered mouse models, we show that hepatocyte-specific expression of unconventional prefoldin RPB5 interactor (URI) leads to a multistep process of HCC development, whereas its genetic reduction in hepatocytes protects against diethylnitrosamine (DEN)-induced HCC. URI inhibits aryl hydrocarbon (AhR)- and estrogen receptor (ER)-mediated transcription of enzymes implicated in L-tryptophan/kynurenine/nicotinamide adenine dinucleotide (NAD(+)) metabolism, thereby causing DNA damage at early stages of tumorigenesis. Restoring NAD(+) pools with nicotinamide riboside (NR) prevents DNA damage and tumor formation. Consistently, URI expression in human HCC is associated with poor survival and correlates negatively with L-tryptophan catabolism pathway. Our results suggest that boosting NAD(+) can be prophylactic or therapeutic in HCC.ElsevierMinisterio de Ciencia (España)Unión Europea. Comisión Europea. European Research Council (ERC)Worldwide Cancer ResearchEuropean Foundation for the Study of DiabetesAssociation for International Cancer Research AICR-UK20242024-02-0820142014-12-0820142014-12-08journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/20.500.12105/17547reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/175472026-06-12T12:43:37Z
dc.title.none.fl_str_mv Inhibition of de novo NAD(+) synthesis by oncogenic URI causes liver tumorigenesis through DNA damage.
title Inhibition of de novo NAD(+) synthesis by oncogenic URI causes liver tumorigenesis through DNA damage.
spellingShingle Inhibition of de novo NAD(+) synthesis by oncogenic URI causes liver tumorigenesis through DNA damage.
Tummala, Krishna S
DNA Damage
Animals
Carcinoma, Hepatocellular
Diethylnitrosamine
Gene Expression Regulation, Neoplastic
Hepatocytes
Humans
title_short Inhibition of de novo NAD(+) synthesis by oncogenic URI causes liver tumorigenesis through DNA damage.
title_full Inhibition of de novo NAD(+) synthesis by oncogenic URI causes liver tumorigenesis through DNA damage.
title_fullStr Inhibition of de novo NAD(+) synthesis by oncogenic URI causes liver tumorigenesis through DNA damage.
title_full_unstemmed Inhibition of de novo NAD(+) synthesis by oncogenic URI causes liver tumorigenesis through DNA damage.
title_sort Inhibition of de novo NAD(+) synthesis by oncogenic URI causes liver tumorigenesis through DNA damage.
dc.creator.none.fl_str_mv Tummala, Krishna S
Gomes, Ana L
Yilmaz, Mahmut
Graña, Osvaldo
Bakiri, Latifa
Ruppen, Isabel
Ximénez-Embún, Pilar
Sheshappanavar, Vinayata
Rodriguez-Justo, Manuel
Pisano, David G
Wagner, Erwin F
Djouder, Nabil
author Tummala, Krishna S
author_facet Tummala, Krishna S
Gomes, Ana L
Yilmaz, Mahmut
Graña, Osvaldo
Bakiri, Latifa
Ruppen, Isabel
Ximénez-Embún, Pilar
Sheshappanavar, Vinayata
Rodriguez-Justo, Manuel
Pisano, David G
Wagner, Erwin F
Djouder, Nabil
author_role author
author2 Gomes, Ana L
Yilmaz, Mahmut
Graña, Osvaldo
Bakiri, Latifa
Ruppen, Isabel
Ximénez-Embún, Pilar
Sheshappanavar, Vinayata
Rodriguez-Justo, Manuel
Pisano, David G
Wagner, Erwin F
Djouder, Nabil
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Ciencia (España)
Unión Europea. Comisión Europea. European Research Council (ERC)
Worldwide Cancer Research
European Foundation for the Study of Diabetes
Association for International Cancer Research AICR-UK
dc.subject.none.fl_str_mv DNA Damage
Animals
Carcinoma, Hepatocellular
Diethylnitrosamine
Gene Expression Regulation, Neoplastic
Hepatocytes
Humans
topic DNA Damage
Animals
Carcinoma, Hepatocellular
Diethylnitrosamine
Gene Expression Regulation, Neoplastic
Hepatocytes
Humans
description Molecular mechanisms responsible for hepatocellular carcinoma (HCC) remain largely unknown. Using genetically engineered mouse models, we show that hepatocyte-specific expression of unconventional prefoldin RPB5 interactor (URI) leads to a multistep process of HCC development, whereas its genetic reduction in hepatocytes protects against diethylnitrosamine (DEN)-induced HCC. URI inhibits aryl hydrocarbon (AhR)- and estrogen receptor (ER)-mediated transcription of enzymes implicated in L-tryptophan/kynurenine/nicotinamide adenine dinucleotide (NAD(+)) metabolism, thereby causing DNA damage at early stages of tumorigenesis. Restoring NAD(+) pools with nicotinamide riboside (NR) prevents DNA damage and tumor formation. Consistently, URI expression in human HCC is associated with poor survival and correlates negatively with L-tryptophan catabolism pathway. Our results suggest that boosting NAD(+) can be prophylactic or therapeutic in HCC.
publishDate 2014
dc.date.none.fl_str_mv 2014
2014-12-08
2014
2014-12-08
2024
2024-02-08
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/20.500.12105/17547
url http://hdl.handle.net/20.500.12105/17547
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
Attribution-NonCommercial-NoDerivatives 4.0 Internacional
http://creativecommons.org/licenses/by-nc-nd/4.0/
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
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.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869422757806080000
score 15,812429

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