dc.contributor.author | Vallejo, Adrián | |
dc.contributor.author | Erice Azparren, Oihane | |
dc.contributor.author | Entrialgo Cadierno, Rodrigo | |
dc.contributor.author | Feliu Gascón, Iker | |
dc.contributor.author | Guruceaga, Elizabeth | |
dc.contributor.author | Perugorria Montiel, María Jesús | |
dc.contributor.author | Olaizola Rebe, Paula | |
dc.contributor.author | Muggli, Alexandra | |
dc.contributor.author | Macaya Erro, Irati | |
dc.contributor.author | O'Dell, Michael | |
dc.contributor.author | Ruiz Fernández de Córdoba, Borja | |
dc.contributor.author | Ortiz Espinosa, Sergio | |
dc.contributor.author | Hezel, Aram F. | |
dc.contributor.author | Arozarena Martinicorena, Imanol | |
dc.contributor.author | Lecanda Cordero, Fernando | |
dc.contributor.author | Ávila, Matías A. ![ORCID](/themes/Mirage2//images/orcid_16x16.png) | |
dc.contributor.author | Fernández-Barrena, Maite G. | |
dc.contributor.author | Evert, Matthias | |
dc.contributor.author | Ponz-Sarvisé, Mariano | |
dc.contributor.author | Calvisi, Diego | |
dc.contributor.author | Bañales Asurmendi, Jesús María ![ORCID](/themes/Mirage2//images/orcid_16x16.png) | |
dc.contributor.author | Vicent, Silve | |
dc.date.accessioned | 2021-08-09T12:10:58Z | |
dc.date.available | 2021-08-09T12:10:58Z | |
dc.date.issued | 2021-04-20 | |
dc.identifier.citation | Journal of Hepatology 75 : 363–376 (2021) | es_ES |
dc.identifier.issn | 0168-8278 | |
dc.identifier.issn | 1600-0641 | |
dc.identifier.uri | http://hdl.handle.net/10810/52794 | |
dc.description.abstract | [EN] Background & Aims: Cholangiocarcinoma (CCA) is a neoplasia of
the biliary tract driven by genetic, epigenetic and transcriptional
mechanisms. Herein, we investigated the role of the transcription
factor FOSL1, as well as its downstream transcriptional effectors,
in the development and progression of CCA.
Methods: FOSL1 was investigated in human CCA clinical samples.
Genetic inhibition of FOSL1 in human and mouse CCA cell
lines was performed in in vitro and in vivo models using
constitutive and inducible short-hairpin RNAs. Conditional
FOSL1 ablation was done using a genetically engineered mouse
(GEM) model of CCA (mutant KRAS and Trp53 knockout). Followup
RNA and chromatin immunoprecipitation (ChIP) sequencing
analyses were carried out and downstream targets were validated
using genetic and pharmacological inhibition.
Results: An inter-species analysis of FOSL1 in CCA was conducted.
First, FOSL1 was found to be highly upregulated in human
and mouse CCA, and associated with poor patient survival.
Pharmacological inhibition of different signalling pathways in
CCA cells converged on the regulation of FOSL1 expression.
Functional experiments showed that FOSL1 is required for cell
proliferation and cell cycle progression in vitro, and for tumour
growth and tumour maintenance in both orthotopic and subcutaneous
xenograft models. Likewise, FOSL1 genetic abrogation
in a GEM model of CCA extended mouse survival by decreasing
the oncogenic potential of transformed cholangiocytes. RNA and
ChIP sequencing studies identified direct and indirect transcriptional
effectors such as HMGCS1 and AURKA, whose genetic
and pharmacological inhibition phenocopied FOSL1 loss.
Conclusions: Our data illustrate the functional and clinical
relevance of FOSL1 in CCA and unveil potential targets amenable
to pharmacological inhibition that could enable the implementation
of novel therapeutic strategies.
Lay summary: Understanding the molecular mechanisms
involved in cholangiocarcinoma (bile duct cancer) development
and progression stands as a critical step for the development of
novel therapies. Through an inter-species approach, this study
provides evidence of the clinical and functional role of the
transcription factor FOSL1 in cholangiocarcinoma. Moreover, we
report that downstream effectors of FOSL1 are susceptible to
pharmacological inhibition, thus providing new opportunities
for therapeutic intervention. | es_ES |
dc.description.sponsorship | A.V. was supported by ADA of the University of Navarra, Spain,
O.E. by FSE; MINECO; FJCI-2017-34233, Spain, R.E. by a donation
from Mauge Burgos de la Iglesia’s family, Spain, and P. Olaizola by
the Basque Government (PRE_2016_1_0269), Basque Country,
Spain. M.J.P. was funded by ISCIII [FIS PI14; 00399, PI17; 00022]
cofinanced by “Fondo Europeo de Desarrollo Regional” (FEDER),
Spain; Spanish Ministry of Economy and Competitiveness
(MINECO: “Ramón y Cajal” Program RYC-2015-17755), Spain.
M.A.A was funded by La Caixa Foundation, HEPACARE project,
Spain, ISCIII FIS PI16/01126 cofinanced by “Fondo Europeo de
Desarrollo Regional” (FEDER), Spain, and “Fundación Científica de
la Asociación Española Contra el Cáncer’’ (AECC Scientific Foundation)
Rare Cancers 2017, Spain. J.M.B. was funded by the
Spanish Carlos III Health Institute (ISCIII) (FIS PI15; 01132, PI18;
01075 and Miguel Servet Program CON14; 00129 and CPII19;
00008), Spain, co-financed by “Fondo Europeo de Desarrollo
Regional” (FEDER), Spain; “Euskadi RIS3” (2019222054) and
BIOEF (Basque Foundation for Innovation and Health Research:
EiTB Maratoia BIO15; CA; 016; BD), Basque Country, Spain;
“Fundación Científica de la Asociación Española Contra el Cáncer”
(AECC Scientific Foundation) Rare Cancers 2017, Spain. S.V. was
supported by FEDER; MINECO (SAF2017-89944-R), Spain, by the
Government of Navarra-Health Research Department (58; 2018),
Navarra, Spain, by La Caixa and Caja Navarra Foundation-CIMA
agreement, Spain. None of the funding sources were involved
in the decision to submit the article for publication. This article is
based upon work from COST Action CA18122 European Cholangiocarcinoma
Network, supported by COST (European Cooperation
in Science and Technology). COST (European Cooperation in Science and Technology) is a funding agency for research and
innovation networks (www.cost.eu). | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | Elsevier | es_ES |
dc.relation | info:eu-repo/grantAgreement/MINECO/FJCI-2017-34233 | es_ES |
dc.relation | info:eu-repo/grantAgreement/MINECO/SAF2017-89944-R | es_ES |
dc.relation | info:eu-repo/grantAgreement/MINECO/FIS PI16/01126 | es_ES |
dc.relation | info:eu-repo/grantAgreement/MINECO/RYC-2015-17755 | es_ES |
dc.rights | info:eu-repo/semantics/openAccess | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/es/ | * |
dc.subject | FOSL1 | es_ES |
dc.subject | cholangiocarcinoma | es_ES |
dc.subject | transcription factors | es_ES |
dc.subject | genetics | es_ES |
dc.subject | targeted therapies | es_ES |
dc.title | FOSL1 promotes cholangiocarcinoma via transcriptional effectors that could be therapeutically targeted | es_ES |
dc.type | info:eu-repo/semantics/article | es_ES |
dc.rights.holder | © 2021 The Authors. Published by Elsevier B.V. on behalf of European
Association for the Study of the Liver. This is an open access article
under the CC BY-NC-ND license (http://creativecommons.org/
licenses/by-nc-nd/4.0/). | es_ES |
dc.rights.holder | Atribución-NoComercial-SinDerivadas 3.0 España | * |
dc.relation.publisherversion | https://www.sciencedirect.com/science/article/pii/S016882782100235X | es_ES |
dc.identifier.doi | 10.1016/j.jhep.2021.03.028 | |
dc.departamentoes | Fisiología | es_ES |
dc.departamentoes | Medicina | es_ES |
dc.departamentoeu | Fisiologia | es_ES |
dc.departamentoeu | Medikuntza | es_ES |