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dc.contributor.authorOlaizola Rebe, Paula
dc.contributor.authorLee-Law, Pui Y.
dc.contributor.authorGarcía Fernández de Barrena, Maite
dc.contributor.authorÁlvarez Asiain, Laura
dc.contributor.authorCadamuro, Massimiliano ORCID
dc.contributor.authorAzkargorta, Mikel
dc.contributor.authorO’Rourke, Colm J.
dc.contributor.authorCaballero Camino, Francisco Javier ORCID
dc.contributor.authorOlaizola, Irene
dc.contributor.authorRodríguez Macías, Rocío Isabel
dc.contributor.authorGarcía Marín, Jose Juan
dc.contributor.authorSerrano Maciá, Marina
dc.contributor.authorMartínez Chantar, María Luz ORCID
dc.contributor.authorÁvila, Matías A. ORCID
dc.contributor.authorAspichueta Celaá, Patricia
dc.contributor.authorCALVISI, Diego Francesco ORCID
dc.contributor.authorEvert, Matthias
dc.contributor.authorFabris, Luca
dc.contributor.authorCastro, Rui ORCID
dc.contributor.authorElortza, Felix
dc.contributor.authorAndersen, Jesper B.
dc.contributor.authorBujanda Fernández de Pierola, Luis ORCID
dc.contributor.authorRodrigues, Pedro M.
dc.contributor.authorPerugorria, Maria Jesus ORCID
dc.contributor.authorBañales Asurmendi, Jesús María ORCID
dc.date.accessioned2022-08-02T11:59:18Z
dc.date.available2022-08-02T11:59:18Z
dc.date.issued2022-07
dc.identifier.citationJournal of Hepatology 77(1) : 177-190 (2022)es_ES
dc.identifier.issn1600-0641
dc.identifier.urihttp://hdl.handle.net/10810/57157
dc.description.abstract[EN] BACKGROUND & AIMS: Cholangiocarcinoma (CCA) comprises a heterogeneous group of malignant tumors associated with dismal prognosis. Alterations in post-translational modifications (PTMs), including NEDDylation, result in abnormal protein dynamics, cell disturbances and disease. Herein, we investigate the role of NEDDylation in CCA development and progression. METHODS: Levels and functions of NEDDylation, together with response to pevonedistat (NEDDylation inhibitor) or CRISPR/Cas9 against NAE1 were evaluated invitro, invivo and/or in patients with CCA. The development of preneoplastic lesions in Nae1+/- mice was investigated using an oncogene-driven CCA model. The impact of NEDDylation in CCA cells on tumor-stroma crosstalk was assessed using CCA-derived cancer-associated fibroblasts (CAFs). Proteomic analyses were carried out by mass-spectrometry. RESULTS: The NEDDylation machinery was found overexpressed and overactivated in human CCA cells and tumors. Most NEDDylated proteins found upregulated in CCA cells, after NEDD8-immunoprecipitation and further proteomics, participate in the cell cycle, proliferation or survival. Genetic (CRISPR/Cas9-NAE1) and pharmacological (pevonedistat) inhibition of NEDDylation reduced CCA cell proliferation and impeded colony formation invitro. NEDDylation depletion (pevonedistat or Nae1+/- mice) halted tumorigenesis in subcutaneous, orthotopic, and oncogene-driven models of CCA invivo. Moreover, pevonedistat potentiated chemotherapy-induced cell death in CCA cells invitro. Mechanistically, impaired NEDDylation triggered the accumulation of both cullin RING ligase and NEDD8 substrates, inducing DNA damage and cell cycle arrest. Furthermore, impaired NEDDylation in CCA cells reduced the secretion of proteins involved in fibroblast activation, angiogenesis, and oncogenic pathways, ultimately hampering CAF proliferation and migration. CONCLUSION: Aberrant protein NEDDylation contributes to cholangiocarcinogenesis by promoting cell survival and proliferation. Moreover, NEDDylation impacts the CCA-stroma crosstalk. Inhibition of NEDDylation with pevonedistat may represent a potential therapeutic strategy for patients with CCA. LAY SUMMARY: Little is known about the role of post-translational modifications of proteins in cholangiocarcinoma development and progression. Herein, we show that protein NEDDylation is upregulated and hyperactivated in cholangiocarcinoma, promoting tumor growth. Pharmacological inhibition of NEDDylation halts cholangiocarcinogenesis and could be an effective therapeutic strategy to tackle these tumors.es_ES
dc.description.sponsorshipThis article is based upon work from the COST Action CA18122 European Cholangiocarcinoma Network supported by COST (European Cooperation in Science and Technology: www.cost.eu).es_ES
dc.language.isoenges_ES
dc.publisherElsevieres_ES
dc.rightsinfo:eu-repo/semantics/openAccesses_ES
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/es/*
dc.subjectcholangiocarcinomaes_ES
dc.subjectprotein NEDDylationes_ES
dc.subjectpathogenesises_ES
dc.subjecttumor microenvironmentes_ES
dc.subjecttherapyes_ES
dc.titleTargeting NAE1-mediated protein hyper-NEDDylation halts cholangiocarcinogenesis and impacts on tumor-stroma crosstalk in experimental models.es_ES
dc.typeinfo:eu-repo/semantics/articlees_ES
dc.rights.holder© 2022 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 license (http://creativecommons.org/licenses/by/4.0/).es_ES
dc.rights.holderAttribution 3.0 Spain*
dc.relation.publisherversionhttps://www.sciencedirect.com/science/article/pii/S0168827822000824?via%3Dihubes_ES
dc.identifier.doi10.1016/j.jhep.2022.02.007
dc.departamentoesFisiologíaes_ES
dc.departamentoeuFisiologiaes_ES


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© 2022 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 license (http://creativecommons.org/licenses/by/4.0/).
Except where otherwise noted, this item's license is described as © 2022 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 license (http://creativecommons.org/licenses/by/4.0/).