The loss of DHX15 impairs endothelial energy metabolism, lymphatic drainage and tumor metastasis in mice

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  • dc.contributor.author Ribera, Jordi
  • dc.contributor.author Portolés, Irene
  • dc.contributor.author Córdova-Jover, Bernat
  • dc.contributor.author Rodríguez-Vita, Juan
  • dc.contributor.author Casals, Gregori
  • dc.contributor.author Gónzalez-de la Presa, Bernardino
  • dc.contributor.author Graupera, Mariona
  • dc.contributor.author Solsona-Vilarrasa, Estel
  • dc.contributor.author Garcia-Ruiz, Carmen
  • dc.contributor.author Fernández-Checa, José C.
  • dc.contributor.author Soria Rodríguez, Guadalupe
  • dc.contributor.author Tudela, Raúl
  • dc.contributor.author Esteve-Codina, Anna
  • dc.contributor.author Espadas, Guadalupe
  • dc.contributor.author Sabidó Aguadé, Eduard, 1981-
  • dc.contributor.author Jiménez, Wladimiro
  • dc.contributor.author Sessa, William C.
  • dc.contributor.author Morales-Ruiz, Manuel
  • dc.date.accessioned 2022-01-12T07:39:01Z
  • dc.date.available 2022-01-12T07:39:01Z
  • dc.date.issued 2021
  • dc.description.abstract DHX15 is a downstream substrate for Akt1, which is involved in key cellular processes affecting vascular biology. Here, we explored the vascular regulatory function of DHX15. Homozygous DHX15 gene deficiency was lethal in mouse and zebrafish embryos. DHX15-/- zebrafish also showed downregulation of VEGF-C and reduced formation of lymphatic structures during development. DHX15+/- mice depicted lower vascular density and impaired lymphatic function postnatally. RNAseq and proteome analysis of DHX15 silenced endothelial cells revealed differential expression of genes involved in the metabolism of ATP biosynthesis. The validation of these results demonstrated a lower activity of the Complex I in the mitochondrial membrane of endothelial cells, resulting in lower intracellular ATP production and lower oxygen consumption. After injection of syngeneic LLC1 tumor cells, DHX15+/- mice showed partially inhibited primary tumor growth and reduced lung metastasis. Our results revealed an important role of DHX15 in vascular physiology and pave a new way to explore its potential use as a therapeutical target for metastasis treatment.
  • dc.description.sponsorship This study was supported by grants from MCIN/AEI/10.13039/501100011033 (SAF2016-75358-R and PDI2019-105502RB-100 to MM-R, SAF2017-85877R, PID2019-111669RB-100, PID2020-115055RB-I00). CIBERehd, CIBERonc and CIBERbbn are financed by the Instituto de Salud Carlos III. I.P. was recipient of a predoctoral fellowship supported by MCIN/AEI/10.13039/501100011033 y FSE “El FSE invierte en tu futuro” (BES-2017-080823). A.E-.C. is funded by ISCIII of the MINECO (reference PT17/0009/0019) and co-financed by FEDER. J.R-.V. was a recipient of a BIOTRACK Postdoctoral Fellowship supported by the European Community’s Seventh Framework Programme and the MINECO (Contract 229673). The CRG/UPF Proteomics Unit is part of the Spanish Infrastructure for Omics Technologies (ICTS OmicsTech) and it is a member of the ProteoRed PRB3 consortium which is supported by grant PT17/0019 of the PE I + D + i 2013-2016 from the Instituto de Salud Carlos III (ISCIII) and ERDF. The center grant P50AA011999 Southern California Research Center for ALPD and Cirrhosis funded by NIAAA/NIH. We acknowledge support from the Spanish Ministry of Science, Innovation and Universities, “Centro de Excelencia Severo Ochoa 2013-2017”, SEV-2012-0208, and “Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya” (2017SGR595)
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Ribera J, Portolés I, Córdova-Jover B, Rodríguez-Vita J, Casals G, González-de la Presa B et al. The loss of DHX15 impairs endothelial energy metabolism, lymphatic drainage and tumor metastasis in mice. Commun Biol. 2021 Oct 15;4(1):1192. DOI: 10.1038/s42003-021-02722-w
  • dc.identifier.doi http://dx.doi.org/10.1038/s42003-021-02722-w
  • dc.identifier.issn 2399-3642
  • dc.identifier.uri http://hdl.handle.net/10230/52189
  • dc.language.iso eng
  • dc.publisher Nature Research
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/229673
  • dc.rights © Jordi Ribera et al. 2021, corrected publication 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri https://creativecommons.org/licenses/by/4.0/
  • dc.subject.other Genètica
  • dc.subject.other Tumors
  • dc.subject.other Metàstasi
  • dc.title The loss of DHX15 impairs endothelial energy metabolism, lymphatic drainage and tumor metastasis in mice
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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