Show simple item record

dc.contributor.authorGerovska, Daniela
dc.contributor.authorLarrinaga Embeita, Gorka ORCID
dc.contributor.authorSolano Iturri, Jon Danel
dc.contributor.authorMárquez Clavijo, Joana ORCID
dc.contributor.authorGarcía Gallastegui, Patricia ORCID
dc.contributor.authorKhatib, Abdel Majid
dc.contributor.authorPoschmann, Gereon
dc.contributor.authorStühler, Kai
dc.contributor.authorArmesto, María
dc.contributor.authorLawrie, Charles
dc.contributor.authorBadiola Echaburu, Iker ORCID
dc.contributor.authorAraúzo Bravo, Marcos J.
dc.date.accessioned2020-10-02T11:31:05Z
dc.date.available2020-10-02T11:31:05Z
dc.date.issued2020-08-22
dc.identifier.citationCancers 12(9) : (2020) // Article ID 2380es_ES
dc.identifier.issn2072-6694
dc.identifier.urihttp://hdl.handle.net/10810/46365
dc.description.abstract(1) Background & Aims: The roles of different cells in the tumor microenvironment (TME) are critical to the metastatic process. The phenotypic transformation of the liver cells is one of the most important stages of the hepatic metastasis progression of colorectal cancer (CRC). Our aim was to identify the major molecules (i.e., genes, miRNAs and proteins) involved in this process. (2) Methods: We isolated and performed whole-genome analysis of gene, miRNA, and protein expression in three types of liver cells (Ito cells, Kupffer cells, and liver sinusoidal endothelial cells) from the TME of a murine model of CRC liver metastasis. We selected the statistically significant differentially expressed molecules using the Student’s t-test with Benjamini-Hochberg correction and performed functional statistically-significant enrichment analysis of differentially expressed molecules with hypergeometric distribution using the curated collection of molecular signatures, MSigDB. To build a gene-miRNA-protein network centered in Brca1, we developed a software package (miRDiana) that collects miRNA targets from the union of the TargetScan, MicroCosm, mirTarBase, and miRWalk databases. This was used to search for miRNAs targeting Brca1. We validated the most relevant miRNAs with real-time quantitative PCR. To investigate BRCA1 protein expression, we built tissue microarrays (TMAs) from hepatic metastases of 34 CRC patients. (3) Results: Using integrated omics analyses, we observed that the Brca1 gene is among the twenty transcripts simultaneously up-regulated in all three types of TME liver cells during metastasis. Further analysis revealed that Brca1 is the last BRCA1-associated genome surveillance complex (BASC) gene activated in the TME. We confirmed this finding in human reanalyzing transcriptomics datasets from 184 patients from non-tumor colorectal tissue, primary colorectal tumor and colorectal liver metastasis of the GEO database. We found that the most probable sequence of cell activation during metastasis is Endothelial→Ito→Kupffer. Immunohistochemical analysis of human liver metastases showed the BRCA1 protein was co-localized in Ito, Kupffer, and endothelial cells in 81.8% of early or synchronous metastases. However, in the greater part of the metachronous liver metastases, this protein was not expressed in any of these TME cells. (4) Conclusions: These results suggest a possible role of the co-expression of BRCA1 in Ito, Kupffer, and sinusoidal endothelial cells in the early occurrence of CRC liver metastases, and point to BRCA1 as a potential TME biomarker.es_ES
dc.description.sponsorshipD.G. and M.J.A.-B. have been supported by Grants DFG113/18 from Diputación Foral de Gipuzkoa (DFG), Spain, Ministry of Economy and Competitiveness, Spain, MINECO Grant BFU2016-77987-P and Instituto de Salud Carlos III (AC17/00012) Grant co-funded by the European Union (Eracosysmed/H2020 Grant Agreement No. 643271) and European Union (H2020-FETOPEN, Project 899417). D.G., M.J.A.-B. and I.B. have been supported by Grants Health Department of the Basque Government (Spain), RIS3 call, Exp. No. 2020333039 and 2020333001.es_ES
dc.language.isoenges_ES
dc.publisherMDPIes_ES
dc.relationinfo:eu-repo/grantAgreement/MINECO/BFU2016-77987-Pes_ES
dc.relationinfo:eu-repo/grantAgreement/EC/H2020/643271es_ES
dc.relationinfo:eu-repo/grantAgreement/EC/H2020/899417es_ES
dc.rightsinfo:eu-repo/semantics/openAccesses_ES
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/es/
dc.subjectcolorectal canceres_ES
dc.subjectliver metastasises_ES
dc.subjecttumor microenvironmentes_ES
dc.subjecttissue microarrayes_ES
dc.subjecttranscriptomicses_ES
dc.subjectmiRNAses_ES
dc.subjectproteomicses_ES
dc.subjectBRCA1es_ES
dc.subjectBRCA1-associated genome surveillance complexes_ES
dc.titleAn Integrative Omics Approach Reveals Involvement of BRCA1 in Hepatic Metastatic Progression of Colorectal Canceres_ES
dc.typeinfo:eu-repo/semantics/articlees_ES
dc.date.updated2020-09-25T13:28:47Z
dc.rights.holder2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).es_ES
dc.relation.publisherversionhttps://www.mdpi.com/2072-6694/12/9/2380es_ES
dc.identifier.doi10.3390/cancers12092380
dc.departamentoesEnfermería
dc.departamentoesFisiología
dc.departamentoesBiología celular e histología
dc.departamentoeuErizaintza
dc.departamentoeuFisiologia
dc.departamentoeuZelulen biologia eta histologia


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record

2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Except where otherwise noted, this item's license is described as 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).