To access the full text documents, please follow this link: http://hdl.handle.net/2445/121365
dc.contributor.author | Prior, Celia |
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dc.contributor.author | Perez-Gracia, Jose Luis |
dc.contributor.author | Garcia Donas, Jesus |
dc.contributor.author | Rodriguez-Antona, Cristina |
dc.contributor.author | Guruceaga, Elisabeth |
dc.contributor.author | Esteban, Emilio |
dc.contributor.author | Suarez, Cristina |
dc.contributor.author | Castellano, Daniel |
dc.contributor.author | González del Alba, Aránzazu |
dc.contributor.author | Lozano, Maria Dolores |
dc.contributor.author | Carles, Joan |
dc.contributor.author | Climent, Miguel Angel |
dc.contributor.author | Arranz, Jose Angel |
dc.contributor.author | Gallardo, Enrique |
dc.contributor.author | Puente, Javier |
dc.contributor.author | Bellmunt Molins, Joaquim, 1959- |
dc.contributor.author | Gurpide, Alfonso |
dc.contributor.author | Lopez-Picazo, Jose Maria |
dc.contributor.author | Gonzalez Hernandez, Alvaro |
dc.contributor.author | Mellado González, Begoña |
dc.contributor.author | Martínez, Esther |
dc.contributor.author | Moreno, Fernando |
dc.contributor.author | Font Pous, Albert |
dc.contributor.author | Calvo, Alfonso |
dc.date | 2018-04-09T12:20:41Z |
dc.date | 2018-04-09T12:20:41Z |
dc.date | 2014-01-24 |
dc.date | 2018-04-09T12:20:41Z |
dc.identifier | 1932-6203 |
dc.identifier | 642456 |
dc.identifier | 24475095 |
dc.identifier.uri | http://hdl.handle.net/2445/121365 |
dc.description | PURPOSE: To identify tissue microRNAs predictive of sunitinib activity in patients with metastatic renal-cell-carcinoma (MRCC) and to evaluate in vitro their mechanism of action in sunitinib resistance. METHODS: We screened 673 microRNAs using TaqMan Low-density-Arrays (TLDAs) in tumors from MRCC patients with extreme phenotypes of marked efficacy and resistance to sunitinib, selected from an identification cohort (n = 41). The most relevant differentially expressed microRNAs were selected using bioinformatics-based target prediction analysis and quantified by qRT-PCR in tumors from patients presenting similar phenotypes selected from an independent cohort (n = 101). In vitro experiments were conducted to study the role of miR-942 in sunitinib resistance. RESULTS: TLDAs identified 64 microRNAs differentially expressed in the identification cohort. Seven candidates were quantified by qRT-PCR in the independent series. MiR-942 was the most accurate predictor of sunitinib efficacy (p = 0.0074). High expression of miR-942, miR-628-5p, miR-133a, and miR-484 was significantly associated with decreased time to progression and overall survival. These microRNAs were also overexpressed in the sunitinib resistant cell line Caki-2 in comparison with the sensitive cell line. MiR-942 overexpression in Caki-2 up-regulates MMP-9 and VEGF secretion which, in turn, promote HBMEC endothelial migration and sunitinib resistance. CONCLUSIONS: We identified differentially expressed microRNAs in MRCC patients presenting marked sensitivity or resistance to sunitinib. MiR-942 was the best predictor of efficacy. We describe a novel paracrine mechanism through which high miR-942 levels in MRCC cells up-regulates MMP-9 and VEGF secretion to enhance endothelial migration and sunitinib resistance. Our results support further validation of these miRNA in clinical confirmatory studies. |
dc.format | 10 p. |
dc.format | application/pdf |
dc.language | eng |
dc.publisher | Public Library of Science (PLoS) |
dc.relation | Reproducció del document publicat a: https://doi.org/10.1371/journal.pone.0086263 |
dc.relation | PLoS One, 2014, vol. 9, num. 1, p. e86263-e86263 |
dc.relation | https://doi.org/10.1371/journal.pone.0086263 |
dc.rights | cc-by (c) Prior, Celia et al., 2014 |
dc.rights | http://creativecommons.org/licenses/by/3.0/es |
dc.rights | info:eu-repo/semantics/openAccess |
dc.subject | Micro RNAs |
dc.subject | Càncer de ronyó |
dc.subject | Marcadors bioquímics |
dc.subject | Resistència als medicaments |
dc.subject | RNA |
dc.subject | Fenotip |
dc.subject | MicroRNAs |
dc.subject | Renal cancer |
dc.subject | Biochemical markers |
dc.subject | Drug resistance |
dc.subject | RNA |
dc.subject | Phenotype |
dc.title | Identification of tissue microRNAs predictive of sunitinib activity in patients with metastatic renal cell carcinoma |
dc.type | info:eu-repo/semantics/article |
dc.type | info:eu-repo/semantics/publishedVersion |