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http://hdl.handle.net/2445/121365
Title: | Identification of tissue microRNAs predictive of sunitinib activity in patients with metastatic renal cell carcinoma |
Author: | Prior, Celia Perez-Gracia, Jose Luis Garcia Donas, Jesus Rodriguez-Antona, Cristina Guruceaga, Elisabeth Esteban, Emilio Suarez, Cristina Castellano, Daniel González del Alba, Aránzazu Lozano, Maria Dolores Carles, Joan Climent, Miguel Angel Arranz, José Ángel Gallardo, Enrique Puente, Javier Bellmunt Molins, Joaquim, 1959- Gurpide, Alfonso Lopez-Picazo, Jose Maria Gonzalez Hernandez, Alvaro Mellado González, Begoña Martínez, Esther Moreno, Fernando Font Pous, Albert Calvo, Alfonso |
Keywords: | Micro RNAs Càncer de ronyó Marcadors bioquímics Resistència als medicaments RNA Fenotip MicroRNAs Renal cancer Biochemical markers Drug resistance RNA Phenotype |
Issue Date: | 24-Jan-2014 |
Publisher: | Public Library of Science (PLoS) |
Abstract: | 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. |
Note: | Reproducció del document publicat a: https://doi.org/10.1371/journal.pone.0086263 |
It is part of: | PLoS One, 2014, vol. 9, num. 1, p. e86263-e86263 |
URI: | http://hdl.handle.net/2445/121365 |
Related resource: | https://doi.org/10.1371/journal.pone.0086263 |
ISSN: | 1932-6203 |
Appears in Collections: | Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer) Articles publicats en revistes (Medicina) |
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