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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, Jose Angel; 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
Notes:	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.
Subject(s):	-Micro RNAs -Càncer de ronyó -Marcadors bioquímics -Resistència als medicaments -RNA -Fenotip -MicroRNAs -Renal cancer -Biochemical markers -Drug resistance -RNA -Phenotype
Rights:	cc-by (c) Prior, Celia et al., 2014 http://creativecommons.org/licenses/by/3.0/es
Document type:	Article Article - Published version
Published by:	Public Library of Science (PLoS)
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