Prior, CeliaLuis Perez-Gracia, JoseGarcia-Donas, JesusRodriguez-Antona, CristinaGuruceaga, ElizabethEsteban, EmilioSuarez, CristinaCastellano, DanieGonzalez del Alba, AranzazuDolores Lozano, MariaCarles, JoanAngel Climent, MiguelAngel Arranz, JoseGallardo, EnriquePuente, JavierBellmunt, JoaquimGurpide, AlfonsoMaria Lopez-Picazo, JoseGonzalez Hernandez, AlvaroMellado, BegonaMartinez, EstherMoreno, FernandoFont, AlbertCalvo, Alfonso2024-07-032024-07-032014-01-24Prior C, Perez-Gracia JL, Garcia-Donas J, Rodriguez-Antona C, Guruceaga E, Esteban E, et al. Identification of Tissue microRNAs Predictive of Sunitinib Activity in Patients with Metastatic Renal Cell Carcinoma. PLoS One. 2014 Jan 24;9(1):e86263.1932-6203http://hdl.handle.net/20.500.13003/11360http://hdl.handle.net/20.500.12105/19967Purpose: 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.enghttps://creativecommons.org/licenses/by/3.0/research articleAttribution 3.0 Unported2447509591e8626310.1371/journal.pone.0086263PloS Oneopen accessResistencia a AntineoplásicosComunicación ParacrinaLínea Celular TumoralResultado del TratamientoReproducibilidad de los ResultadosFemeninoMetaloproteinasa 9 de la MatrizIndolesMetástasis de la NeoplasiaCarcinoma de Células RenalesNeoplasias RenalesFactor A de Crecimiento Endotelial VascularMasculinoPirrolesAntineoplásicosHumanosPersona de Mediana EdadModelos BiológicosPronósticoAncianoAnciano de 80 o más AñosAdultoPerfilación de la Expresión GénicaMicroARNs2-s2.0-84898478153330339800035L373030799