Prior, CeliaPerez-Gracia, Jose LuisGarcia Donas, JesusRodriguez-Antona, CristinaGuruceaga, ElisabethEsteban, EmilioSuarez, CristinaCastellano, DanielGonzález del Alba, AránzazuLozano, Maria DoloresCarles, JoanCliment, Miguel AngelArranz, José ÁngelGallardo, EnriquePuente, JavierBellmunt Molins, Joaquim, 1959-Gurpide, AlfonsoLopez-Picazo, Jose MariaGonzalez Hernandez, AlvaroMellado González, BegoñaMartínez, EstherMoreno, FernandoFont Pous, AlbertCalvo, Alfonso2018-04-092018-04-092014-01-241932-6203https://hdl.handle.net/2445/121365PURPOSE: 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.10 p.application/pdfengcc-by (c) Prior, Celia et al., 2014http://creativecommons.org/licenses/by/3.0/esMicro RNAsCàncer de ronyóMarcadors bioquímicsResistència als medicamentsRNAFenotipMicroRNAsRenal cancerBiochemical markersDrug resistanceRNAPhenotypeinfo:eu-repo/semantics/article6424562018-04-09info:eu-repo/semantics/openAccess24475095