%0 Journal Article %T Identification of Tissue microRNAs Predictive of Sunitinib Activity in Patients with Metastatic Renal Cell Carcinoma %A Celia Prior %A Jose Luis Perez-Gracia %A Jesus Garcia-Donas %A Cristina Rodriguez-Antona %A Elizabeth Guruceaga %A Emilio Esteban %A Cristina Suarez %A Daniel Castellano %A Ar¨¢nzazu Gonz¨¢lez del Alba %A Maria Dolores Lozano %A Joan Carles %A Miguel Angel Climent %A Jose Angel Arranz %A Enrique Gallardo %A Javier Puente %A Joaquim Bellmunt %A Alfonso Gurpide %A Jose Maria Lopez-Picazo %A Alvaro Gonzalez Hernandez %A Bego£¿a Mellado %A Esther Mart¨ªnez %A Fernando Moreno %A Albert Font %A Alfonso Calvo %J PLOS ONE %D 2014 %I Public Library of Science (PLoS) %R 10.1371/journal.pone.0086263 %X 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. %U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0086263