%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