Detalle Publicación

Identification of tissue microRNAs predictive of sunitinib activity in patients with metastatic renal cell carcinoma

Autores: Prior Darbonnens, Celia; Pérez Gracia, José Luis (Autor de correspondencia); García-Donas , J.; Rodríguez-Antona , C.; Guruceaga Martínez, Elisabet; Esteban , E.; Suarez , C.; Castellano , D.; Del Alba , A. G.; Lozano Escario, María Dolores; Carles , J.; Climent , M. A.; Arranz , J. A.; Gallardo , E.; Puente , J.; Bellmunt , J.; Gurpide Ayarra, Luis Alfonso; López-Picazo González, José María; González Hernández, Álvaro; Mellado , B.; Martínez, E.; Moreno , F.; Font , A.; Calvo González, Alfonso
Título de la revista: PLOS ONE
ISSN: 1932-6203
Volumen: 9
Número: 1
Fecha de publicación: 2014
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.