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

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 pa...

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Detalhes bibliográficos
Autores: Prior, Celia, Perez-Gracia, Jose Luis, Garcia Donas, Jesus, Rodriguez-Antona, Cristina, Guruceaga, Elisabeth, Esteban, Emilio, Suarez, Cristina, Castellano, Daniel, González del Alba, Aránzazu, Lozano, Maria Dolores, Carles, Joan, Climent, Miguel Angel, Arranz, José Ángel, Gallardo, Enrique, Puente, Javier, Bellmunt Molins, Joaquim, 1959-, Gurpide, Alfonso, Lopez-Picazo, Jose Maria, Gonzalez Hernandez, Alvaro, Mellado González, Begoña, Martínez, Esther, Moreno, Fernando, Font Pous, Albert, Calvo, Alfonso
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2014
País:España
Recursos:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/121365
Acesso em linha:https://hdl.handle.net/2445/121365
Access Level:acceso abierto
Palavra-chave:Micro RNAs
Càncer de ronyó
Marcadors bioquímics
Resistència als medicaments
RNA
Fenotip
MicroRNAs
Renal cancer
Biochemical markers
Drug resistance
Phenotype
Descrição
Resumo: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.

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