Por favor, use este identificador para citar o enlazar este Item:http://hdl.handle.net/20.500.12105/19967
Título
Identification of Tissue microRNAs Predictive of Sunitinib Activity in Patients with Metastatic Renal Cell Carcinoma
Autor(es)
Prior, Celia | Luis Perez-Gracia, Jose | Garcia-Donas, Jesus | Rodriguez-Antona, Cristina | Guruceaga, Elizabeth | Esteban, Emilio | Suarez, Cristina | Castellano, Danie | Gonzalez del Alba, Aranzazu | Dolores Lozano, Maria | Carles, Joan | Angel Climent, Miguel | Angel Arranz, Jose | Gallardo, Enrique | Puente, Javier | Bellmunt, Joaquim | Gurpide, Alfonso | Maria Lopez-Picazo, Jose | Gonzalez Hernandez, Alvaro | Mellado, Begona | Martinez, Esther | Moreno, Fernando | Font, Albert | Calvo, Alfonso
Fecha de publicación
2014-01-24
Cita
Prior C, Perez-Gracia JL, Garcia-Donas J, Rodriguez-Antona C, Guruceaga E, Esteban E, et al. Identification of Tissue microRNAs Predictive of Sunitinib Activity in Patients with Metastatic Renal Cell Carcinoma. PLoS One. 2014 Jan 24;9(1):e86263.
Idioma
Inglés
Tipo de documento
research article
Resumen
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.
MESH
Aged, 80 and over | Vascular Endothelial Growth Factor A | Aged | Matrix Metalloproteinase 9 | Adult | Humans | Models, Biological | Cell Line, Tumor | Antineoplastic Agents | Middle Aged | Prognosis | Carcinoma, Renal Cell | Indoles | Male | MicroRNAs | Kidney Neoplasms | Neoplasm Metastasis | Female | Gene Expression Profiling | Pyrroles | Treatment Outcome | Drug Resistance, Neoplasm | Paracrine Communication | Reproducibility of Results
DECS
Resistencia a Antineoplásicos | Comunicación Paracrina | Línea Celular Tumoral | Resultado del Tratamiento | Reproducibilidad de los Resultados | Femenino | Metaloproteinasa 9 de la Matriz | Indoles | Metástasis de la Neoplasia | Carcinoma de Células Renales | Neoplasias Renales | Factor A de Crecimiento Endotelial Vascular | Masculino | Pirroles | Antineoplásicos | Humanos | Persona de Mediana Edad | Modelos Biológicos | Pronóstico | Anciano | Anciano de 80 o más Años | Adulto | Perfilación de la Expresión Génica | MicroARNs
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