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Title: Identification of tissue microRNAs predictive of sunitinib activity in patients with metastatic renal cell carcinoma
Author: 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, Jose Angel
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
Keywords: Micro RNAs
Càncer de ronyó
Marcadors bioquímics
Resistència als medicaments
Renal cancer
Biochemical markers
Drug resistance
Issue Date: 24-Jan-2014
Publisher: Public Library of Science (PLoS)
Abstract: 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.
Note: Reproducció del document publicat a:
It is part of: PLoS One, 2014, vol. 9, num. 1, p. e86263-e86263
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ISSN: 1932-6203
Appears in Collections:Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)
Articles publicats en revistes (Medicina)

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