2026-05-17T05:52:39Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/199672024-11-29T01:08:45Zcom_20.500.12105_15322com_20.500.12105_2051col_20.500.12105_16967

00925njm 22002777a 4500 dc Prior, Celia author Luis Perez-Gracia, Jose author Garcia-Donas, Jesus author Rodriguez-Antona, Cristina author Guruceaga, Elizabeth author Esteban, Emilio author Suarez, Cristina author Castellano, Danie author Gonzalez del Alba, Aranzazu author Dolores Lozano, Maria author Carles, Joan author Angel Climent, Miguel author Angel Arranz, Jose author Gallardo, Enrique author Puente, Javier author Bellmunt, Joaquim author Gurpide, Alfonso author Maria Lopez-Picazo, Jose author Gonzalez Hernandez, Alvaro author Mellado, Begona author Martinez, Esther author Moreno, Fernando author Font, Albert author Calvo, Alfonso author 2014-01-24 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. 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. 10.1371/journal.pone.0086263 1932-6203 PloS One http://hdl.handle.net/20.500.13003/11360 24475095 L373030799 2-s2.0-84898478153 http://hdl.handle.net/20.500.12105/19967 330339800035 Identification of Tissue microRNAs Predictive of Sunitinib Activity in Patients with Metastatic Renal Cell Carcinoma