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

• Published in: PloS one Vol. 9; no. 1; p. e86263
• Main Authors: Prior, Celia, Perez-Gracia, Jose Luis, Garcia-Donas, Jesus, Rodriguez-Antona, Cristina, Guruceaga, Elizabeth, Esteban, Emilio, Suarez, Cristina, Castellano, Daniel, del Alba, Aránzazu González, Lozano, Maria Dolores, Carles, Joan, Climent, Miguel Angel, Arranz, Jose Angel, Gallardo, Enrique, Puente, Javier, Bellmunt, Joaquim, Gurpide, Alfonso, Lopez-Picazo, Jose Maria, Hernandez, Alvaro Gonzalez, Mellado, Begoña, Martínez, Esther, Moreno, Fernando, Font, Albert, Calvo, Alfonso
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 24.01.2014; Public Library of Science (PLoS)
• Subjects: Adult; Aged; Aged, 80 and over; Analysis; Antineoplastic agents; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Biochemical markers; Bioinformatics; Biology; Biomarkers; Cancer metastasis; Cancer therapies; Carcinoma; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - mortality; Carcinoma, Renal Cell - pathology; Care and treatment; Cell Line, Tumor; Cell survival; Càncer de ronyó; Drug resistance; Drug Resistance, Neoplasm - genetics; Effectiveness; Female; Fenotip; Gelatinase B; Gene expression; Gene Expression Profiling; Humans; Indoles - pharmacology; Indoles - therapeutic use; Kidney cancer; Kidney Neoplasms - drug therapy; Kidney Neoplasms - genetics; Kidney Neoplasms - mortality; Kidney Neoplasms - pathology; Male; Marcadors bioquímics; Matrix Metalloproteinase 9 - secretion; Medical prognosis; Medicine; Metastases; Metastasis; Micro RNAs; MicroRNA; MicroRNAs; MicroRNAs - genetics; Middle Aged; miRNA; Models, Biological; Neoplasm Metastasis; Oncology; Paracrine Communication; Paracrine signalling; Patients; Phenotype; Predictions; Prognosis; Prostate cancer; Pyrroles - pharmacology; Pyrroles - therapeutic use; Renal cancer; Renal cell carcinoma; Reproducibility of Results; Resistència als medicaments; RNA; Secretion; Treatment Outcome; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - secretion
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0086263

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. 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. 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. 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.