Identification of tissue microRNAs predictive of sunitinib activity in patients with metastatic renal cell carcinoma.
PLoS One, 2014;9(1):e86263.
Prior C[1], Perez-Gracia JL[2], Garcia-Donas J[3], Rodriguez-Antona C[4], Guruceaga E[5], Esteban E[6], Suarez C[7], Castellano D[8], del Alba AG[9], Lozano MD[10], Carles J[7], Climent MA[11], Arranz JA[12], Gallardo E[13], Puente J[14], Bellmunt J[15], Gurpide A[2], Lopez-Picazo JM[2], Hernandez AG[16], Mellado B[17], Martínez E[18], Moreno F[14], Font A[19], Calvo A[1]
Affiliations
PMID: 24475095DOI: 10.1371/journal.pone.0086263
Impact factor: 3.752
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.
MeSH terms
Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Cell Line, Tumor; Drug Resistance, Neoplasm; Female; Gene Expression Profiling; Humans; Indoles; Kidney Neoplasms; Male; Matrix Metalloproteinase 9; MicroRNAs; Middle Aged; Models, Biological; Neoplasm Metastasis; Paracrine Communication; Prognosis; Pyrroles; Reproducibility of Results; Sunitinib; Treatment Outcome; Vascular Endothelial Growth Factor A
More resources
Full text:
Europe PubMed Central; PubMed Central
EndNote: Download