التفاصيل البيبلوغرافية
| العنوان: |
Identification of Tissue microRNAs Predictive of Sunitinib Activity in Patients with Metastatic Renal Cell Carcinoma. |
| المؤلفون: |
Prior, Celia, Perez-Gracia, Jose Luis, Garcia-Donas, Jesus, Rodriguez-Antona, Cristina, Guruceaga, Elizabeth, Esteban, Emilio, Suarez, Cristina, Castellano, Daniel, Alba, Aránzazu González del, 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 |
| المصدر: |
PLoS ONE; Jan2014, Vol. 9 Issue 1, p1-10, 10p |
| مصطلحات موضوعية: |
MICRORNA, RENAL cell carcinoma, METASTASIS, DRUG resistance, ENDOTHELIAL cells, GENE expression, CANCER treatment |
| مستخلص: |
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. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |
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