Identification of tissue microRNAs predictive of sunitinib activity in patients with metastatic renal cell carcinoma.
OBJECTIVE
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.
Oncology Division, CIMA, University of Navarra, Pamplona, Spain.
Celia
C
Prior
Oncology Department, Clinica Universidad de Navarra, Pamplona, Spain.
Jose Luis
JL
Perez-Gracia
Fundacion Hospital de Alcorcon, Madrid, Spain.
Jesus
J
Garcia-Donas
Human Cancer Genetics Programme, CNIO, Madrid, Spain.
Cristina
C
Rodriguez-Antona
Proteomics, Genomics and Bioinformatics Unit, CIMA, University of Navarra, Pamplona, Spain.
Elizabeth
E
Guruceaga
Medical Oncology Department, Hospital Universitario Central de Asturias, Oviedo, Spain.
Emilio
E
Esteban
Medical Oncology Department, Hospital Universitario Vall de Hebron, Barcelona, Spain.
Cristina
C
Suarez
Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain.
Daniel
D
Castellano
Medical Oncology Department, Hospital Universitario Son Espases, Palma de Mallorca, Spain.
Aránzazu González
AG
del Alba
Pathology Department, University Clinic of Navarra, University of Navarra, Pamplona, Spain.
Maria Dolores
MD
Lozano
Medical Oncology Department, Hospital Universitario Vall de Hebron, Barcelona, Spain.
Joan
J
Carles
Medical Oncology Department, Instituto Valenciano de Oncología, Valencia, Spain.
Miguel Angel
MA
Climent
Medical Oncology Department, Hospital Universitario Gregorio Marañon, Madrid, Spain.
Jose Angel
JA
Arranz
Medical Oncology Department, Parc Taulí Sabadell Hospital Universitari, Sabadell, Spain.
Enrique
E
Gallardo
Medical Oncology Department, Hospital Clinico Universitario San Carlos, Madrid, Spain.
Javier
J
Puente
Medical Oncology Department, University Hospital del Mar, Barcelona, Spain.
Joaquim
J
Bellmunt
Oncology Department, Clinica Universidad de Navarra, Pamplona, Spain.
Alfonso
A
Gurpide
Oncology Department, Clinica Universidad de Navarra, Pamplona, Spain.
Jose Maria
JM
Lopez-Picazo
Biochemistry Department, Clinica Universidad de Navarra, Pamplona, Spain.
Alvaro Gonzalez
AG
Hernandez
Medical Oncology Department, IDIBAPS, Hospital Clinic, Barcelona, Spain.
Begoña
B
Mellado
Medical Oncology Department, Hospital de Jaen, Jaen, Spain.
Esther
E
Martínez
Medical Oncology Department, Hospital Clinico Universitario San Carlos, Madrid, Spain.
Fernando
F
Moreno
Medical Oncology Service, Institut Català d'Oncologia, Hospital Germans Trias i Pujol, Badalona, Spain.
Albert
A
Font
Oncology Division, CIMA, University of Navarra, Pamplona, Spain.
Alfonso
A
Calvo
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D008954:Models, Biological; D009362:Neoplasm Metastasis; D019899:Paracrine Communication; D011379:Prognosis; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D015203:Reproducibility of Results; D000077210:Sunitinib; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D000970:Antineoplastic Agents; D007211:Indoles; D035683:MicroRNAs; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D020780:Matrix Metalloproteinase 9; D000077210:Sunitinib