Journal
BRITISH JOURNAL OF CANCER
Volume 107, Issue 6, Pages 967-976Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/bjc.2012.356
Keywords
miR-204; neuroblastoma; BCL2; NTRK2; tumour suppressor; cisplatin
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Funding
- Children's Medical and Research Foundation, Dublin, Ireland
- Science Foundation Ireland [07/IN.1/B1776]
- NIH [5R01CA127496]
- Science Foundation Ireland (SFI) [07/IN.1/B1776] Funding Source: Science Foundation Ireland (SFI)
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BACKGROUND: Neuroblastoma remains a major cause of cancer-linked mortality in children. miR-204 has been used in microRNA expression signatures predictive of neuroblastoma patient survival. The aim of this study was to explore the independent association of miR-204 with survival in a neuroblastoma cohort, and to investigate the phenotypic effects mediated by miR-204 expression in neuroblastoma. METHODS: Neuroblastoma cell lines were transiently transfected with miR-204 mimics and assessed for cell viability using MTS assays. Apoptosis levels in cell lines were evaluated by FACS analysis of Annexin V-/propidium iodide-stained cells transfected with miR-204 mimics and treated with chemotherapy drug or vehicle control. Potential targets of miR-204 were validated using luciferase reporter assays. RESULTS: miR-204 expression in primary neuroblastoma tumours was predictive of patient event-free and overall survival, independent of established known risk factors. Ectopic miR-204 expression significantly increased sensitivity to cisplatin and etoposide in vitro. miR-204 direct targeting of the 3' UTR of BCL2 and NTRK2 (TrkB) was confirmed. CONCLUSION: miR-204 is a novel predictor of outcome in neuroblastoma, functioning, at least in part, through increasing sensitivity to cisplatin by direct targeting and downregulation of anti-apoptotic BCL2. miR-204 also targets full-length NTRK2, a potent oncogene involved with chemotherapy drug resistance in neuroblastoma. British Journal of Cancer (2012) 107, 967-976. doi:10.1038/bjc.2012.356 www.bjcancer.com Published online 14 August 2012 (C) 2012 Cancer Research UK
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