title: microRNA signature and expression of Dicer and Drosha can predict prognosis and delineate risk groups in neuroblastoma.
abstract: Neuroblastoma is a common childhood tumor and accounts for 15% of pediatric cancer deaths. To investigate the microRNA (miRNA) profile and role of Dicer and Drosha in neuroblastoma, we assessed the expression of 162 human miRNAs, Dicer and Drosha in 66 neuroblastoma tumors by using real-time PCR methods. We found global downregulation of miRNA expression in advanced neuroblastoma and identified 27 miRNAs that can clearly distinguish low- from high-risk patients. Furthermore, expression levels of Dicer or Drosha were low in high-risk neuroblastoma tumors, which accounted for global downregulation of miRNAs in advanced disease and correlated with poor outcome. Notably, for patients with non-MYCN-amplified tumors, low expression of Dicer can serve as a significant and independent predictor of poor outcome (hazard ratio, 9.6; P = 0.045; n = 52). Using plausible neural networks to select a combination of 15 biomarkers that consist of 12 miRNAs' signature, expression levels of Dicer and Drosha, and age at diagnosis, we were able to segregate all patients into four distinct patterns that were highly predictive of clinical outcome. In vitro studies also showed that knockdown of either Dicer or Drosha promoted the growth of neuroblastoma cell lines. Our results reveal that a combination of 15 biomarkers can delineate risk groups of neuroblastoma and serve as a powerful predictor of clinical outcome. Moreover, our findings of growth promotion by silencing Dicer/Drosha implied their potential use as therapeutic targets for neuroblastoma.
authors.affiliation: Graduate Institute of Life Science, National Defense Medical Center, and Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Ruey-Jen
authors.initials: RJ
authors.lastname: Lin
authors.forename: You-Chin
authors.initials: YC
authors.lastname: Lin
authors.forename: Jeremy
authors.initials: J
authors.lastname: Chen
authors.forename: Huan-Hsien
authors.initials: HH
authors.lastname: Kuo
authors.forename: Yuan-Yan
authors.initials: YY
authors.lastname: Chen
authors.forename: Mitchell B
authors.initials: MB
authors.lastname: Diccianni
authors.forename: Wendy B
authors.initials: WB
authors.lastname: London
authors.forename: Chih-Hao
authors.initials: CH
authors.lastname: Chang
authors.forename: Alice L
authors.initials: AL
authors.lastname: Yu
mesh_terms: D045744:Cell Line, Tumor; D003114:Colony-Forming Units Assay; D017931:DNA Primers; D015870:Gene Expression; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009447:Neuroblastoma / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics*; D010957:Plasmids; D016133:Polymerase Chain Reaction / Q000379:methods; D011237:Predictive Value of Tests; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D043244:Ribonuclease III / Q000172:deficiency / Q000235:genetics*; D018570:Risk Assessment; D014162:Transfection
chemical_list: D017931:DNA Primers; D035683:MicroRNAs; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C517918:DROSHA protein, human; D043244:Ribonuclease III
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