title: Deep MicroRNA sequencing reveals downregulation of miR-29a in neuroblastoma central nervous system metastasis.
abstract: Central nervous system (CNS) is an increasingly common site of isolated metastasis for patients with Stage 4 neuroblastoma. To explore the microRNA (miRNA) profile of this metastatic process, miRNA sequencing was performed to identify miRNA sequence families with differential expression between tumor pairs (pre-CNS primary and CNS metastasis) from 13 patients with Stage 4 neuroblastoma. Seven miRNA sequence families had distinct expression in CNS metastases when compared with their corresponding pre-CNS primaries. MiR-7 was upregulated (3.75-fold), and miR-21, miR-22, miR-29a, miR-143, miR-199a-1-3p, and miR-199a-1-5p were downregulated (3.5-6.1-fold), all confirmed by quantitative reverse transcription-PCR. MiR-29a, previously shown to be downregulated in a broad spectrum of solid tumors including neuroblastoma, had the most significant decrease in all 13 CNS metastases (P = 0.001). Its known onco-targets CDC6, CDK6, and DNMT3A, as well as B7-H3, an inhibitory ligand for T cells, and natural killer cells, were found to have higher differential expression in these 13 CNS metastases when compared with their paired primaries. Additionally, miR-29a expression in primary tumors was significantly lower among patients who eventually relapsed in the CNS. Irrespective of the amplification status of MYCN, which is known to be associated with metastasis, pre-CNS primaries, and CNS metastases had significantly lower miR-29a expression than non-CNS primary tumors. Among MYCN amplified cell lines, those from CNS relapse also had lower miR-29a expression than non-CNS relapse. These findings raised the hypothesis that miR-29a could be a biomarker for neuroblastoma CNS metastasis, and its downregulation may play a pivotal role in CNS progression.
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, 10065.
authors.forename: Irene Y
authors.initials: IY
authors.lastname: Cheung
authors.forename: Thalia A
authors.initials: TA
authors.lastname: Farazi
authors.forename: Irina
authors.initials: I
authors.lastname: Ostrovnaya
authors.forename: Hong
authors.initials: H
authors.lastname: Xu
authors.forename: Hoa
authors.initials: H
authors.lastname: Tran
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Mihailovic
authors.forename: Thomas
authors.initials: T
authors.lastname: Tuschl
authors.forename: Nai-Kong V
authors.initials: NK
authors.lastname: Cheung
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D016543:Central Nervous System Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D015536:Down-Regulation; D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007694:Killer Cells, Natural / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D000071447:N-Myc Proto-Oncogene Protein; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000378:metabolism; D009367:Neoplasm Staging; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins / Q000378:metabolism*; D015513:Oncogene Proteins / Q000378:metabolism*; D017423:Sequence Analysis, RNA; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; C532045:MIRN29a microRNA, human; C459801:MYCN protein, human; D035683:MicroRNAs; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins