title: The RNA-binding protein Musashi1 affects medulloblastoma growth via a network of cancer-related genes and is an indicator of poor prognosis.
abstract: Musashi1 (Msi1) is a highly conserved RNA-binding protein that is required during the development of the nervous system. Msi1 has been characterized as a stem cell marker, controlling the balance between self-renewal and differentiation, and has also been implicated in tumorigenesis, being highly expressed in multiple tumor types. We analyzed Msi1 expression in a large cohort of medulloblastoma samples and found that Msi1 is highly expressed in tumor tissue compared with normal cerebellum. Notably, high Msi1 expression levels proved to be a sign of poor prognosis. Msi1 expression was determined to be particularly high in molecular subgroups 3 and 4 of medulloblastoma. We determined that Msi1 is required for tumorigenesis because inhibition of Msi1 expression by small-interfering RNAs reduced the growth of Daoy medulloblastoma cells in xenografts. To characterize the participation of Msi1 in medulloblastoma, we conducted different high-throughput analyses. Ribonucleoprotein immunoprecipitation followed by microarray analysis (RIP-chip) was used to identify mRNA species preferentially associated with Msi1 protein in Daoy cells. We also used cluster analysis to identify genes with similar or opposite expression patterns to Msi1 in our medulloblastoma cohort. A network study identified RAC1, CTGF, SDCBP, SRC, PRL, and SHC1 as major nodes of an Msi1-associated network. Our results suggest that Msi1 functions as a regulator of multiple processes in medulloblastoma formation and could become an important therapeutic target.
authors.affiliation: Greehey Children's Cancer Research Institute, University of Texas Health Science Center, San Antonio, USA.
authors.forename: Dat T
authors.initials: DT
authors.lastname: Vo
authors.forename: Dharmalingam
authors.initials: D
authors.lastname: Subramaniam
authors.forename: Marc
authors.initials: M
authors.lastname: Remke
authors.forename: Tarea L
authors.initials: TL
authors.lastname: Burton
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Uren
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Gelfond
authors.forename: Raquel
authors.initials: R
authors.lastname: de Sousa Abreu
authors.forename: Suzanne C
authors.initials: SC
authors.lastname: Burns
authors.forename: Mei
authors.initials: M
authors.lastname: Qiao
authors.forename: Uthra
authors.initials: U
authors.lastname: Suresh
authors.forename: Andrey
authors.initials: A
authors.lastname: Korshunov
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Dubuc
authors.forename: Paul A
authors.initials: PA
authors.lastname: Northcott
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Smith
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.forename: Sarath C
authors.initials: SC
authors.lastname: Janga
authors.forename: Shrikant
authors.initials: S
authors.lastname: Anant
authors.forename: Christine
authors.initials: C
authors.lastname: Vogel
authors.forename: Luiz O F
authors.initials: LO
authors.lastname: Penalva
mesh_terms: D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002528:Cerebellar Neoplasms / Q000235:genetics* / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks / Q000235:genetics*; D020868:Gene Silencing; D052138:Genes, Neoplasm / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D008527:Medulloblastoma / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D014176:Protein Biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D012074:Remission Induction; D023041:Xenograft Model Antitumor Assays
chemical_list: C491297:MSI1 protein, human; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins