title: Suppression of miR-184 in malignant gliomas upregulates SND1 and promotes tumor aggressiveness.
abstract: BACKGROUND
  Malignant glioma is an aggressive cancer requiring new therapeutic targets. MicroRNAs (miRNAs) regulate gene expression post transcriptionally and are implicated in cancer development and progression. Deregulated expressions of several miRNAs, specifically hsa-miR-184, correlate with glioma development.
  
  
  METHODS
  Bioinformatic approaches were used to identify potential miR-184-regulated target genes involved in malignant glioma progression. This strategy identified a multifunctional nuclease, SND1, known to be overexpressed in multiple cancers, including breast, colon, and hepatocellular carcinoma, as a putative direct miR-184 target gene. SND1 levels were evaluated in patient tumor samples and human-derived cell lines. We analyzed invasion and signaling in vitro through SND1 gain-of-function and loss-of-function. An orthotopic xenograft model with primary glioma cells demonstrated a role of miR-184/SND1 in glioma pathogenesis in vivo.
  
  
  RESULTS
  SND1 is highly expressed in human glioma tissue and inversely correlated with miR-184 expression. Transfection of glioma cells with a miR-184 mimic inhibited invasion, suppressed colony formation, and reduced anchorage-independent growth in soft agar. Similar phenotypes were evident when SND1 was knocked down with siRNA. Additionally, knockdown (KD) of SND1 induced senescence and improved the chemoresistant properties of malignant glioma cells. In an orthotopic xenograft model, KD of SND1 or transfection with a miR-184 mimic induced a less invasive tumor phenotype and significantly improved survival of tumor bearing mice.
  
  
  CONCLUSIONS
  Our study is the first to show a novel regulatory role of SND1, a direct target of miR-184, in glioma progression, suggesting that the miR-184/SND1 axis may be a useful diagnostic and therapeutic tool for malignant glioma.
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia (L.E., A.J., M.A.-Z., B.H., P.K.S., M.E.M., X.-N.S., S.K.D., D.S., P.B.F.); VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia (L.E., S.K.D., D.S., P.B.F.); VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia (L.E., D.S., P.B.F.).
authors.forename: Luni
authors.initials: L
authors.lastname: Emdad
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia (L.E., A.J., M.A.-Z., B.H., P.K.S., M.E.M., X.-N.S., S.K.D., D.S., P.B.F.); VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia (L.E., S.K.D., D.S., P.B.F.); VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia (L.E., D.S., P.B.F.).
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Janjic
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia (L.E., A.J., M.A.-Z., B.H., P.K.S., M.E.M., X.-N.S., S.K.D., D.S., P.B.F.); VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia (L.E., S.K.D., D.S., P.B.F.); VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia (L.E., D.S., P.B.F.).
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Alzubi
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia (L.E., A.J., M.A.-Z., B.H., P.K.S., M.E.M., X.-N.S., S.K.D., D.S., P.B.F.); VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia (L.E., S.K.D., D.S., P.B.F.); VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia (L.E., D.S., P.B.F.).
authors.forename: Bin
authors.initials: B
authors.lastname: Hu
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia (L.E., A.J., M.A.-Z., B.H., P.K.S., M.E.M., X.-N.S., S.K.D., D.S., P.B.F.); VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia (L.E., S.K.D., D.S., P.B.F.); VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia (L.E., D.S., P.B.F.).
authors.forename: Prasanna K
authors.initials: PK
authors.lastname: Santhekadur
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia (L.E., A.J., M.A.-Z., B.H., P.K.S., M.E.M., X.-N.S., S.K.D., D.S., P.B.F.); VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia (L.E., S.K.D., D.S., P.B.F.); VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia (L.E., D.S., P.B.F.).
authors.forename: Mitchell E
authors.initials: ME
authors.lastname: Menezes
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia (L.E., A.J., M.A.-Z., B.H., P.K.S., M.E.M., X.-N.S., S.K.D., D.S., P.B.F.); VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia (L.E., S.K.D., D.S., P.B.F.); VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia (L.E., D.S., P.B.F.).
authors.forename: Xue-Ning
authors.initials: XN
authors.lastname: Shen
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia (L.E., A.J., M.A.-Z., B.H., P.K.S., M.E.M., X.-N.S., S.K.D., D.S., P.B.F.); VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia (L.E., S.K.D., D.S., P.B.F.); VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia (L.E., D.S., P.B.F.).
authors.forename: Swadesh K
authors.initials: SK
authors.lastname: Das
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia (L.E., A.J., M.A.-Z., B.H., P.K.S., M.E.M., X.-N.S., S.K.D., D.S., P.B.F.); VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia (L.E., S.K.D., D.S., P.B.F.); VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia (L.E., D.S., P.B.F.).
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia (L.E., A.J., M.A.-Z., B.H., P.K.S., M.E.M., X.-N.S., S.K.D., D.S., P.B.F.); VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia (L.E., S.K.D., D.S., P.B.F.); VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia (L.E., D.S., P.B.F.).
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D045744:Cell Line, Tumor; D018450:Disease Progression; D004720:Endonucleases; D005786:Gene Expression Regulation; D005910:Glioma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C534424:MIRN184 microRNA, human; D035683:MicroRNAs; D009687:Nuclear Proteins; D004720:Endonucleases; C095221:SND1 protein, human
keywords: SND1; intracranial injection; invasion; malignant glioma; miR-184