title: MicroRNA 218 acts as a tumor suppressor by targeting multiple cancer phenotype-associated genes in medulloblastoma.
abstract: Aberrant expression of microRNAs has been implicated in many cancers. We recently demonstrated differential expression of several microRNAs in medulloblastoma. In this study, the regulation and function of microRNA 218 (miR-218), which is significantly underexpressed in medulloblastoma, was evaluated. Re-expression of miR-218 resulted in a significant decrease in medulloblastoma cell growth, cell colony formation, cell migration, invasion, and tumor sphere size. We used C17.2 neural stem cells as a model to show that increased miR-218 expression results in increased cell differentiation and also decreased malignant transformation when transfected with the oncogene REST. These results suggest that miR-218 acts as a tumor suppressor in medulloblastoma. MicroRNAs function by down-regulating translation of target mRNAs. Targets are determined by imperfect base pairing of the microRNA to the 3'-UTR of the mRNA. To comprehensively identify actual miR-218 targets, medulloblastoma cells overexpressing miR-218 and control cells were subjected to high throughput sequencing of RNA isolated by cross-linking immunoprecipitation, a technique that identifies the mRNAs bound to the RNA-induced silencing complex component protein Argonaute 2. High throughput sequencing of mRNAs identified 618 genes as targets of miR-218 and included both previously validated targets and many targets not predicted computationally. Additional work further confirmed CDK6, RICTOR, and CTSB (cathepsin B) as targets of miR-218 and examined the functional role of one of these targets, CDK6, in medulloblastoma.
authors.affiliation: Department of Pediatrics, Children’s Hospital Colorado, University of Colorado, Denver, Colorado 80045, USA.
authors.forename: Sujatha
authors.initials: S
authors.lastname: Venkataraman
authors.forename: Diane K
authors.initials: DK
authors.lastname: Birks
authors.forename: Ilango
authors.initials: I
authors.lastname: Balakrishnan
authors.forename: Irina
authors.initials: I
authors.lastname: Alimova
authors.forename: Peter S
authors.initials: PS
authors.lastname: Harris
authors.forename: Purvi R
authors.initials: PR
authors.lastname: Patel
authors.forename: Michael H
authors.initials: MH
authors.lastname: Handler
authors.forename: Adrian
authors.initials: A
authors.lastname: Dubuc
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Foreman
authors.forename: Rajeev
authors.initials: R
authors.lastname: Vibhakar
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D060565:Argonaute Proteins / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002401:Cathepsin B / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D002528:Cerebellar Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002531:Cerebellum / Q000378:metabolism* / Q000473:pathology; D002675:Child, Preschool; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008527:Medulloblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009361:Neoplasm Invasiveness; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D012333:RNA, Messenger / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D012097:Repressor Proteins; D015398:Signal Transduction; D000099229:RE1-Silencing Transcription Factor
chemical_list: D020413:3' Untranslated Regions; D060565:Argonaute Proteins; D002352:Carrier Proteins; D002401:Cathepsin B; D051361:Cyclin-Dependent Kinase 6; D035683:MicroRNAs; D012333:RNA, Messenger; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor; C466422:AGO2 protein, human; C547471:MIRN218 microRNA, human; C492571:RICTOR protein, human; C495911:CDK6 protein, human; C533912:CTSB protein, human