title: miR-34a confers chemosensitivity through modulation of MAGE-A and p53 in medulloblastoma.
abstract: Recent studies have established miR-34a as a key effector of the p53 signaling pathway and have implicated its role in multiple cancer types. Here, we establish that miR-34a induces apoptosis, G2 arrest, and senescence in medulloblastoma and renders these cells more sensitive to chemotherapeutic agents. These effects are mediated in part by the direct post-transcriptional repression of the oncogenic MAGE-A gene family. We demonstrate that miR-34a directly targets the 3' untranslated regions of MAGE-A genes and decreases MAGE-A protein levels. This decrease in MAGE-A results in a concomitant increase in p53 and its associated transcriptional targets, p21/WAF1/CIP1 and, importantly, miR-34a. This establishes a positive feedback mechanism where miR-34a is not only induced by p53 but increases p53 mRNA and protein levels through the modulation of MAGE-A genes. Additionally, the forced expression of miR-34a or the knockdown of MAGE-A genes by small interfering RNA similarly sensitizes medulloblastoma cells to several classes of chemotherapeutic agents, including mitomycin C and cisplatin. Finally, the analysis of mRNA and micro-RNA transcriptional profiles of a series of primary medulloblastomas identifies a subset of tumors with low miR-34a expression and correspondingly high MAGE-A expression, suggesting the coordinate regulation of these genes. Our work establishes a role for miR-34a in modulating responsiveness to chemotherapy in medulloblastoma and presents a novel positive feedback mechanism involving miR-34a and p53, via direct targeting of MAGE-A.
authors.affiliation: Department of Neurology, Children's Hospital Boston/Harvard Medical School, 3 Blackfan Circle, CLS 14072, Boston, MA 02115, USA.
authors.forename: Shyamal D
authors.initials: SD
authors.lastname: Weeraratne
authors.forename: Vladimir
authors.initials: V
authors.lastname: Amani
authors.forename: Adrianne
authors.initials: A
authors.lastname: Neiss
authors.forename: Natalia
authors.initials: N
authors.lastname: Teider
authors.forename: Deborah K
authors.initials: DK
authors.lastname: Scott
authors.forename: Scott L
authors.initials: SL
authors.lastname: Pomeroy
authors.forename: Yoon-Jae
authors.initials: YJ
authors.lastname: Cho
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002528:Cerebellar Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D020869:Gene Expression Profiling; D006801:Humans; D007124:Immunoenzyme Techniques; D008156:Luciferases / Q000378:metabolism; D008527:Medulloblastoma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D058950:Melanoma-Specific Antigens; D035683:MicroRNAs / Q000502:physiology*; D016685:Mitomycin / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C072011:MAGEA1 protein, human; C522425:MIRN34 microRNA, human; D058950:Melanoma-Specific Antigens; D035683:MicroRNAs; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D016685:Mitomycin; D008156:Luciferases; D002945:Cisplatin