title: Molecular mechanisms of regulation and action of microRNA-199a in testicular germ cell tumor and glioblastomas.
abstract: MicroRNA-199a (miRNA-199a) has been shown to have comprehensive functions and behave differently in different systems and diseases. It is encoded by two loci in the human genome, miR-199a-1 in chromosome 19 and miR-199a-2 in chromosome 1. Both loci give rise to the same miRNAs (miR-199a-5p and miR-199a-3p). The cause of the diverse action of the miRNA in different systems is not clear. However, it is likely due to different regulation of the two genomic loci and variable targets of the miRNA in different cells and tissues. Here we studied promoter methylation of miR-199a in testicular germ cell tumors (TGCTs) and glioblastomas (gliomas) and discovered that hypermethylation in TGCTs of both miR-199a-1 and -2 resulted in its reduced expression, while hypomethylation of miR-199a-2 but not -1 in gliomas may be related to its elevated expression. We also identified a common regulator, REST, which preferentially bound to the methylated promoters of both miR-199a-1 and miR-199a-2. The action of miR-199a is dependent on its downstream targets. We identified MAFB as a putative target of miRNA-199a-5p in TGCTs and confirmed that the tumor suppression activity of the microRNA is mediated by its target MAFB. By studying the mechanisms that control the expressions of miR-199a and its various downstream targets, we hope to use miR-199a as a model to understand the complexity of miRNA biology.
authors.affiliation: School of Biomedical Sciences, The Chinese University of Hong Kong, HKSAR, China.
authors.forename: Shen
authors.initials: S
authors.lastname: Gu
authors.affiliation: Section on Clinical and Developmental Genomics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Hoi Hung
authors.initials: HH
authors.lastname: Cheung
authors.affiliation: School of Biomedical Sciences, The Chinese University of Hong Kong, HKSAR, China.
authors.forename: Tin Lap
authors.initials: TL
authors.lastname: Lee
authors.affiliation: School of Biomedical Sciences, The Chinese University of Hong Kong, HKSAR, China ; Department of Surgery, The Chinese University of Hong Kong, HKSAR, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Lu
authors.affiliation: Department of Surgery, The Chinese University of Hong Kong, HKSAR, China.
authors.forename: Wai Sang
authors.initials: WS
authors.lastname: Poon
authors.affiliation: School of Biomedical Sciences, The Chinese University of Hong Kong, HKSAR, China.
authors.forename: Wai Yee
authors.initials: WY
authors.lastname: Chan
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics*; D006801:Humans; D007124:Immunoenzyme Techniques; D051258:MafB Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D009373:Neoplasms, Germ Cell and Embryonal / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013736:Testicular Neoplasms / Q000235:genetics*; D013737:Testis / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; C490407:MAFB protein, human; D051258:MafB Transcription Factor; D035683:MicroRNAs; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C531408:mirn199 microRNA, human