title: Anti-oncogenic microRNA-203 induces senescence by targeting E2F3 protein in human melanoma cells.
abstract: MicroRNAs regulate gene expression by repressing translation or directing sequence-specific degradation of their complementary mRNA. We recently reported that miR-203 is down-regulated, and its exogenous expression inhibits cell growth in canine oral malignant melanoma tissue specimens as well as in canine and human malignant melanoma cells. A microRNA target database predicted E2F3 and ZBP-89 as putative targets of microRNA-203 (miR-203). The expression levels of E2F3a, E2F3b, and ZBP-89 were markedly up-regulated in human malignant melanoma Mewo cells compared with those in human epidermal melanocytes. miR-203 significantly suppressed the luciferase activity of reporter plasmids containing the 3'-UTR sequence of either E2F3 or ZBP-89 complementary to miR-203. The ectopic expression of miR-203 in melanoma cells reduced the levels of E2F3a, E2F3b, and ZBP-89 protein expression. At the same time, miR-203 induced cell cycle arrest and senescence phenotypes, such as elevated expression of hypophosphorylated retinoblastoma and other markers for senescence. Silencing of E2F3, but not of ZBP-89, inhibited cell growth and induced cell cycle arrest and senescence. These results demonstrate a novel role for miR-203 as a tumor suppressor acting by inducing senescence in melanoma cells.
authors.affiliation: United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Noguchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Mori
authors.forename: Yusami
authors.initials: Y
authors.lastname: Otsuka
authors.forename: Nami
authors.initials: N
authors.lastname: Yamada
authors.forename: Yuki
authors.initials: Y
authors.lastname: Yasui
authors.forename: Junya
authors.initials: J
authors.lastname: Iwasaki
authors.forename: Minami
authors.initials: M
authors.lastname: Kumazaki
authors.forename: Kohji
authors.initials: K
authors.lastname: Maruo
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Akao
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D016922:Cellular Senescence; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D050699:E2F3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D008545:Melanoma; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D038621:Regulatory Sequences, Ribonucleic Acid; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D050699:E2F3 Transcription Factor; C098319:E2F3 protein, human; C546703:MIRN203 microRNA, human; C489427:MYC protein, human; D035683:MicroRNAs; D020033:Protein Isoforms; D016271:Proto-Oncogene Proteins c-myc; D038621:Regulatory Sequences, Ribonucleic Acid; D014157:Transcription Factors; C110951:ZNF148 protein, human; C447939:SIRT1 protein, human; D056564:Sirtuin 1