title: miR-17* suppresses tumorigenicity of prostate cancer by inhibiting mitochondrial antioxidant enzymes.
abstract: Aberrant micro RNA (miRNA) expression has been implicated in the pathogenesis of cancer. Recent studies have shown that the miR-17-92 cluster is overexpressed in many types of cancer. The oncogenic function of mature miRNAs encoded by the miR-17-92 cluster has been identified from the 5' arm of six precursors. However, the function of the miRNAs produced from the 3' arm of these precursors remains unknown. The present study demonstrates that miR-17* is able to suppress critical primary mitochondrial antioxidant enzymes, such as manganese superoxide dismutase (MnSOD), glutathione peroxidase-2 (GPX2) and thioredoxin reductase-2 (TrxR2). Transfection of miR-17* into prostate cancer PC-3 cells significantly reduces levels of the three antioxidant proteins and activity of the luciferase reporter under the control of miR-17* binding sequences located in the 3'-untranslated regions of the three target genes. Disulfiram (DSF), a dithiolcarbomate drug shown to have an anticancer effect, induces the level of mature miR-17* and cell death in PCa cells, which can be attenuated by transfection of antisense miR-17*. Increasing miR-17* level in PC-3 cells by a Tet-on based conditional expression system markedly suppresses its tumorigencity. These results suggest that miR-17* may suppress tumorigenicity of prostate cancer through inhibition of mitochondrial antioxidant enzymes.
authors.affiliation: Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.forename: Fang
authors.initials: F
authors.lastname: Fang
authors.forename: Jiayou
authors.initials: J
authors.lastname: Zhang
authors.forename: Sajni
authors.initials: S
authors.lastname: Josson
authors.forename: William H
authors.initials: WH
authors.lastname: St Clair
authors.forename: Daret K
authors.initials: DK
authors.lastname: St Clair
mesh_terms: D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism*; D002219:Carbamates / Q000737:chemistry; D045744:Cell Line, Tumor; D004221:Disulfiram / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D005979:Glutathione Peroxidase / Q000378:metabolism; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D005810:Multigene Family; D011471:Prostatic Neoplasms / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D054482:Thioredoxin Reductase 2 / Q000378:metabolism; D014050:Toluene / Q000031:analogs & derivatives; D014162:Transfection
chemical_list: D000975:Antioxidants; D002219:Carbamates; C524941:MIRN17 microRNA, human; D035683:MicroRNAs; D014050:Toluene; C117436:GPX2 protein, human; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D054482:Thioredoxin Reductase 2; D004221:Disulfiram; C004848:dithiol