title: Tissue-specific microRNA responses in rats treated with mutagenic and carcinogenic doses of aristolochic acid.
abstract: Aristolochic acid (AA) is an active component in herbal drugs derived from the Aristolochia species. Although these drugs have been used since antiquity, AA is both genotoxic and carcinogenic in animals and humans, resulting in kidney tumours in rats and upper urinary tract tumours in humans. In the present study, we conducted microarray analysis of microRNA (miRNA) expression in tissues from transgenic Big Blue rats that were treated for 12 weeks with 0.1-10mg/kg AA, using a protocol that previous studies indicate eventually results in kidney tumours and mutations in kidney and liver. Global analysis of miRNA expression of rats treated with 10 mg/kg AA indicated that 19 miRNAs were significantly dysregulated in the kidney, with most of the miRNAs related to carcinogenesis. Only one miRNA, miR-34a (a tumour suppressor), was differentially expressed in the liver. The expression of the two most responsive kidney miRNAs (miR-21, an oncomiR and miR-34a) was further examined in the kidney, liver and testis of rats exposed to 0, 0.1, 1.0 and 10mg/kg AA. Expression of miR-21 was up-regulated in the kidney only, while miR-34a was dose-dependently up-regulated in both the kidney and liver; the expression of miR-21 and miR-34a was unaltered by the AA treatment in the testis. Analysis of cII mutations in the testis of treated rats also was negative. Our results indicate that AA treatment of rats produced dysregulation of a large number of miRNAs in the tumour target tissue and that the up-regulation of miR-21 correlated with the carcinogenicity of AA while the up-regulation of miR-34a correlated with its mutagenicity.
authors.affiliation: Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, USA, Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, 9 Lvshun Road South, Dalian, Liaoning 116044, China and Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: Fanxue
authors.initials: F
authors.lastname: Meng
authors.affiliation: Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, 9 Lvshun Road South, Dalian, Liaoning 116044, China and.
authors.forename: Zhiguang
authors.initials: Z
authors.lastname: Li
authors.affiliation: Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, USA, Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, 9 Lvshun Road South, Dalian, Liaoning 116044, China and Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Yan
authors.affiliation: Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, USA, Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, 9 Lvshun Road South, Dalian, Liaoning 116044, China and Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: Mugimane
authors.initials: M
authors.lastname: Manjanatha
authors.affiliation: Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, USA, Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, 9 Lvshun Road South, Dalian, Liaoning 116044, China and Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Shelton
authors.affiliation: Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Yarborough
authors.affiliation: Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, USA, Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, 9 Lvshun Road South, Dalian, Liaoning 116044, China and Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712, USA tao.chen@fda.hhs.gov.
authors.forename: Tao
authors.initials: T
authors.lastname: Chen
mesh_terms: D000818:Animals; D034341:Aristolochic Acids / Q000008:administration & dosage / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D004249:DNA Damage / Q000187:drug effects; D007668:Kidney / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D046228:Microarray Analysis; D009153:Mutagens / Q000633:toxicity*; D051381:Rats; D055647:Rats, Transgenic; D013737:Testis / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D034341:Aristolochic Acids; D002273:Carcinogens; C560944:MIRN34 microRNA, rat; D035683:MicroRNAs; D009153:Mutagens; C546082:mirn21 microRNA, rat; C000228:aristolochic acid I