title: The natural inhibitor of DNA topoisomerase I, camptothecin, modulates HIF-1α activity by changing miR expression patterns in human cancer cells.
abstract: DNA topoisomerase I (Top1) inhibition by camptothecin derivatives can impair the hypoxia-induced cell transcriptional response. In the present work, we determined molecular aspects of the mechanism of camptothecin's effects on hypoxia-inducible factor-1α (HIF-1α) activity in human cancer cells. In particular, we provide evidence that low concentrations of camptothecin, without interfering with HIF-1α mRNA levels, can reduce HIF-1α protein expression and activity. As luciferase assays demonstrated the involvement of the HIF-1α mRNA 3' untranslated region in camptothecin-induced impairment of HIF-1α protein regulation, we performed microarray analysis to identify camptothecin-induced modification of microRNAs (miRNA) targeting HIF-1α mRNA under hypoxic-mimetic conditions. The selected miRNAs were then further analyzed, demonstrating a role for miR-17-5p and miR-155 in HIF-1α protein expression after camptothecin treatments. The present findings establish miRNAs as key factors in a molecular pathway connecting Top1 inhibition and human HIF-1α protein regulation and activity, widening the biologic and molecular activity of camptothecin derivatives and the perspective for novel clinical interventions.
authors.affiliation: Corresponding Author: G. Capranico, Department of Pharmacy and Biotechnology, University of Bologna, via Irnerio 48, 40126 Bologna, Italy. giovanni.capranico@unibo.it.
authors.forename: Davide
authors.initials: D
authors.lastname: Bertozzi
authors.forename: Jessica
authors.initials: J
authors.lastname: Marinello
authors.forename: Stefano G
authors.initials: SG
authors.lastname: Manzo
authors.forename: Francesca
authors.initials: F
authors.lastname: Fornari
authors.forename: Laura
authors.initials: L
authors.lastname: Gramantieri
authors.forename: Giovanni
authors.initials: G
authors.lastname: Capranico
mesh_terms: D002166:Camptothecin / Q000008:administration & dosage; D015687:Cell Hypoxia / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis* / Q000235:genetics; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D059004:Topoisomerase I Inhibitors / Q000008:administration & dosage
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C524942:MIRN155 microRNA, human; C524941:MIRN17 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D059004:Topoisomerase I Inhibitors; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin