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  2. The natural inhibitor of DNA topoisomerase I, camptothecin, modulates HIF-1α activity by changing miR expression patterns in human cancer cells

The natural inhibitor of DNA topoisomerase I, camptothecin, modulates HIF-1α activity by changing miR expression patterns in human cancer cells

  • Mol Cancer Ther. 2014 Jan;13(1):239-48. doi: 10.1158/1535-7163.MCT-13-0729.
Davide Bertozzi 1 Jessica Marinello Stefano G Manzo Francesca Fornari Laura Gramantieri Giovanni Capranico
Affiliations

Affiliation

  • 1 Corresponding Author: G. Capranico, Department of Pharmacy and Biotechnology, University of Bologna, via Irnerio 48, 40126 Bologna, Italy. giovanni.capranico@unibo.it.
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.

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