E-MTAB-2022 - microRNA profiling by array to identify Camptothecin induced modification of miRNAs targeting HIF-1alpha mRNA under hypoxic-mimetic conditions
Released on 2 December 2013, last updated on 3 June 2014
DNA Topoisomerase I inhibition by Camptothecin (CPT) derivatives can impair the hypoxia-induced cell transcriptional response. In the present work, we determined molecular aspects of the mechanism of CPT effects on HIF-1alpha activity in human cancer cells. In particular, we provide evidence that low concentrations of CPT, without interfering with HIF-1alpha mRNA levels, can reduce HIF-1alpha protein expression and activity. As luciferase assays demonstrated the involvement of the HIF-1alpha mRNA 3’UTR in CPT-induced impairment of HIF-1alpha protein regulation, we performed microarray analysis to identify CPT-induced modification of miRNAs targeting HIF-1alpha mRNA under hypoxic-mimetic conditions. The selected miRNAs were then further analyzed demonstrating a role for miR-17-5p and miR-155 in HIF-1alpha protein expression after CPT treatments. The present findings establish miRNAs as key factors in a molecular pathway connecting Top1 inhibition and human HIF-1alpha protein regulation and activity, widening the biological and molecular activity of CPT derivatives and the perspective for novel clinical interventions.
microRNA profiling by array, co-expression, compound treatment design, in vitro, replicate design
The natural inhibitor of DNA topoisomerase I, camptothecin, modulates HIF-1alpha activity by changing miR expression patterns in human cancer cells. Davide Bertozzi; Jessica Marinello; Stefano G. Manzo; Francesca Fornari; Laura Gramantieri; Giovanni Capranico;.