miR-875-5p counteracts epithelial-to-mesenchymal transition and enhances radiation response in prostate cancer through repression of the EGFR-ZEB1 axis.

Rihan El Bezawy, Denis Cominetti, Nicola Fenderico, Valentina Zuco, Giovanni Luca Beretta, Matteo Dugo, Noemi Arrighetti, Claudio Stucchi, Tiziana Rancati, Riccardo Valdagni, Nadia Zaffaroni, Paolo Gandellini

Research output: Contribution to journalArticlepeer-review

Abstract

Radiotherapy is one of the main treatment choices for non-metastatic prostate cancer (PCa), although development of radioresistance limits its effectiveness. Mounting evidence supports the ability of microRNAs to interfere with different radioresistance-associated pathways, suggesting their potential as radiosensitizers. Here, we demonstrate that reconstitution of miR-875-5p, whose expression is down-regulated in PCa clinical samples and directly correlates with that of E-cadherin, was able to enhance radiation response in PCa cell lines and xenografts through EGFR direct targeting. Consistent with the established role of EGFR in sustaining epithelial-to-mesenchymal transition (EMT) and promoting DNA repair following radiation-induced nuclear translocation, we found that miR-875-5p reconstitution in PCa cells counteracted EMT and impaired DNA lesion clearance. Down-regulation of the EMT-inducing transcription factor ZEB1, which also plays a role in homologous recombination-mediated repair of DNA lesions by regulating CHK1 expression, was found to be a major determinant of miR-875-5p-induced radiosensitization, as confirmed by phenocopy experiments showing that siRNA-mediated ZEB1 knock-down was able to reproduce the microRNA radiosensitizing effect. Overall, our data support the clinical interest in developing a novel therapeutic approach based on miR-875-5p reconstitution to increase PCa response to radiotherapy.
Original languageUndefined/Unknown
Pages (from-to)53-62
Number of pages10
JournalCancer Letters
Volume395
DOIs
Publication statusPublished - Mar 1 2017

Keywords

  • EGFR, EMT, microRNAs, Prostate cancer, Radiosensitivity

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