title: miR-875-5p counteracts epithelial-to-mesenchymal transition and enhances radiation response in prostate cancer through repression of the EGFR-ZEB1 axis.
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.
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy. Electronic address: Rihan.elbezawy@istitutotumori.mi.it.
authors.forename: Rihan
authors.initials: R
authors.lastname: El Bezawy
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy. Electronic address: Denis.cominetti@istitutotumori.mi.it.
authors.forename: Denis
authors.initials: D
authors.lastname: Cominetti
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy. Electronic address: N.Fenderico@umcutrecht.nl.
authors.forename: Nicola
authors.initials: N
authors.lastname: Fenderico
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy. Electronic address: Valentina.zuco@istitutotumori.mi.it.
authors.forename: Valentina
authors.initials: V
authors.lastname: Zuco
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy. Electronic address: Giovanni.Beretta@istitutotumori.mi.it.
authors.forename: Giovanni Luca
authors.initials: GL
authors.lastname: Beretta
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy. Electronic address: Matteo.dugo@istitutotumori.mi.it.
authors.forename: Matteo
authors.initials: M
authors.lastname: Dugo
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy. Electronic address: Noemi.arrighetti@istitutotumori.mi.it.
authors.forename: Noemi
authors.initials: N
authors.lastname: Arrighetti
authors.affiliation: Unit of Medical Physics, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy. Electronic address: Claudio.Stucchi@istitutotumori.mi.it.
authors.forename: Claudio
authors.initials: C
authors.lastname: Stucchi
authors.affiliation: Prostate Cancer Program, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy. Electronic address: Tiziana.rancati@istitutotumori.mi.it.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Rancati
authors.affiliation: Prostate Cancer Program, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy; Radiation Oncology 1, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy. Electronic address: Riccardo.valdagni@istitutotumori.mi.it.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Valdagni
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy. Electronic address: nadia.zaffaroni@istitutotumori.mi.it.
authors.forename: Nadia
authors.initials: N
authors.lastname: Zaffaroni
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy. Electronic address: Paolo.gandellini@istitutotumori.mi.it.
authors.forename: Paolo
authors.initials: P
authors.lastname: Gandellini
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004260:DNA Repair; D058750:Epithelial-Mesenchymal Transition; D066246:ErbB Receptors / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D011836:Radiation Tolerance; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000502:physiology*
chemical_list: C000606835:MIRN-875 microRNA, human; D035683:MicroRNAs; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D066246:ErbB Receptors
keywords: EGFR; EMT; Prostate cancer; Radiosensitivity; microRNAs