Abstract A134: MiR-875-5p impairs prostate cancer metastasis by remodeling tumor secretome and enhances tumor radiation response via EGFR suppression

Abstract

Abstract Acquisition of mesenchymal features by carcinoma cells through the epithelial-mesenchymal transition (EMT) is responsible for the initiation and sustainment of the metastatic cascade, as well as the establishment of a chemo- and radio-resistant phenotype. In prostate cancer (PCa), metastatic disease remains incurable despite the approval of several new drugs for clinical use in recent years. In addition, emergence of resistance to radiotherapy, which is one of the mostly used therapeutic options for PCa, still represents a clinical challenge. In the study, we reported for the first time on the possible therapeutic utility of miR-875-5p, a microRNA the role of which in human cancer has not been so far investigated. By exploiting the correlation with E-cadherin levels in a series of PCa clinical specimens, we identified miR-875-5p as a novel microRNA able to impair metastasis in PCa experimental models by repressing EMT and remodeling tumor secretome, mainly reducing cytokine secretion. Indeed, the sole intratumoral administration of the culture media obtained from PCa cells ectopically overexpressing miR-875-5p showed antitumor (max tumor volume inhibition: 49%, P<0.01) and antimetastatic (significant reduction of spontaneous dissemination to the lung) effects in SCID mice subcutaneously xenotransplanted with PCa cells. We additionally found that the reversion of EMT operated by miR-875-5p depends at least in part on the repression of epidermal growth factor receptor (EGFR), a direct target of the microRNA as confirmed in a luciferase assay, and consequent reduction of interleukin-8 secretion. Consistent with the known role of EGFR in determining response to ionizing radiation, we found that miR-875-5p overexpression increased the radiosensitivity of PCa cells, in terms of reduced clonogenic cell survival and decreased DNA damage repair, as assessed by γH2AX foci and DNA comet tail in individual cells. Overall, our data support the clinical interest in developing a novel therapeutic approach for PCa based on miR-875-5p reconstitution to counteract tumor dissemination and increase response to radiotherapy. Citation Format: Nicola Fenderico, Denis Cominetti, Rihan El Bezawy, Monica Tortoreto, Matteo Dugo, Riccardo Valdagni, Paolo Gandellini, Nadia Zaffaroni. MiR-875-5p impairs prostate cancer metastasis by remodeling tumor secretome and enhances tumor radiation response via EGFR suppression. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A134.