Dissecting the Role of microRNAs in the Radiation Response of Human Prostate Cancer

El Bezawy, Rihan (2018). Dissecting the Role of microRNAs in the Radiation Response of Human Prostate Cancer. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000d9df

Abstract

Radiotherapy is one of the gold standard treatments 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.

To identify miRNAs likely to be involved in influencing PCa radiation response, we first performed miRNA profiling analysis of PCa cell lines exposed to photon irradiation. Based on their modulation upon radiation exposure, and their role in regulating pathways associated with radiation response we singled-out and characterized miR-23a-3p and miR-24-3p as potential radiosensitizer molecules in PCa, unrevealing a central role of miR- 23a-3p-IL-6 axis.

In the framework of miRNAs downregulated in PCa and known to regulate genes relevant to radiation, miR-875-5p and miR-205 were identified. Reconstitution of miR-875-5p, the expression of which 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, we found that miR-875-5p reconstitution in PCa cells counteracted EMT and impaired DNA lesion clearance, mainly via impairment of EGFR-ZEB1 axis.

Restoration of miR-205 was able to significantly enhance PCa sensitivity to radiation, in both cell and animal models. Specifically, we found that miR-205 radiosensitizing effect was imputable to the downregulation of PKC-ε. Consistent with PKC-ε well-established role in DNA damage repair, we found that pEGFR and, consequently, pDNA-PK levels were significantly reduced by miR-205 reconstitution, thus suggesting that miR-205 enhances PCa radiation response via disruption of PKC-ε−EGFR−DNA-PK axis.

Overall, the results of this project support the clinical interest in developing novel therapeutic approaches based on miRNA reconstitution (miR-23a-3p, miR-875-5p and miR-205) to enhance PCa response to radiotherapy.