EP-1237: Identification of MiRNAs associated with radioresistance in a prostate cancer model

N. McDermott, A. Meunier, C. Hernandez, K.J. Bowman, G.D. Jones, L. Marignol
2015 Radiotherapy and Oncology  
Purpose/Objective: High risk of tumour regrowth following treatment with radiation therapy for a subset of prostate cancer patients highlights the need for prognostic biomarkers. miRNAs are key regulators of cancer cell behavior that could control their response to ionizing radiation. Owing to their availability in tissues, serum and urine, miRNAs are ideal candidates for the development of novel biological tests. This study aimed to identify key miRNAs associated with a radioresistant
more » ... oresistant phenotype in cancer cells, as a prerequisite for the future development of a novel pre-treatment assay for the identification of radiotherapy prostate cancer patients at risk of biochemical failure. Materials and Methods: A dual approach was used for the identification of candidate miRNAs associated with radioresistance: (1) an isogenic radiation resistant model was generated using the 22Rv1 (primary) prostate cancer (CaP) cell line through weekly exposure to 2-Gy fractionated ionising radiation. (2) chronically hypoxic 22Rv1 cells (48hrs) were used as an additional model for radioresistance. miRNA profiling of radioresistant and wild type cells was performed using the Exiqon miRCURY array and overlapping differentially expressed miRs were identified. Results: Following a cumulative total dose of 60Gy, the radiation survival curve of the resulting subline RR22Rv1 was associated with a significant increase in clonogenic survival (1.3 fold increase in survival after 2Gy and 2.2 fold increase after 10Gy), when compared to both parent 22Rv1 and agedmatched controls. The RR22Rv1 cell line is associated with decreased sensitivity to DNA damage (comet assay), enlargement of the S-phase cell population (PI staining) but no evidence for expansion of the senescent cell fraction (β-Gal assay). miRNA profiling identified 105 significantly differentially expressed miRNAs in RR22Rv1, when compared to the parent and age-matched control 22RV1 cells. A total of 12 miRNA were differentially expressed in chronically hypoxic compared to normoxic 22Rv1 cells. Three candidate miRNAs were associated with a radioresistant phenotype across the models: miR200a, miR210 and miR4284. Functional validation of these candidates is currently under way. Conclusions: This study demonstrates a role for miRNAs in the radioresponse of prostate cancer cells and highlights their potential for the development of novel prognostic biomarkers for radiotherapy prostate cancer patients.
doi:10.1016/s0167-8140(15)41229-0 fatcat:nrrejksy5jgyxhvf72aisataoe