Abstract
Abstract Introduction Radiotherapy (RT) has a prominent role when used as a single modality or in combination with androgen deprivation therapy (ADT) in the management of prostate cancer patients. However, even with currently available high-dose RT protocols, many patients develop recurrence or “biochemical failure” associated with a rise in PSA, and ultimately reduced overall survival. Key regulators of cancer cell behavior, dysregulation of miRNAs expression is associated with both prostate cancer pathogenesis and treatment resistance. This study aimed to identify a miRNAs signature of radioresistance in a prostate cancer model, 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. Methods Two models of radioresistance were used : (1) an isogenic radiation resistant model generated through weekly exposure to 2-Gy fractionated ionising radiation of 22Rv1 (primary) prostate cancer (CaP) cells to a cumulative dose of 60Gy. (2) chronically hypoxic 22Rv1 cells (48hrs). miRNA profiling of radioresistant and wild type cells was performed using the Exiqon miRCURY array and overlapping differentially expressed miRs were identified. Results 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 aged-matched 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. Conclusion Available in tissues, serum and urine, miRNAs are ideal candidates for the development of novel biological tests. This study identifies a miRNAs signature of radioresistance in prostate cancer cells with potential for the development of a miRNA-based prognostic assay for radiotherapy prostate cancer patients. Citation Format: Niamh McDermott, Armelle Meunier, Christopher Hernandez, Karen J. Bowman, George D. Jones, Laure Marignol. Identification of a miRNAs signature of radioresistance in a prostate cancer model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3444. doi:10.1158/1538-7445.AM2015-3444
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