Abstract 830: MiRNA-106a and LITAF are novel modulators of prostate cancer radioresistance
Authors: Christianne Hoey, Jessica Ray, Paul Boutros, Stanley K. Liu
Journal: Cancer Research (2017)

Abstract Prostate cancer (PCa) is the second most prevalent cancer affecting men worldwide, with radiotherapy being a primary treatment modality. PCa recurrence is a major clinical problem with up to a 40% biochemical recurrence rate at five years after external beam radiotherapy (ionizing radiation, IR). Therefore, there is an unmet need to characterize radioresistance in order to improve therapy and patient outcomes. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression. MiRNAs are aberrantly expressed in cancer, specifically, miR-106a has been found to be overexpressed in various cancer types. The purpose of this study is to determine whether miR-106a confers IR resistance and tumor aggression in PCa. Utilizing The Cancer Genome Atlas Data Portal, bioinformatics analysis discovered that miR-106a was significantly overexpressed in PCa samples relative to normal prostate. This suggests that miR-106a is involved in prostate carcinogenesis. Clonogenic survival assays revealed that cells overexpressing miR-106a had increased survival after IR treatment compared to control cells. Proliferation assays showed that miR-106a cells had a higher proliferation rate than control cells in both unirradiated and IR-treated cells. Affymetrix gene array analysis was used to identify possible targets of miR-106a. Combining results from the gene array, in silico prediction algorithms, and in vitro analyses, we identified lipopolysaccharide-induced TNFα factor (LITAF) as a target of miR-106a. In addition, LITAF knockdown lead to increased proliferation and clonogenic survival following IR, recapitulating the phenotype of miR-106a overexpression. Cells were stained for β-galactosidase expression following IR to assess senescence, as a mode of cell death. We found that both miR-106a overexpression and LITAF knockdown resulted in significantly fewer senescent cells post-IR. Upon examination of critical DNA damage response genes, we found that miR-106a overexpression and LITAF knockdown increased expression of ATM mRNA and protein. Upregulation of ATM is associated with IR resistance, elucidating the mechanism by which miR-106a overexpression and LITAF knockdown are involved in radioresistance. Tumor xenograft experiments, using a PCa cell line stably overexpressing miR-106a, confirmed that miR-106a increases proliferation compared to control tumors before and after IR. Thus, our results strongly suggest that miR-106a is involved in PCa aggression and confers a radiation-resistant phenotype, by targeting the novel radiation response gene LITAF. Note: This abstract was not presented at the meeting. Citation Format: Christianne Hoey, Jessica Ray, Paul Boutros, Stanley K. Liu. MiRNA-106a and LITAF are novel modulators of prostate cancer radioresistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 830. doi:10.1158/1538-7445.AM2017-830