Abstract
Recurrence of high‐grade prostate cancer after radiotherapy is a significant clinical problem, resulting in increased morbidity and reduced patient survival. The molecular mechanisms of radiation resistance are being elucidated through the study of microRNA (miR) that negatively regulate gene expression. We performed bioinformatics analyses of The Cancer Genome Atlas (TCGA) dataset to evaluate the association between miR‐106a and its putative target lipopolysaccharide‐induced TNF‐α factor (LITAF) in prostate cancer. We characterized the function of miR‐106a through in vitro and in vivo experiments and employed transcriptomic analysis, western blotting, and 3′UTR luciferase assays to establish LITAF as a bona fide target of miR‐106a. Using our well‐characterized radiation‐resistant cell lines, we identified that miR‐106a was overexpressed in radiation‐resistant cells compared to parental cells. In the TCGA, miR‐106a was significantly elevated in high‐grade human prostate tumors relative to intermediate‐ and low‐grade specimens. An inverse correlation was seen with its target, LITAF. Furthermore, high miR‐106a and low LITAF expression predict for biochemical recurrence at 5 years after radical prostatectomy. miR‐106a overexpression conferred radioresistance by increasing proliferation and reducing senescence, and this was phenocopied by knockdown of LITAF. For the first time, we describe a role for miRNA in upregulating ATM expression. LITAF, not previously attributed to radiation response, mediates this interaction. This route of cancer radioresistance can be overcome using the specific ATM kinase inhibitor, KU‐55933. Our research provides the first report of miR‐106a and LITAF in prostate cancer radiation resistance and high‐grade disease, and presents a viable therapeutic strategy that may ultimately improve patient outcomes.
Highlights
Prostate cancer is the most common nonmelanoma skin cancer affecting men, and a leading cause of cancerrelated death worldwide
This study has identified a new miRNA involved in prostate cancer radiotherapy resistance. miR-106a is significantly upregulated in human prostate tumors, with increased expression in high-grade (Gleason 8–10) compared to low- and intermediate-grade tumors (Gleason 6&7)
We show for the first time a novel role for lipopolysaccharide-induced TNF-a factor (LITAF) in regulating radioresistance, where knockdown of LITAF induces increased survival and proliferation after radiation
Summary
Prostate cancer is the most common nonmelanoma skin cancer affecting men, and a leading cause of cancerrelated death worldwide. Radiation is a primary treatment modality for localized prostate cancer, with equivalent survival outcomes for low- and intermediate-risk patients compared to radical prostatectomy (Hamdy et al, 2016). Despite administration of escalated doses of radiation to the prostate, high-risk patients with prostate cancer are at a significantly higher risk of disease relapse (Chang et al, 2014). The dominant RNA strand is incorporated into the RNA silencing complex to facilitate target mRNA binding, and the complementary strand is degraded (He and Hannon, 2004). MiRNA decrease protein expression of their target mRNA by binding imperfectly to 6–7 nucleotides in the seed sequence in the mRNA 30 untranslated region (UTR) (He and Hannon, 2004). Transcript degradation is the major outcome of miRNA-mRNA binding, occurring through the 50-to-30 mRNA decay pathway (Huntzinger and Izaurralde, 2011)
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