Journal
ONCOTARGET
Volume 8, Issue 3, Pages 4668-4689Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.13576
Keywords
lncRNA; UCA1; irradiation resistant; prostate cancer; biomarker
Categories
Funding
- Canadian Association of Radiation Oncology (CARO) Fellowship Award
- University of Toronto Postgraduate Medical Education (PGME) Research Awards
- Prostate Cancer Canada (PCC)
- Movember Foundation [RS2014-03, D2015-12, RS2014-01]
- Ministry of Research and Innovation Early Researcher Award
- Telus Motorcycle Ride For Dad
- Dean's Fund (Faculty of Medicine, University of Toronto)
- Prostate Cancer Canada
- Terry Fox Research Institute New Investigator Award
- CIHR New Investigator Award
- Ontario Institute for Cancer Research - Government of Ontario
- Princess Margaret Cancer Centre Foundation
- Radiation Medicine Program Academic Enrichment Fund
- Canadian Cancer Society Research Scientist Award
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Radioresistance remains a significant obstacle in the treatment of Prostate Cancer (PCa). To simulate the clinical scenario of irradiation resistance (IRR), we created DU145-IRR PCa cell lines by treatment with 2 Gy daily IR for 59 fractions. DU145-IRR cells acquired an aggressive phenotype as evidenced by increased clonogenic survival, tumorigenic potential and invasiveness. We performed transcriptome profiling to discover dysregulated genes in DU145-IRR cells and identified the long non-coding RNA (lncRNA), Urothelial carcinoma-associated 1 (UCA1). We first investigated the role of UCA1 in radiation response and found that UCA1 abundance was significantly higher in DU145-IRR cells compared to control cells. UCA1 siRNA-knockdown reversed the aggressive phenotype and significantly increased sensitivity to IR. UCA1 depletion inhibited growth, induced cell cycle arrest at the G2/M transition and decreased activation of the pro-survival Akt pathway. We then studied the clinical significance of UCA1 expression in two independent cohorts of PCa patients: MSKCC (130 patients) and CPC-GENE (209 patients). UCA1 over-expression was associated with decreased 5-year disease-free survival in MSKCC patients (HR = 2.9; p = 0.007) and a trend toward lower biochemical recurrence-free survival in CPC-GENE patients (HR = 2.7; p = 0.05). We showed for the first time that UCA1 depletion induces radiosensitivity, decreases proliferative capacity and disrupts cell cycle progression, which may occur through altered Akt signaling and induced cell cycle arrest at the G2/M transition. Our results indicate that UCA1 might have prognostic value in PCa and be a potential therapeutic target.
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