Oncotarget

Research Papers:

Long non-coding RNA urothelial carcinoma associated 1 (UCA1) mediates radiation response in prostate cancer

Alireza Fotouhi Ghiam, Samira Taeb, Xiaoyong Huang, Vincent Huang, Jessica Ray, Seville Scarcello, Christianne Hoey, Sahar Jahangiri, Emmanouil Fokas, Andrew Loblaw, Robert G. Bristow, Danny Vesprini, Paul Boutros and Stanley K. Liu _

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Oncotarget. 2017; 8:4668-4689. https://doi.org/10.18632/oncotarget.13576

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Abstract

Alireza Fotouhi Ghiam1,2, Samira Taeb1, Xiaoyong Huang1, Vincent Huang3, Jessica Ray1,4, Seville Scarcello1, Christianne Hoey1,4, Sahar Jahangiri1, Emmanouil Fokas5, Andrew Loblaw1,2, Robert G. Bristow2,3, Danny Vesprini1,2, Paul Boutros3,4, Stanley K. Liu1,2,4

1Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada

2Department of Radiation Oncology, University of Toronto, Canada

3Ontario Institute for Cancer Research, University of Toronto, Canada

4Department of Medical Biophysics, University of Toronto, Canada

5Oxford Institute for Radiation Oncology, University of Oxford, UK

Correspondence to:

Stanley K. Liu, email: stanley.liu@sunnybrook.ca

Keywords: lncRNA, UCA1, irradiation resistant, prostate cancer, biomarker

Received: May 26, 2016    Accepted: November 06, 2016    Published: November 24, 2016

ABSTRACT

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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