title: Long non-coding RNA urothelial carcinoma associated 1 (UCA1) mediates radiation response in prostate cancer.
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.
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada.|Department of Radiation Oncology, University of Toronto, Toronto, Canada.
authors.forename: Alireza
authors.initials: A
authors.lastname: Fotouhi Ghiam
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada.
authors.forename: Samira
authors.initials: S
authors.lastname: Taeb
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada.
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Huang
authors.affiliation: Ontario Institute for Cancer Research, University of Toronto, Toronto, Canada.
authors.forename: Vincent
authors.initials: V
authors.lastname: Huang
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Canada.
authors.forename: Jessica
authors.initials: J
authors.lastname: Ray
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada.
authors.forename: Seville
authors.initials: S
authors.lastname: Scarcello
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Canada.
authors.forename: Christianne
authors.initials: C
authors.lastname: Hoey
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada.
authors.forename: Sahar
authors.initials: S
authors.lastname: Jahangiri
authors.affiliation: Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Fokas
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada.|Department of Radiation Oncology, University of Toronto, Toronto, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Loblaw
authors.affiliation: Department of Radiation Oncology, University of Toronto, Toronto, Canada.|Ontario Institute for Cancer Research, University of Toronto, Toronto, Canada.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Bristow
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada.|Department of Radiation Oncology, University of Toronto, Toronto, Canada.
authors.forename: Danny
authors.initials: D
authors.lastname: Vesprini
authors.affiliation: Ontario Institute for Cancer Research, University of Toronto, Toronto, Canada.|Department of Medical Biophysics, University of Toronto,, Toronto, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Boutros
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada.|Department of Radiation Oncology, University of Toronto, Toronto, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Canada.
authors.forename: Stanley K
authors.initials: SK
authors.lastname: Liu
mesh_terms: D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D060787:Neoplasm Grading; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology* / Q000532:radiotherapy; D062085:RNA, Long Noncoding / Q000235:genetics*; D011836:Radiation Tolerance; D016019:Survival Analysis; D015854:Up-Regulation
chemical_list: D062085:RNA, Long Noncoding; C515159:UCA1 RNA, human
keywords: UCA1; biomarker; irradiation resistant; lncRNA; prostate cancer