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2017 ; 8
(3
): 4668-4689
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Long non-coding RNA urothelial carcinoma associated 1 (UCA1) mediates radiation
response in prostate cancer
#MMPMID27902466
Fotouhi Ghiam A
; Taeb S
; Huang X
; Huang V
; Ray J
; Scarcello S
; Hoey C
; Jahangiri S
; Fokas E
; Loblaw A
; Bristow RG
; Vesprini D
; Boutros P
; Liu SK
Oncotarget
2017[Jan]; 8
(3
): 4668-4689
PMID27902466
show ga
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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