Urine exosomal lncRNAs as novel biomarkers for early diagnosis of bladder cancer based on microarray differential expression profiling.

Abstract

Purpose: We aimed to exploit a urine exosomal long non-coding RNAs (lncRNAs) fingerprint to facilitate the early diagnosis of bladder cancer.

Methods: Microarray differential expression profiling of lncRNAs was for the first time employed in urine exosomes from 10 non-muscle-invasive bladder cancer (NMIBC) patients and 10 healthy controls to screen out candidate exosomal lncRNA biomarkers, which were then verified by quantitative real-time polymerase chain reaction in three independent phases including bladder cancer cells, culture fluid and 200 NMIBC participants. Logistic regression was performed to construct a diagnostic model-the diagnostic potency of which was assessed.

Results: The profile of three exosome-derived lncRNAs (CCDC148-AS1, XLOC_006419, and RP5-1148A21.3) was screened and further verified to be notably over-expressed in NMIBC patients and bladder cancer cell lines, and exhibited area under the receiver-operating characteristic curve values of 0.873, 0.825, and 0.834, respectively, in training, validation, and double-blind validation phases. The profile was superior to urinary cytology in discriminating NMIBC from healthy controls (P < 0.0001). A significant correlation existed between a higher level of CCDC148-AS1 and a higher tumor grade (P < 0.001), and up-regulated CCDC148-AS1 as well as XLOC_006419 were statistically related with tumor node metastasis stage (P = 0.004 and P = 0.031, respectively). These three identified lncRNAs were confirmed to originate from bladder cancer cells and be packaged within exosomes, thus staying sufficiently stable in urine.

Conclusions: Tumor-originated urine exosomal lncRNAs, as fingerprint in NMIBC, exhibited satisfying clinical significance in early diagnosis of bladder cancer.