Cell-Free Urinary MicroRNA-99a and MicroRNA-125b Are Diagnostic Markers for the Non-Invasive Screening of Bladder Cancer

Abstract

BackgroundEvidence implicated the diagnostic significance of microRNAs in whole urine/urine sediments in urothelial carcinoma of the bladder (UCB). However, the contaminated blood cells in patients with haematouria significantly altered the expression profiles of urinary microRNA, influencing the test accuracy.MethodsMicroRNA profiles of the urine supernatants of UCB patients and controls without any malignancy and profiles of malignant and corresponding normal mucosa tissues from the patients were determined by microRNA microarray and compared to identify differentially expressed microRNAs. The differential expression was verified in the tissues of an independent patient cohort by RT-qPCR. The diagnostic significance of selected microRNAs as biomarkers in the urine supernatant was investigated in the expanded cohorts.ResultsMicroRNA-99a and microRNA-125b were down-regulated in the urine supernatants of UCB patients. The degree of down-regulation was associated with the tumor grade. A diagnostic model was developed using a combined index of the levels of microRNA-99a and microRNA-125b in the urine supernatant with a sensitivity of 86.7%, a specificity of 81.1% and a positive predicted value (PPV) of 91.8%. Discriminating between high- and low-grade UCB, the model using the level of microRNA-125b alone exhibited a sensitivity of 81.4%, a specificity of 87.0% and a PPV of 93.4%.ConclusionsThe results revealed a unique microRNA expression signature in the urine supernatants of UCB patients for the development of molecular diagnostic tests. An effective cell-free urinary microRNA-based model was developed using a combined index of the levels of microRNA-99a and microRNA-125b to detect UCB with good discriminating power, high sensitivity and high specificity.

MicroRNAs in urine supernatant as potential non-invasive markers for bladder cancer detection

“…Our results are in partial agreement with the results of previous studies listed in Supplement 1, namely with regard to the decreased levels of miR-99a and miR-125b, found in urine supernatant [18,19]. The partial overlap among different studies may be regarded as the consequence of applications of the broad spectrum of methodological approaches by different researchers [33].…”

“…Previous studies found the decreased levels of miR-125b and miR-99a not only in patient's bladder cancer tissue [17,18,34] in comparison with normal tissue, but also in urine supernatant [18,19].…”

“…This finding confirmed the theory that miR-143 may act as a tumor suppressor. zhang et al [18] analyzed miRNA composition in bladder tissue. They revealed six down-regulated miRNAs (miR-1, miR-99a, miR-125b, miR-133a, miR-133b and miR-143) in cancer tissues.…”

“…Some studies focused on miRNAs in urine supernatant. zhang et al [18] also evaluated the urine supernatant and found four down-regulated miRNAs (miR-99a, miR-125b, miR-133b and miR-143). They proposed miR-99a and miR-125b as a non-invasive marker, whose concentration were significantly lower in the patients' urine and showed a correlation with a tumor grade.…”

Comprehensive investigation of aberrant microRNA profiling in bladder cancer tissues

“…MiR-99a-5p was significantly down-regulated in bladder cancer tissues, and the lower expression of miR-99a was correlated with the more aggressive phenotypes of bladder cancer. Moreover, miR-99a-5p was also decreased in plasma and urine supernatants of bladder cancer patients [24,26,27]. Besides the diagnostic value, miR99a-5p was a predictive marker of OS of bladder cancer by both of studies based on clinical samples and TCGA resource [17,28].…”