miRNA Profiling Identifies Candidate miRNAs for Bladder Cancer Diagnosis and Clinical Outcome

Abstract

Bladder cancer is a common cancer in the Western world. The current prognosticators such as tumor grade, stage, size, and multifocality do not accurately reflect the clinical outcome. It is of clinical interest to identify biomarkers that could improve diagnostic and/or prognostic predictions. The objectives of this study were to identify deregulated miRNAs in bladder cancer samples and evaluate their potential as diagnostic and prognostic biomarkers. We screened 723 miRNAs by microarray and selected a subset of 15 distinctively deregulated miRNAs for further validation by real-time quantitative RT-(q)PCR. Seven miRNAs (miR-20a, miR-106b, miR-130b, miR-141, miR-200a, miR-200a*, and miR-205) were found to be up-regulated and eight miRNAs (miR-100, miR-125b, miR-130a, miR-139-5p, miR-145*, miR-199a-3p, miR-214, and miR-222) were found to be down-regulated in malignant bladder tissue samples compared to healthy tissue. Four miRNAs that have already been described in the literature (miR-141, miR-199a-3p, miR-205, and miR-214) were significantly differentially expressed between nonmuscle-invasive and muscle-invasive bladder cancer. Furthermore, real-time RT-qPCR of all miRNAs provided high overall correct classification (>75%) of bladder cancer diagnosis. Two miRNAs (miR-141 and miR-205) were associated with overall survival time. The verification of tumor-specific miRNA expression profile, together with the observed association of miR-141 and miR-205 expression with overall survival, underline the potential of miRNAs to function as diagnostic and/or prognostic markers of bladder cancer.

Clinical and pathological implications of miRNA in bladder cancer

“…Studies show that miR-9, miR-182, and miR200b appear to be related to MIBC tumor aggressiveness and recurrence-free and overall survival. 5,11 Ratert et al 5 observed a correlation between miR-141 and miR-205 expression levels with the overall survival of the patients. Other studies revealed that some miRNAs, particularly miR-126, miR-182, and miR-199a could be found in larger quantities in the urine of bladder cancer patients than in the urine of controls, either healthy subjects or patients with infections.…”

“…16 Despite the limitations caused by the low number of participants, this proofof-concept study provides preliminary data that suggest the practicality of this method for the early detection of bladder cancer. A screening study performed by Ratert et al, 5 using microarray technology followed by a validation step using quantitative reverse transcription polymerase chain reaction (qRT-PCR), reveals a specific miRNA signature containing 15 miRNAs, of which seven (miR-100, miR-125b, miR130a, miR-139-5p, miR-145*, miR-199a-3p, miR-214, and miR-222) were upregulated and eight were downregulated 5 in tumor tissue versus healthy tissue. Furthermore, miR20a, miR-106b, miR-141, and miR-205 were found to be upregulated in bladder cancer, 17,18 in contrast to an inverse expression behavior in other locations such as renal or prostate cancer.…”

“…47 For instance, miR-143, miR-222, and miR-452 detected in urine specimens were clinically useful for noninvasive bladder cancer diagnostics, 6 and miR-9, miR-182, and miR-200b were found to be related to bladder tumor aggressiveness and survival. 48 Moreover, miR-141 and miR-205 were associated with overall survival time, 5 underlining the potential of miRNAs to function as diagnostic and/or prognostic markers for bladder cancer. Studies show that miR-9, miR-182, and miR200b appear to be related to MIBC tumor aggressiveness and recurrence-free and overall survival.…”

“…4 It was observed that 75% of diagnosed bladder cancer cases are localized in the mucosa or submucosa (non-muscleinvasive bladder cancer), whereas in 25% of situations, the tumor cells have already infiltrated the muscle (muscleinvasive bladder cancer [MIBC]). 5 This malignancy has a complex and multifactorial etiology, incorporating both genetic and environmental causes. Two main types of bladder cancers can be described: lowgrade superficial tumors (papillary and multifocal, which occasionally progress to invasive disease and have a good prognosis) and high-grade invasive cancer (nodular, metastasizes in the early phases, and has a poor prognosis).…”

miR-141-3p Suppresses Expression of Androgen Receptors and Functions as a Tumor Suppressor Gene in Prostate Carcinogenesis

“…Using deep-sequencing analysis, we found that miR-141-3p expression was decreased by 1.26-fold in early PCa compared to that in BPH (P < 0.05), and confirmed a similar 1.17-fold decrease in early PCa compared to that in BPH (P = 0.2053) by qRT-PCR. In addition, miR-141-3p expression levels vary in different tumors, with overexpression observed in bladder [16], urothelial [17], breast [18] [19], ovarian [20], endometrioid [21], cholangiocytes [22] and colorectal cancers [23] and NSCLC [24], while expression is downregulated in gastric cancer [25], hepatocellular carcinomas [26] [27], renal cell carcinoma [28], lymphatic metastatic pancreatic cancer [29], pituitary tumors [30], craniopharyngioma [31], head and neck cancer [32], osteosarcoma [33], and cutaneous T cell lymphoma [34]. These reports provide compelling evidence for a role of miR-141-3p as an oncogene or tumor suppressor in different tumors and at different stages.…”