MiR‐96 and miR‐183 detection in urine serve as potential tumor markers of urothelial carcinoma: correlation with stage and grade, and comparison with urinary cytology

Abstract

A new diagnostic marker for urothelial carcinoma (UC) is needed to avoid painful cystoscopy during the initial diagnosis and follow-up period. However, the current urine markers are useless because of the low sensitivities and specificities for UC detection. MiR-96 and miR-183 were differentially upregulated microRNA in our previous microRNA screening for UC. The expression levels of miR-96 and miR-183 in the urine samples were significantly higher in 100 UC than in healthy controls (miR-96, P = 0.0059; and miR-183, P = 0.0044). The receiver-operating characteristic curve analyses demonstrated that each microRNA had good sensitivity and specificity for distinguishing UC patients from non-UC patients (miR-96, 71.0% and 89.2%; and miR-183, 74.0% and 77.3%). Our cohort included 78 UC patients who had undergone urinary cytology. MiR-96 was positively detected in 27 of 44 patients who had had a ''negative'' urinary cytology diagnosis. We combined the miR-96 detection data with the urinary cytology data, and diagnosed 61 of 78 cases as UC; sensitivity rose from 43.6% to 78.2%. We found significant stepwise increases in miR-96 and miR-183 expression with advancing tumor grade (miR-96, P = 0.0057; and miR-183, P = 0.0036) and pathological stage (miR-96, P = 0.0332; and miR-183, P = 0.0117). The expression levels of the microRNA were significantly lower in urine collected after surgery (miR-96, P = 0.0241; and miR-183, P = 0.0045). In conclusion, miR-96 and miR-183 in urine are promising tumor markers for UC. In particular, miR-96 may be a good diagnostic marker in combination with urinary cytology. (Cancer Sci 2011; 102: 522-529) U rothelial carcinoma (UC) is among the five most common malignancies worldwide, and it is the second most common tumor of the genitourinary tract and the second most common cause of death in patients with genitourinary tract malignancies.(1) The current standard of diagnostic tool for UC depends on urethro-cystoscopy. This approach is costly, invasive and uncomfortable. The endoscopic approach using nephroureteroscope is also invasive for patients with upper urinary tract UC (renal pelvic and ureter UC). Urinary cytology is a reliable urine marker for UC diagnosis because of its high specificity (90-95%). In contrast, it has low sensitivity (30-40%) and patients are forced to undergo a painful cystoscopy to confirm diagnoses.(2) For these reasons, many new urine-based tests for UCC have been developed, and Bladder Tumor Antigen (BTA), Nuclear Matrix Protein 22 (NMP22), Urine fibrin fibrinogen Degradation Products (FDP), ImmunoCyt and FISH (UroVysion), etc., have been approved for clinical use.(3,4) However, the specificities of these new urine markers are rather low (60-80%) in comparison with urinary cytology, although they have higher sensitivities (50-70%). This implies that specificity may come at the cost of sensitivity, conventional urinary cytology being a good example of this.(3) Because of their insufficient sensitivity and specificity, none of the new urine markers can replace cys...

miR-183-96-182 Cluster Is Overexpressed in Prostate Tissue and Regulates Zinc Homeostasis in Prostate Cells

“…They further found that expression of these miR along with miR-149, -181b, -205, and -375 correctly identified PC from normal tissue with an area under the curve of 0.88 (34). miR-96 and miR-182 are expressed at a high level in urothelial carcinoma and detection of the miR in urine correlated with disease stage and grade (35). Dai et al (36) recently reported a 10-fold increase in miR-183-96-182 cluster expression in splenocytes in a mouse model of lupus, suggesting a role for this cluster in autoimmunity.…”

Clinical value and potential pathways of miR-183-5p in bladder cancer: A study based on miRNA-seq data and bioinformatics analysis

“…In detail, the expression of miR-183-5p in 104 urothelial carcinomas (4.225±0.414) was significantly higher than that in 31 normal bladder epitheliums (1.224±0.224, P<0.0001) (Fig. 3B) (27). All of the eligible expression data of miR-183-5p extracted from TCGA, one GEO microarray and one literature research provided an overall SMD of 3.76 (0.34-7.19) as analyzed by STATA software (Fig.…”

“…miR-183-5p, located on chromosome 7q32.2, has been studied in various types of cancers, such as human breast cancer (20), esophageal squamous cell carcinoma (21), esophageal squamous cell carcinoma (22), gastric cancer (23), human pancreatic adenocarcinoma (24) and melanoma (25). The expression of miR-183 in BC patients was higher in tissues (26)(27)(28) and serum (29) and showed a moderate value of the BC diagnosis (27). However, no functional study of miR-183-5p in BC has been reported previously.…”

“…Most of the published studies on miR-183-5p tended to focus on the higher expression of miR-183-5p in samples from patients with BC, including tissues, urine and serum, than in samples from normal individuals, or the diagnostic efficiency of miR-183-5p. However, the clinical significance, as well as the promising target genes of miR-183-5p in BC, needs to be explored (26)(27)(28)(29). In addition, the studies mentioned above were based on a small scale of BC patient cohorts, and big data analysis was needed to uncover the real role of miR-183-5p in BC.…”

MicroRNA-183/182/96 cooperatively regulates the proliferation of colon cancer cells

“…Mihelich et al (26) identified the members of this cluster as having diagnostic and prognostic implications in prostate cancer. In addition, Yamada et al (27) identified two members of the cluster, miR-96 and miR-183 serve as potential tumor markers of urothelial carcinoma and Weeraratne et al (28) reported that the effects of the miR-183/96/182 cluster converge to regulate cell survival, proliferation and migration in medulloblastoma. The miR-183/96/182 cluster was also found to regulate oxidative apoptosis and sensitize cells to chemotherapy in gliomas (16,(25)(26)(27)(28)(29).…”