Original study
Expression of microRNAs in the Urine of Patients With Bladder Cancer

https://doi.org/10.1016/j.clgc.2012.01.001Get rights and content

Abstract

Background

MicroRNAs (miRNA) have been implicated to play an important role in the pathogenesis of a variety of cancers. We studied the levels of miRNAs related to epithelial-mesenchymal transition (EMT) in the urine of patients with bladder cancer.

Method

The expression of the miR-200 family, miR-205, miR-192, miR-155, and miR-146a in the urine sediment and supernatant of 51 patients with bladder cancer and in 24 controls was determined by real-time quantitative polymerase chain reaction.

Results

Compared with controls, the patients with bladder cancer had a lower expression of the miR-200 family, miR-192, and miR-155 in the urinary sediment; lower expression of miR-192; and higher expression of miR-155 in the urinary supernatant. The expression of the miR-200 family, miR-205, and miR-192 in the urine sediment significantly correlated with urinary expression of EMT markers, including zinc finger E-box-binding homeobox 1, vimentin, transforming growth factor β1, and Ras homolog gene family, member A. Furthermore, the levels of miR-200c and miR-141 in the urine sediment became normalized after surgery.

Conclusion

We found that the urinary miR-200 family, miR-155, miR-192, and miR-205 levels are depressed in patients with bladder cancer. The level of these miRNA targets in urine has the potential to be developed as noninvasive markers for bladder cancer.

Introduction

Bladder cancer is the second most common malignancy that involves the urinary system. The disease is characterized by frequent recurrence, and the clinical outcome is often poor when the tumor becomes invasive.1 Although a number of risk factors (such as smoking, chemical exposure, race, age, sex, chronic bladder inflammation) have been linked to the development of bladder cancer, the pathogenesis of bladder cancer remains largely unknown.2

MicroRNAs (miRNA) are noncoding, single-stranded RNA molecules of approximately 20 to 22 nucleotides in length that can regulate gene expression at the posttranscriptional level through nucleotide bases pairing between the complementary sequences of miRNAs and the 3'-untranslated regions of messenger RNA (mRNA).3 miRNAs have been shown to play important roles in embryonic development, cancer, and many other physiological and pathologic processes.4 As to bladder cancer, results of previous studies identified novel miRNA targets based on miRNA signatures, with pathologic subtypes of urothelial carcinoma that show distinct miRNA gene expression signatures.5, 6 Notably, members of the miR-200 family appear to control the epithelial-to-mesenchymal transition (EMT) process,7 which is the transcriptional reprogramming that occurs during embryonic development and tissue repair, and plays an important role in the progression and metastasis of bladder cancer.8, 9

Currently, miRNA research in bladder cancer was mostly studied in tumor tissue collected by cystoscopy. For example, a diagnostic test based on the most discriminatory miRNAs showed excellent sensitivity and specificity to identify invasive bladder tumors from bladder biopsy specimens.10 Recently, the miRNA level could be measured in serum and other body fluids.11 In urine, miRNA could be quantified in both the urinary sediment as well as the supernatant after centrifugation,11 and the 2 components probably have different biologic meanings.12, 13 In this study, we investigated the expression of miRNA targets related to the EMT process in urinary sediment as well as the supernatant of patients with bladder cancer.

Section snippets

Subjects

The study was approved by the clinical research ethical committee of the Chinese University of Hong Kong. All the patients provided informed consent. Consecutive patients with newly diagnosed untreated bladder cancer confirmed by biopsy were recruited for the study (Study group). Whole-stream early-morning urine (approximately 300 mL) was collected from the patients before surgery for the bladder tumor, either transurethral resection of bladder tumor (TURBT) or radical cystectomy. In some

Results

Fifty-one patients with bladder cancer confirmed by biopsy (Patient group) and 24 patients who had a history of hematuria but normal urologic workup (Control group) were recruited for the study. Nine study subjects also had post-TURBT urine collected. The baseline demographic and clinical data are summarized in Table 1. The Patient group was significantly older than the Control group (2P < .001). Among the Patient group, 33 had noninvasive papillary transitional cell carcinoma (ie, stage Ta),

Discussion

Results of previous studies showed that the miR-200 family determines the epithelial phenotype of cancer cells, as well as inhibits EMT and cancer cell migration by directly targeting transcriptional repressors of E-cadherin, namely ZEB1 and ZEB2.14 Members of the miR-200 family were found downregulated in a variety of cancers,15, 16 and this phenomenon was associated with EMT and metastasis of cancer cells.17 In line with these previous studies, we found the expression of the miR-200 family in

Disclosure

The authors have stated that they have no conflicts of interest.

Acknowledgment

This study was supported in part by the CUHK research accounts 6,901,031 and 7,101,215.

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