BACKGROUND: Dysregulation of microRNAs (miRNAs) has been implicated in bladder cancer (BCa), although the mechanism is not fully understood.
OBJECTIVE: We aimed to explore the involvement of epigenetic alteration of miRNA expression in BCa.
DESIGN, SETTING AND PARTICIPANTS: Two BCa cell lines (T24 and UM-UC-3) were treated with 5-aza-2'-deoxycytidine (5-aza-dC) and 4-phenylbutyric acid (PBA), after which their miRNA expression profiles were analyzed using a TaqMan array (Life Technologies, Carlsbad, CA, USA). Bisulfite pyrosequencing was used to assess miRNA gene methylation in 5 cancer cell lines, 83 primary tumors, and 120 preoperative and 47 postoperative urine samples.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Receiver operating characteristic (ROC) curve analysis was used to assess the diagnostic performance of the miRNA gene panel.
RESULTS AND LIMITATIONS: Of 664 miRNAs examined, 146 were upregulated by 5-aza-dC plus PBA. CpG islands were identified in the proximal upstream of 23 miRNA genes, and 12 of those were hypermethylated in cell lines. Among them, miR-137, miR-124-2, miR-124-3, and miR-9-3 were frequently and tumor-specifically methylated in primary cancers (miR-137: 68.7%; miR-124-2: 50.6%; miR-124-3: 65.1%; miR-9-3: 45.8%). Methylation of the same four miRNAs in urine specimens enabled BCa detection with 81% sensitivity and 89% specificity; the area under the ROC curve was 0.916. Ectopic expression of silenced miRNAs in BCa cells suppressed growth and cell invasion.
CONCLUSIONS: Our results indicate that epigenetic silencing of miRNA genes may be involved in the development of BCa and that methylation of miRNA genes could be a useful biomarker for cancer detection.
Written by:
Shimizu T, Suzuki H, Nojima M, Kitamura H, Yamamoto E, Maruyama R, Ashida M, Hatahira T, Kai M, Masumori N, Tokino T, Imai K, Tsukamoto T, Toyota M. Are you the author?
Department of Urology, Sapporo Medical University, Sapporo, Japan; Department of Molecular Biology, Sapporo Medical University, Sapporo, Japan.
Reference: Eur Urol. 2012 Nov 23. pii: S0302-2838(12)01405-4(Epub ahead of print)
doi: 10.1016/j.eururo.2012.11.030
PubMed Abstract
PMID: 23200812
