microRNA expression profile in a large series of bladder tumors: Identification of a 3‐miRNA signature associated with aggressiveness of muscle‐invasive bladder cancer

Abstract

The aim of this study was to evaluate the expression levels of microRNAs (miRNAs) in bladder tumors in order to identify miRNAs involved in bladder carcinogenesis with potential prognostic implications. Expression levels of miRNAs were assessed by quantitative real-time RT-PCR in 11 human normal bladder and 166 bladder tumor samples (86 non-muscle-invasive bladder cancer (NMIBC) and 80 muscle-invasive bladder cancer (MIBC)). The expression level of 804 miRNAs was initially measured in a well-defined series of seven NMIBC, MIBC and normal bladder samples (screening set). The most strongly deregulated miRNAs in tumor samples compared to normal bladder tissue were then selected for RT-PCR validation in a well-characterized independent series of 152 bladder tumors (validation set), and in six bladder cancer cell lines. Expression levels of these miRNAs were tested for their association with clinical outcome. A robust group of 15 miRNAs was found to be significantly deregulated in bladder cancer. Except for two miRNAs, miR-146b and miR-9, which were specifically upregulated in MIBC, the majority of miRNAs (n 5 13) were deregulated in the same way in the two types of bladder tumors, irrespective of pathological stage : three miRNAs were upregulated (miR-200b, miR-182 and miR-138) and the other 10 miRNAs were downregulated (miR-1, miR-133a, miR-133b, miR-145, miR-143, miR-204, miR-921, miR-1281, miR-199a and miR-199b). A 3-miRNA signature (miR-9, miR-182 and miR-200b) was found to be related to MIBC tumor aggressiveness and was associated with both recurrence-free and overall survival in univariate analysis with a trend to significance in the multivariate analysis (p 5 0.05). Our results suggested a promising individual prognostic value of these new markers.

Transformer 2β and miR-204 regulate apoptosis through competitive binding to 3′ UTR of BCL2 mRNA

“…In addition, downregulation of miR-204 has been documented in several types of cancers. [37][38][39][40][41] Decreased expression of miR-204 results in overexpression of its target, myeloid cell leukemia sequence 1 (Mcl-1) mRNA, and induces anti-apoptotic signaling in pancreatic cancers. 42 miR-204 also regulates expression of an oncogene, neurotrophic receptor tyrosine kinase B, and promotes metastasis in endometrial carcinoma.…”

Roles of the canonical myomiRs miR-1, -133 and -206 in cell development and disease

“…downregulated and upregulated myomiRs respectively, and Table 6 lists validated myomiR targets related to enhanced cancer progression. An excellent review by Nohata et al [84] (2012) reported changes in the expression of the miR1/ 133a and miR206/133b cistron clusters in numerous cancers, typically finding reduced expression of different combinations of myomiRs, such as in lung cancer [85] , colorectal cancer [86,87] , rhabdomyosarcoma [88,89] , chordoma [90] osteosarcoma [91] , muscleinvasive bladder cancer [92] , bladder cancer (transitional cell carcinoma) (TCC) [93] , ESCC [94] , breast cancer [95] and prostate cancer [9597] . In different cancers (Figure 3) deregulation typically involves downregulation of one or more myomiR isomers, indicating they normally function as tumor suppressors in the tissues, limiting Metastatic CRC [301] Notch3, Hes1, Bcl-2 and MMP-9; Exogenous upregulation of miR-206 expression;…”

miR-574-3p acts as a tumor promoter in osteosarcoma by targeting SMAD4 signaling pathway

“…miRNAs are critical regulators and biomarkers for numerous types of cancers (8,(21)(22)(23)(24). There are several miRNAs that have been found to be abnormal in human osteosarcoma, including miR-141, miR-429, miR-451, miR-195, miR-183 miR-199a-3p, miR-127-3p and miR-376c (3,5,10,(25)(26)(27). In the present study, it was reported that miR-574-3p was highly expressed in human osteosarcoma cells lines and tissues, and it was indicated that miR-574-3p may be used as a biomarker for the diagnosis of osteosarcoma.…”