Genomic profiling of microRNAs in bladder cancer: miR-129 is associated with poor outcome and promotes cell death in vitro.
microRNAs (miRNA) are involved in cancer development and progression, acting as tumor suppressors or oncogenes. Here, we profiled the expression of 290 unique human miRNAs in 11 normal and 106 bladder tumor samples using spotted locked nucleic acid-based oligonucleotide microarrays. We identified several differentially expressed miRNAs between normal urothelium and cancer and between the different disease stages. miR-145 was found to be the most down-regulated in cancer compared with normal, and miR-21 was the most up-regulated in cancer. Furthermore, we identified miRNAs that significantly correlated to the presence of concomitant carcinoma in situ. We identified several miRNAs with prognostic potential for predicting disease progression (e.g., miR-129, miR-133b, and miR-518c*). We localized the expression of miR-145, miR-21, and miR-129 to urothelium by in situ hybridization. We then focused on miR-129 that exerted significant growth inhibition and induced cell death upon transfection with a miR-129 precursor in bladder carcinoma cell lines T24 and SW780 cells. Microarray analysis of T24 cells after transfection showed significant miR-129 target down-regulation (P = 0.0002) and pathway analysis indicated that targets were involved in cell death processes. By analyzing gene expression data from clinical tumor samples, we identified significant expression changes of target mRNA molecules related to the miRNA expression. Using luciferase assays, we documented a direct link between miR-129 and the two putative targets GALNT1 and SOX4. The findings reported here indicate that several miRNAs are differentially regulated in bladder cancer and may form a basis for clinical development of new biomarkers for bladder cancer.
Dyrskjøt
Lars
L
Molecular Diagnostic Laboratory, Department of Molecular Medicine, Aarhus University Hospital, Skejby, DK-8200 Aarhus N, Denmark. lars@ki.au.dk
Ostenfeld
Marie S
MS
Bramsen
Jesper B
JB
Silahtaroglu
Asli N
AN
Lamy
Philippe
P
Ramanathan
Ramshanker
R
Fristrup
Niels
N
Jensen
Jens L
JL
Andersen
Claus L
CL
Zieger
Karsten
K
Kauppinen
Sakari
S
Ulhøi
Benedicte P
BP
Kjems
Jørgen
J
Borre
Michael
M
Orntoft
Torben F
TF
D001706:Biopsy; D002295:Carcinoma, Transitional Cell / Q000235:genetics* / Q000473:pathology; D002478:Cells, Cultured; D016000:Cluster Analysis; D018450:Disease Progression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000502:physiology; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D055751:SOXC Transcription Factors / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology; D000097763:Polypeptide N-acetylgalactosaminyltransferase
D035683:MicroRNAs; D017350:N-Acetylgalactosaminyltransferases; D055751:SOXC Transcription Factors; D000097763:Polypeptide N-acetylgalactosaminyltransferase; C541915:Mirn129 microRNA, human; C083431:SOX4 protein, human