Coordinated epigenetic repression of the miR-200 family and miR-205 in invasive bladder cancer.

Abstract

MicroRNAs (miRNA) are small noncoding RNAs commonly deregulated in cancer. The miR-200 family (miR-200a, -200b, -200c, -141 and -429) and miR-205 are frequently silenced in advanced cancer and have been implicated in epithelial to mesenchymal transition (EMT) and tumor invasion by targeting the transcriptional repressors of E-cadherin, ZEB1 and ZEB2. ZEB1 is also known to repress miR-200c-141 transcription in a negative feedback loop, but otherwise little is known about the transcriptional regulation of the miR-200 family and miR-205. Recently, miR-200 silencing was also reported in cancer stem cells, implying that miR-200 deregulation is a key event in multiple levels of tumor biology. However, what prevents miR-200 expression remains largely unanswered. Here we report concerted transcriptional regulation of the miR-200 and miR-205 loci in bladder tumors and bladder cell lines. Using a combination of miRNA expression arrays, qPCR assays and mass spectrometry DNA methylation analyses, we show that the miR-200 and miR-205 loci are specifically silenced and gain promoter hypermethylation and repressive chromatin marks in muscle invasive bladder tumors and undifferentiated bladder cell lines. Moreover, we report that miR-200c expression is significantly correlated with early stage T1 bladder tumor progression, and propose miR-200 and miR-205 silencing and DNA hypermethylation as possible prognostic markers in bladder cancer. In addition, we observe that the mesoderm transcription factor TWIST1 and miR-200 expression are inversely correlated in bladder tumor samples and cell lines. TWIST1 associates directly with the miR-200 and miR-205 promoters, and may act as a repressor of miR-200 and miR-205 expression.

• Authors: Erik D Wiklund, Jesper B Bramsen, Toby Hulf, Lars Dyrskjøt, Ramshanker Ramanathan, Thomas B Hansen, Sune B Villadsen, Shan Gao, Marie S Ostenfeld, Michael Borre, Marcus E Peter, Torben F Ørntoft, Jørgen Kjems, Susan J Clark
• Journal: International journal of cancer (Int J Cancer) Vol. 128 Issue 6 Pg. 1327-34 (Mar 15 2011) ISSN: 1097-0215 [Electronic] United States
• PMID: 20473948 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 UICC.

Chemical References

• MIRN200 microRNA, human
• MIRN205 microRNA, human
• MicroRNAs

Topics

• Cells, Cultured
• DNA Methylation
• Epigenomics
• Gene Expression Regulation, Neoplastic
• Humans
• MicroRNAs (genetics)
• Neoplasm Invasiveness
• Polymerase Chain Reaction
• Urinary Bladder (metabolism, pathology)
• Urinary Bladder Neoplasms (genetics, pathology)