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) MicroRNAs (miRNA) are a class of $22nt noncoding RNAs that regulate gene expression post-transcriptionally.1 It is widely accepted that miRNA expression is broadly altered in most forms of cancer, 2 and loss of miR-200 family (miR200a, -200b, -200c, -141 and-429) expression has been reported in several types of advanced carcinoma, including bladder cancer. 3,4 Recently, several independent reports have implicated miR-200 and miR-205 in epithelial to mesenchymal transition (EMT), an important event in tumorigenesis associated with a decrease in E-cadherin levels, loss of cell adhesion and subsequent tumor invasion and metastasis. 5-9The miR-200s and miR-205 are key determinators of the epithelial phenotype by directly targeting ZEB1 (also known as TCF8) and ZEB2 (also known as SIP-1), which are transcriptional repressors of E-cadherin (CDH1). Loss of miR-200 expression thus leads to accumulation of ZEB1 and ZEB2, which is sufficient to silence CDH1 and promote EMT and tumor invasion. Interestingly, ZEB1 has been shown to act as a transcriptional repressor of miR-200c and miR-141 by directly interacting with E-and/or Z-box motifs in the miR-200c-141 promoter through a double-negative feedback mechanism. 8,9 However, the mechanisms regulating miR-200 and miR-205 expression remain otherwise largely uncharacterized. A recent study also concluded that ZEB1 is necessary for development and maintenance of stemness in cancer cells, thereby

Diagnostic and prognostic signatures from the small non-coding RNA transcriptome in prostate cancer

“…It has been suggested that the tumorsuppressive function of miR-205 takes place through counteracting epithelial-to-mesenchymal transition and reducing cell migration and invasion in the human prostate (Gandellini et al, 2009;Majid et al, 2010). K27me3 modifications of the miR-205 locus was reported to occur in the PCa cell line PC3 (Ke et al, 2009) and in muscle-invasive bladder tumors and undifferentiated bladder cell lines (Wiklund et al, 2010). These findings, together with the early loss of miR-205 during PCa progression observed by us and others (Porkka et al, 2007;Ambs et al, 2008;Schaefer et al, 2010) present miR-205 as an attractive diagnostic marker for PCa disease.…”

Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity

“…ZEB1 and ZEB2 are regulated by members of the miR-200 family and miR-205 161 . miR-200 is downregulated in bladder cancer cell lines with mesenchymal phenotype and epigenetic silencing is reported in MIBC 162 .…”

Smad3 regulates E-cadherin via miRNA-200 pathway

“…Previous reports showed that miR-200 family members were downregulated in many tumors, including breast, pancreatic and bladder cancers because of hypermethylation of the miR-200 promoter Neves et al, 2010;Vrba et al, 2010;Wiklund et al, 2011). To test whether the downregulation of miR-200 family members in SNU484-LPCX cells resulted from miR-200 promoter hypermethylation, we treated SNU484-LPCX cells with 5-aza-2 0 -deoxycytidine.…”