Journal
ONCOTARGET
Volume 6, Issue 39, Pages 42258-42275Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.5546
Keywords
miRNA; Polycomb; bladder cancer; recurrence; epigenetics
Categories
Funding
- Juan de la Cierva [JCI-2010-06167]
- EMBO [EMBO ASTF 81-2014/Award]
- MINECO [SAF2012-34378]
- Comunidad Autonoma de Madrid (Oncocycle Program) [S2010/BMD-2470]
- AES [ISCIII-RETIC RD12/0036/0009]
- MMA Foundation [AP99782012]
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Bladder cancer (BC) is a highly prevalent disease, ranking fifth in the most common cancers worldwide. Various miRNAs have recently emerged as potential prognostic biomarkers in cancer. The miR-200 family, which repressed the epithelial-to-mesenchymal transition (EMT), is repressed in multiple advanced cancers. However, its expression and function in BC is still poorly understood. Here we show that miR-200 family displays increased expression, probably due to the activation of specific oncogenic signaling pathways, and reduced promoter methylation, in BC compared to normal bladder samples. Furthermore, we show that the expression of these miRNAs is decreased in high grade and stage tumors, and the down-regulation is associated with patient's poor clinical outcome. Our data indicate that the miR-200 family plays distinct roles in Non-Muscle (NMIBC) and Muscle-Invasive BC (MIBC). In MIBC, miR-200 expression post transcriptionally regulates EMT-promoting transcription factors ZEB1 and ZEB2, whereas suppresses BMI1 expression in NMIBC. Interestingly, we show that increased EZH2 and/or BMI1 expression repress the expression of miR-200 family members. Collectively, these findings support a model of BC progression through a coordinated action between the Polycomb Repression Complex (PRC) members repressing the miR-200 expression, which ultimately favors invasive BC development. Since pharmacological inhibition of EZH2 in BC cell lines lead to increased miR-200 expression, our findings may support new therapeutic strategies for BC clinical management.
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