A Bmi1-miRNAs Cross-Talk Modulates Chemotherapy Response to 5-Fluorouracil in Breast Cancer Cells

作者：Yin, Jiang; Zheng, Guopei; Jia, Xiaoting; Zhang, Zhijie; Zhang, Weijia; Song, Ying; Xiong, Yan; He, Zhimin^*

来源：PLos One, 2013, 8(9): e73268.

DOI：10.1371/journal.pone.0073268

• EPITHELIAL-MESENCHYMAL TRANSITION
• MULTIPLE-DRUG RESISTANCE
• STEM-CELLS
• BMI-1
• CHEMORESISTANCE
• MICRORNAS
• IDENTIFICATION
• EXPRESSION
• INK4A-ARF
• THERAPY

The polycomb group transcriptional modifier Bmi1 is often upregulated in numerous cancers and is intensely involved in normal and cancer stem cells, and importantly is as a prognostic indicator for some cancers, but its role in breast cancer remains unclear. Here, we found Bmi1 overexpression in 5-Fu (5-fluorouracil)-resistant MCF-7 cells (MCF-7/5-Fu) derived from MCF-7 breast cancer cells, MDA-MB-231 and MDA-MB-453 breast cancer cells compared to MCF-7 cells, was related with 5-Fu resistance and enrichment of CD44(+)/CD24(-) stem cell subpopulation. Bmi1 knockdown enhanced the sensitivity of breast cancer cells to 5-Fu and 5-Fu induced apoptosis via mitochondrial apoptotic pathway, and decreased the fraction of CD44(+)/CD24(-) subpopulation. In addition, our analysis showed inverse expression pattern between Bmi1 and miR-200c and miR-203 in selected breast cancer cell lines, and miR-200c and miR-203 directly repressed Bmi1 expression in protein level confirmed by luciferase reporter assay. MiR-200c and miR-203 overexpression in breast cancer cells downregulated Bmi1 expression accompanied with reversion of resistance to 5-Fu mediated by Bmi1. Inversely, Bmi1 overexpression inhibited miR-200c expression in MCF-7 cells, but not miR-203, however ectopic wild-type p53 expression reversed Bmi1 mediated miR-200c downregulation, suggesting the repressive effect of Bmi1 on miR-200c maybe depend on p53. Thus, our study suggests a cross-talk between Bmi1 and miR-200c mediated by p53, and Bmi1 interference would improve chemotherapy efficiency in breast cancer via susceptive apoptosis induction and cancer stem cell enrichment inhibition.

• 出版日期2013-9-9
• 单位广州医科大学