Cancer Research Institute and Cancer Hospital, Guangzhou Medical University, Guangzhou, Guangdong, P. R. China.
PLoS One. 2013 Sep 9;8(9):e73268. doi: 10.1371/journal.pone.0073268. eCollection 2013.
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.
多梳组转录修饰因子 Bmi1 在许多癌症中常被上调，它在正常和癌症干细胞中都有强烈的作用，并且是某些癌症的预后指标，但它在乳腺癌中的作用尚不清楚。在这里，我们发现 5-氟尿嘧啶（5-Fu）耐药 MCF-7 细胞（MCF-7/5-Fu）中 Bmi1 的过表达，与 MCF-7 细胞相比，MCF-7 乳腺癌细胞、MDA-MB-231 和 MDA-MB-453 乳腺癌细胞中的 Bmi1 过表达与 5-Fu 耐药和 CD44(+)/CD24(-)干细胞亚群的富集有关。Bmi1 敲低增强了乳腺癌细胞对 5-Fu 的敏感性，并通过线粒体凋亡途径诱导 5-Fu 诱导的细胞凋亡，减少了 CD44(+)/CD24(-)亚群的比例。此外，我们的分析表明，在选定的乳腺癌细胞系中，Bmi1 与 miR-200c 和 miR-203 之间存在相反的表达模式，并且通过荧光素酶报告基因测定证实，miR-200c 和 miR-203 直接在蛋白质水平上抑制 Bmi1 的表达。乳腺癌细胞中 miR-200c 和 miR-203 的过表达下调了 Bmi1 的表达，同时逆转了由 Bmi1 介导的对 5-Fu 的耐药性。相反，Bmi1 在 MCF-7 细胞中的过表达抑制了 miR-200c 的表达，但不抑制 miR-203 的表达，然而外源性野生型 p53 的表达逆转了 Bmi1 介导的 miR-200c 下调，表明 Bmi1 对 miR-200c 的抑制作用可能依赖于 p53。因此，我们的研究表明，Bmi1 和 miR-200c 之间存在由 p53 介导的交叉对话，通过诱导敏感凋亡和抑制癌症干细胞富集，Bmi1 的干扰可以提高乳腺癌的化疗效率。
