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Screening of polycomb Bmi1 targets for development of Cancer Stem Cell-targeted therapy for neuroblastoma

筛选多梳 Bmi1 靶点以开发神经母细胞瘤的癌症干细胞靶向治疗

基本信息

批准号：
21591377
负责人：
KAMIJO Takehiko
金额：
$ 3.08万
依托单位：
Chiba Cancer Center (Research Institute)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2009
资助国家：
日本
起止时间：
2009 至 2011
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21591377/
关键词：
Bmi1 小児腫瘍ポリコームがん幹細胞 BMI1 アポトーシス

项目摘要

We clarified the direct binding of MYCN to Bmi1 promoter and upregulation of Bmi1 transcription by MYCN. A correlation between MYCN and polycomb protein Bmi1 expression was observed in primary NB tumors. Expression of Bmi1 resulted in the acceleration of proliferation and colony formation in NB cells. Bmi1-related inhibition of NB cell differentiation was confirmed by neurite extension assay and analysis of differentiation marker molecules. Intriguingly, the above-mentioned Bmi1-related regulation of the NB cell phenotype seems not to be mediated only by p14ARF/p16INK4a in NB cells. Expression profiling analysis using a tumor-specific cDNA microarray addressed the Bmi1-dependent repression of KIF1Bb and TSLC1, which have important roles in predicting the prognosis of NB. Chromatin immunoprecipitation assay showed that KIF1Bb and TSLC1 are direct targets of Bmi1 in NB cells.Further comprehensive molecular analysis indicated that RUNX3 appears to be a target of Bmi1 and its transcription was suppressed by Bmi1 in several malignancies, including neuroblastoma.Analysis of the molecular mechanism of Bmi1-knockdown-induced apoptosis clarified that DNA damage induced by Bmi1 knockdown has an important role. This apoptosis is dependent on p53 and/or p73 and accompanied by production of reactive oxygen species. Furthermore, we studied the role of the other polycomb group molecules in the Bmi1-knockdown-induced apoptotic cell death.

我们阐明了MYCN与Bmi 1启动子的直接结合以及MYCN对Bmi 1转录的上调。在原发性NB肿瘤中观察到MYCN和多梳蛋白Bmi 1表达之间的相关性。Bmi 1的表达导致NB细胞增殖和集落形成的加速。通过轴突延伸测定和分化标记分子分析证实了Bmi 1相关的NB细胞分化抑制。有趣的是，上述NB细胞表型的Bmi 1相关调节似乎不仅由NB细胞中的p14 ARF/p16 INK 4a介导。使用肿瘤特异性cDNA微阵列的表达谱分析解决了KIF 1Bb和TSLC 1的Bmi 1依赖性抑制，这在预测NB的预后中具有重要作用。染色质免疫沉淀实验表明，KIF 1Bb和TSLC 1是Bmi 1在NB细胞中的直接靶点;进一步的分子分析表明，RUNX 3似乎是Bmi 1的靶点，在包括神经母细胞瘤在内的多种恶性肿瘤中，Bmi 1抑制了RUNX 3的转录;对Bmi 1敲低诱导细胞凋亡的分子机制的分析表明，Bmi 1敲低诱导的DNA损伤具有重要作用。这种凋亡依赖于p53和/或p73，并伴随着活性氧的产生。此外，我们研究了其他polycomb组分子在Bmi 1敲低诱导的凋亡性细胞死亡中的作用。