Bmi-1 promotes the aggressiveness of glioma via activating the NF-kappaB/MMP-9 signaling pathway.
Bmi-1 promotes the aggressiveness of glioma via activating the NF-kappaB/MMP-9 signaling pathway.
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Bmi-1通过激活NF-kappaB/MMP-9信号通路促进胶质瘤的侵袭性
DOI：
10.1186/1471-2407-12-406
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发表时间：
2012-09-11
期刊：
影响因子：
3.8
通讯作者：
Li M
中科院分区：
文献类型：
--
作者：
Jiang L;Wu J;Yang Y;Liu L;Song L;Li J;Li M
背景人脑胶质瘤的预后差，其高度侵袭性是目前治疗的主要障碍。B细胞特异性Moloney鼠白血病病毒整合位点1蛋白（Bmi-1）与胶质瘤的发生发展有关，但Bmi-1在胶质瘤侵袭中的生物学作用尚不清楚。采用创伤愈合实验、Transwell迁移实验、Transwell基质穿透实验和三维球体侵袭实验检测细胞的迁移和侵袭能力。采用实时荧光定量PCR、ELISA和明胶酶谱法检测MMP-9的表达和活性。使用实时PCR定量NF-κ B靶基因的表达。使用NF-κ B荧光素酶报告系统评估NF-κ B转录活性。结果Bmi-1的异位过表达显著增强胶质瘤细胞的侵袭性和迁移性，而内源性Bmi-1的敲低则降低胶质瘤细胞的侵袭性和迁移性。NF-κ B转录活性和MMP-9表达和活性在Bmi-1过表达的细胞中显著增加，但在Bmi-1沉默的细胞中降低。在Bmi-1过表达细胞中，MMP-9启动子驱动的报告荧光素酶活性依赖于NF-κ B结合位点的存在，阻断NF-κ B信号通路可抑制MMP-9在Bmi-1过表达细胞中的上调。结论Bmi-1可能通过激活NF-κ B/MMP-9通路在胶质瘤侵袭表型的形成中发挥重要作用，可能成为胶质瘤治疗的新靶点。
BackgroundThe prognosis of human glioma is poor, and the highly invasive nature of the disease represents a major impediment to current therapeutic modalities. The oncoprotein B-cell-specific Moloney murine leukemia virus integration site 1 protein (Bmi-1) has been linked to the development and progression of glioma; however, the biological role of Bmi-1 in the invasion of glioma remains unclear.MethodsA172 and LN229 glioma cells were engineered to overexpress Bmi-1 via stable transfection or to be silenced for Bmi-1 expression using RNA interfering method. Migration and invasiveness of the engineered cells were assessed using wound healing assay, Transwell migration assay, Transwell matrix penetration assay and 3-D spheroid invasion assay. MMP-9 expression and activity were measured using real-time PCR, ELISA and the gelatin zymography methods. Expression of NF-kappaB target genes was quantified using real-time PCR. NF-kappaB transcriptional activity was assessed using an NF-kappaB luciferase reporter system. Expression of Bmi-1 and MMP-9 in clinical specimens was analyzed using immunohistochemical assay.ResultsEctopic overexpression of Bmi-1 dramatically increased, whereas knockdown of endogenous Bmi-1 reduced, the invasiveness and migration of glioma cells. NF-kappaB transcriptional activity and MMP-9 expression and activity were significantly increased in Bmi-1-overexpressing but reduced in Bmi-1-silenced cells. The reporter luciferase activity driven byMMP-9promoter in Bmi-1-overexpressing cells was dependent on the presence of a functional NF-kappaB binding site, and blockade of NF-kappaB signaling inhibited the upregulation of MMP-9 in Bmi-1 overexpressing cells. Furthermore, expression of Bmi-1 correlated with NF-kappaB nuclear translocation as well as MMP-9 expression in clinical glioma samples.ConclusionsBmi-1 may play an important role in the development of aggressive phenotype of glioma via activating the NF-kappaB/MMP-9 pathway and therefore might represent a novel therapeutic target for glioma.
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作者：
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通讯作者：
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影响因子：
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影响因子：
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作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
11.2
作者：
Liu, Liping;Wu, Jueheng;Li, Mengfeng
通讯作者：
Li, Mengfeng