The polycomb group protein Bmi-1 represses the tumor suppressor PTEN and induces epithelial-mesenchymal transition in human nasopharyngeal epithelial cells
The polycomb group protein Bmi-1 represses the tumor suppressor PTEN and induces epithelial-mesenchymal transition in human nasopharyngeal epithelial cells
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多梳族蛋白 Bmi-1 抑制肿瘤抑制因子 PTEN，并诱导人鼻咽上皮细胞上皮间质转化。
DOI：
10.1172/jci39374
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发表时间：
2009-12-01
影响因子：
15.9
通讯作者：
Zeng, Mu-Sheng
中科院分区：
文献类型：
--
作者：
Song, Li-Bing;Li, Jun;Zeng, Mu-Sheng
多梳族蛋白 B 淋巴瘤 Mo-MLV 插入区 1 同源物 (Bmi-1) 在多种癌症中失调，其上调与鼻咽癌患者的侵袭性表型和不良预后密切相关。然而，Bmi-1 介导的侵袭性的潜在机制仍不清楚。在目前的研究中，我们发现Bmi-1的上调诱导上皮间质转化（EMT）并增强人鼻咽上皮细胞的运动性和侵袭性，而沉默内源性Bmi-1表达则逆转EMT并降低运动性。此外，Bmi-1 的上调通过调节 PI3K/Akt/GSK-3beta 信号传导导致 Snail（一种与 EMT 相关的转录抑制因子）的稳定。染色质免疫沉淀分析显示，Bmi-1 通过与 PTEN 位点直接关联，转录下调肿瘤细胞中肿瘤抑制因子 PTEN 的表达。该体外分析与在一组人鼻咽癌活检中检测到的 Bmi-1 和 PTEN 表达之间的统计负相关一致。此外，PTEN表达的消除部分挽救了Bmi-1沉默细胞的迁移/侵袭表型，表明PTEN可能是Bmi-1诱导的EMT的主要介质。我们的结果提供了癌蛋白 Bmi-1 和肿瘤抑制因子 PTEN 在癌症发生和进展中的功能和机制联系。
The polycomb group protein B lymphoma Mo-MLV insertion region 1 homolog (Bmi-1) is dysregulated in various cancers, and its upregulation strongly correlates with an invasive phenotype and poor prognosis in patients with nasopharyngeal carcinomas. However, the underlying mechanism of Bmi-1-mediated invasiveness remains unknown. In the current study, we found that upregulation of Bmi-1 induced epithelial-mesenchymal transition (EMT) and enhanced the motility and invasiveness of human nasopharyngeal epithelial cells, whereas silencing endogenous Bmi-1 expression reversed EMT and reduced motility. Furthermore, upregulation of Bmi-1 led to the stabilization of Snail, a transcriptional repressor associated with EMT, via modulation of PI3K/Akt/GSK-3beta signaling. Chromatin immunoprecipitation assays revealed that Bmi-1 transcriptionally downregulated expression of the tumor suppressor PTEN in tumor cells through direct association with the PTEN locus. This in vitro analysis was consistent with the statistical inverse correlation detected between Bmi-1 and PTEN expression in a cohort of human nasopharyngeal carcinoma biopsies. Moreover, ablation of PTEN expression partially rescued the migratory/invasive phenotype of Bmi-1-silenced cells, indicating that PTEN might be a major mediator of Bmi-1-induced EMT. Our results provide functional and mechanistic links between the oncoprotein Bmi-1 and the tumor suppressor PTEN in the development and progression of cancer.