The polycomb gene product BMI1 contributes to the maintenance of tumor-initiating side population cells in hepatocellular carcinoma
The polycomb gene product BMI1 contributes to the maintenance of tumor-initiating side population cells in hepatocellular carcinoma
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DOI：
10.1158/0008-5472.can-07-5882
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发表时间：
2008-10-01
期刊：
影响因子：
11.2
通讯作者：
Iwama, Atsushi
中科院分区：
文献类型：
--
作者：
Chiba, Tetsuhiro;Miyagi, Satoru;Iwama, Atsushi
侧群（SP）细胞分析和分选已成功应用于肝细胞癌（HCC）细胞系，以识别具有癌症干细胞特性的小细胞群。然而，SP细胞中的分子机制仍不清楚。polycomb基因产物BMI 1在多种组织和器官中的体干细胞的自我更新中起核心作用，并且似乎与肿瘤的发展有关。在这项研究中，我们确定了BMI 1在维持HCC细胞系中具有SP表型的癌症干细胞中的关键作用。在Huh 7和PLC/PRF/5 HCC细胞中，与相应的非SP细胞相比，BMI 1优先在SP细胞中表达。慢病毒敲除BMI 1显著降低了Huh 7和PLC/PRF/5细胞中SP细胞的数量。纯化的SP细胞的长期培养导致SP亚群在BMI 1敲低后急剧减少，表明BMI 1是培养中SP细胞自我更新所需的。更重要的是，BMI 1基因敲除消除了非肥胖糖尿病/严重联合免疫缺陷小鼠中SP细胞的肿瘤起始能力。INK 4A和ARF基因是BMI 1的主要靶点，它们的去抑制不一定与BMI 1敲低引起的SP细胞自我更新受损相关。总之，我们的研究结果定义了一个重要的作用，BMI 1在维持肿瘤启动SP细胞在肝癌。BMI 1有可能成为肝癌干细胞治疗的新靶点。
Side population (SP) cell analysis and sorting have been successfully applied to hepatocellular carcinoma (HCC) cell lines to identify a minor cell population with cancer stem cell properties. However, the molecular mechanisms operating in SP cells remain unclear. The polycomb gene product BMI1 plays a central role in the self-renewal of somatic stem cells in a variety of tissues and organs and seems to be implicated in tumor development. In this study, we determined the critical role of BMI1 in the maintenance of cancer stem cells with the SP phenotype in HCC cell lines. BMI1 was preferentially expressed in SP cells in Huh7 and PLC/PRF/5 HCC cells compared with the corresponding non-SP cells. Lentiviral knockdown of BMI1 considerably decreased the number of SP cells in both Huh7 and PLC/PRF/5 cells. Long-term culture of purified SP cells resulted in a drastic reduction in the SP subpopulation upon the BMI1 knockdown, indicating that BMI1 is required for the self-renewal of SP cells in culture. More importantly, the BMI1 knockdown abolished the tumor-initiating ability of SP cells in nonobese diabetic/severe combined immunodeficiency mice. Derepression of the INK4A and ARF genes that are major targets for BMI1 was not necessarily associated with impaired self-renewal of SP cells caused by BMI1 knockdown. In conclusion, our findings define an important role for BMI1 in the maintenance of tumor-initiating SP cells in HCC. BMI1 might be a novel therapeutic target for the eradication of cancer stem cells in HCC.