Loss of the human polycomb group protein BMI1promotes cancer-specific cell death
Loss of the human polycomb group protein BMI1promotes cancer-specific cell death
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DOI：
10.1038/sj.onc.1209454
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发表时间：
2006-07-20
期刊：
影响因子：
8
通讯作者：
Tollefsbol, T. O.
中科院分区：
文献类型：
--
作者：
Liu, L.;Andrews, L. G.;Tollefsbol, T. O.
polycomb group蛋白BMI1已被证明通过其假定的干细胞因子功能支持正常的干细胞增殖，但尚不清楚BMI1是否也可能作为癌症干细胞因子促进癌症的发展。为了确定人类BMI1在癌症生长和生存中的作用，我们通过RNA干扰（RNAi）在正常和恶性人类细胞中对BMI1进行了功能丧失分析。我们的研究结果表明，BMI1对癌细胞的短期存活至关重要，而对正常细胞则不然。我们还证明，BMI1的缺失在抑制癌细胞生长方面比类维甲酸治疗更有效，存活的癌细胞显示出显著降低的致瘤性。肿瘤特异性生长迟缓是由BMI1缺失导致的细胞凋亡水平升高和细胞周期进展延迟介导的。相比之下，BMI1缺乏仅对正常肺细胞的细胞周期进程产生中度抑制。在正常细胞和癌细胞中，BMI1的缺失导致INK4A-ARF的上调，但对端粒酶基因表达水平无显著影响，提示除了INK4A-ARF激活外，BMI1的其他协同因子可能参与了BMI1依赖性癌症特异性生长迟缓。因此，人类BMI1对癌细胞的短期存活至关重要，抑制BMI1对正常细胞的存活影响很小。这些发现为开发针对BMI1的癌症特异性治疗提供了基础。
The polycomb group protein BMI1 has been shown to support normal stem cell proliferation via its putative stem cell factor function, but it is not known if BMI1 may also act as a cancer stem cell factor to promote cancer development. To determine the role of human BMI1 in cancer growth and survival, we performed a loss-of-function analysis of BMI1 by RNA interference (RNAi) in both normal and malignant human cells. Our results indicate that BMI1 is crucial for the short-term survival of cancer cells but not of normal cells. We also demonstrated that loss of BMI1 was more effective in suppressing cancer cell growth than retinoid-treatment, and surviving cancer cells showed significantly reduced tumorigenicity. The cancer-specific growth retardation was mediated by an increased level of apoptosis and a delayed cell cycle progression due to the loss of BMI1. By comparison, BMI1 deficiency caused only a moderate inhibition of the cell cycle progression in normal lung cells. In both normal and cancer cells, the loss of BMI1 led to an upregulation of INK4A-ARF, but with no significant effect on the level of telomerase gene expression, suggesting that other BMI1-cooperative factors in addition to INK4A-ARF activation may be involved in the BMI1-dependent cancer-specific growth retardation. Thus, human BMI1 is critical for the short-term survival of cancer cells, and inhibition of BMI1 has minimal effect on the survival of normal cells. These findings provide a foundation for developing a cancer-specific therapy targeting BMI1.