Division of Cancer Diagnosis, Research Institute for Clinical Oncology, Saitama Cancer Center, Ina, Saitama 362-0806, Japan.
Proc Natl Acad Sci U S A. 2012 Oct 30;109(44):18048-53. doi: 10.1073/pnas.1205525109. Epub 2012 Oct 11.
Asymmetric cell division (ACD) is believed to be a physiological event that occurs during development and tissue homeostasis in a large variety of organisms. ACD produces two unequal daughter cells, one of which resembles a multipotent stem and/or progenitor cell, whereas the other has potential for differentiation. Although recent studies have shown that the balance between self-renewal and differentiation potentials is precisely controlled and that alterations in the balance may lead to tumorigenesis in Drosophila neuroblasts, it is largely unknown whether human cancer cells directly show ACD in an evolutionarily conserved manner. Here, we show that the conserved polarity/spindle protein NuMA is preferentially localized to one side of the cell cortex during cell division, generating unequal inheritance of fate-altering molecules in human neuroblastoma cell lines. We also show that the cells with a single copy of MYCN showed significantly higher percentages of ACD than those with MYCN amplification. Moreover, suppression of MYCN in MYCN-amplified cells caused ACD, whereas expression of MYCN in MYCN-nonamplified cells enhanced symmetric cell division. Furthermore, we demonstrate that centrosome inheritance follows a definite rule in ACD: The daughter centrosome with younger mother centriole is inherited to the daughter cell with NuMA preferentially localized to the cell cortex, whereas the mother centrosome with the older mother centriole migrates to the other daughter cell. Thus, the mechanisms of cell division of ACD or symmetric cell division and centrosome inheritance are recapitulated in human cancer cells, and these findings may facilitate studies on cancer stem cells.
不对称细胞分裂（ACD）被认为是一种在多种生物体的发育和组织稳态过程中发生的生理事件。ACD 产生两个不均等的子细胞，其中一个类似于多能干细胞和/或祖细胞，而另一个则具有分化潜能。尽管最近的研究表明，自我更新和分化潜能之间的平衡受到精确控制，并且平衡的改变可能导致果蝇神经母细胞瘤的肿瘤发生，但人类癌细胞是否以进化上保守的方式直接表现出 ACD 还很大程度上未知。在这里，我们显示保守的极性/纺锤体蛋白 NuMA 在细胞分裂过程中优先定位于细胞皮质的一侧，从而导致人类神经母细胞瘤系中命运改变分子的不均等遗传。我们还表明，具有单个 MYCN 拷贝的细胞显示出明显更高比例的 ACD，而 MYCN 扩增的细胞则更低。此外，在 MYCN 扩增的细胞中抑制 MYCN 会导致 ACD，而在 MYCN 非扩增的细胞中表达 MYCN 会增强对称细胞分裂。此外，我们证明 ACD 中的中心体遗传遵循明确的规则：具有年轻母中心粒的子中心体被遗传到具有优先定位于细胞皮质的 NuMA 的子细胞中，而具有较老母中心粒的母中心体则迁移到另一个子细胞中。因此，ACD 或对称细胞分裂和中心体遗传的细胞分裂机制在人类癌细胞中得到了再现，这些发现可能有助于癌症干细胞的研究。
