Nuclear accumulation of annexin A2 contributes to chromosomal instability by coilin-mediated centromere damage
Nuclear accumulation of annexin A2 contributes to chromosomal instability by coilin-mediated centromere damage
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DOI：
10.1038/onc.2014.345
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发表时间：
2015-08-06
期刊：
影响因子：
8
通讯作者：
Nomura, F.
中科院分区：
文献类型：
--
作者：
Kazami, T.;Nie, H.;Nomura, F.
大多数人类癌症表现出染色体不稳定(CIN)，但确切的机制仍不确定。膜联蛋白A2在人类癌症中经常过度表达，其与肿瘤发生的关系尚不清楚。我们发现，与微卫星不稳定(MIN)细胞相比，Annexin A2在CIN细胞的细胞核中过表达。异位膜联蛋白A2在MIN细胞中的表达导致高水平的非整倍体，并诱导落后的染色体；抑制CIN细胞中的膜联蛋白A2会减少这种CIN特征，并导致高度非整倍体细胞的凋亡。膜联蛋白A2在MIN细胞中的异位表达降低着丝粒蛋白的表达。相反，在CIN细胞中，Annexin A2基因敲除会增加着丝粒蛋白的表达。此外，与MIN细胞系相比，CIN细胞中着丝粒蛋白的内源性表达水平显著降低。着丝粒蛋白表达的减少可能是由于Cajal小体的主要成分Colin的着丝粒定位异常所致。这些结果表明，Annexin A2的核积聚通过破坏着丝粒功能在CIN中起着至关重要的作用。
Most human cancers show chromosomal instability (CIN), but the precise mechanisms remain uncertain. Annexin A2 is frequently overexpressed in human cancers, and its relationship to tumorigenesis is poorly understood. We found that annexin A2 is overexpressed in the nuclei of CIN cells compared with cells with microsatellite instability (MIN). Ectopic annexin A2 expression in MIN cells results in a high level of aneuploidy and induces lagging chromosomes; suppression of annexin A2 in CIN cells reduces such CIN signatures with apoptosis of highly aneuploid cells. Ectopic expression of annexin A2 in MIN cells reduces the expression of centromere proteins. Conversely, annexin A2-knockdown in CIN cells increases the expression of centromere proteins. Moreover, the endogenous expression levels of centromere proteins in CIN cells were greatly reduced compared with MIN cell lines. The reduced expression of centromere proteins likely occurred due to aberrant centromere localization of coilin, a major component of the Cajal bodies. These results suggest that nuclear accumulation of annexin A2 has a crucial role in CIN by disrupting centromere function.