Deregulated Aurora-B induced tetraploidy promotes tumorigenesis
Deregulated Aurora-B induced tetraploidy promotes tumorigenesis
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DOI：
10.1096/fj.09-130963
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发表时间：
2009-08-01
期刊：
影响因子：
4.8
通讯作者：
Ravid, Katya
中科院分区：
文献类型：
--
作者：
Nguyen, Hao G.;Makitalo, Maria;Ravid, Katya
Aurora-B的高表达已经在各种癌症中被观察到，抑制这种激酶已被证明可以阻止细胞增殖。然而，Aurora-B对细胞转化的作用机制尚未得到充分的探讨。在这里，我们发现小鼠上皮细胞中极光- b的过表达促进了四倍体的产生。为了寻找相关的机制，进行了光谱核型分析，发现染色单体过早分离（PCS）。有趣的是，PCS是罗伯特综合征的标志，它也涉及细胞多倍体和非整倍体。与注射未分离的细胞相比，将经过分类的四倍体过表达aurora - b的细胞注射到裸鼠体内时，显著促进了乳腺上皮癌的发生，这表明四倍体是aurora - b诱导肿瘤发生的重要介质。对来自四倍体细胞诱导肿瘤的DNA进行的比较染色体杂交表明，整个基因组区域的扩增和缺失，分别包括肿瘤促进或肿瘤抑制基因。因此，持续表达Aurora-B诱导四倍体，这反过来又促进了异种移植模型中基因组的不稳定性和肿瘤的发展。-Nguyen， H. G., Makitalo， M., Yang， D., Chinnappan， D., St. Hilaire， C., Ravid， K.解除调控的Aurora-B诱导的四倍体促进肿瘤发生。中华医学杂志23,2741-2748 （2009）
High expression of Aurora-B has been observed in various cancers, and inhibition of this kinase has been shown to halt cellular proliferation. However, the mechanism of effect of Aurora-B on cellular transformation has not been fully explored. Here, we show that overexpression of Aurora-B in murine epithelial cells promotes generation of tetraploids. In search of a related mechanism, spectral karyotyping was carried out, showing premature chromatid separation (PCS). Of interest, PCS is a hallmark of Robert's syndrome, which also involves cellular polyploidy and aneuploidy. Sorted tetraploid Aurora-B-overexpressing cells promoted significant mammary epithelial cancers when injected into nude mice, as compared to injection of nonfractionated cells, suggesting that tetraploidy is an important mediator of Aurora-B-induced tumorigenesis. Comparative chromosome hybridization performed on DNA derived from tetraploid cell-induced tumors indicates amplifications and deletions of regions throughout the genome, which include tumor-promoting or tumor-suppressing genes, respectively. Thus, sustained expression of Aurora-B induces tetraploidy, which, in turn, facilitates genomic instability and tumor development in a xenograft model.-Nguyen, H. G., Makitalo, M., Yang, D., Chinnappan, D., St. Hilaire, C., Ravid, K. Deregulated Aurora-B induced tetraploidy promotes tumorigenesis. FASEB J. 23, 2741-2748 ( 2009)