Centrosome abnormalities are frequently observed in non-small-cell lung cancer and are associated with aneuploidy and cyclin E overexpression
Centrosome abnormalities are frequently observed in non-small-cell lung cancer and are associated with aneuploidy and cyclin E overexpression
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DOI：
10.1002/path.2005
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发表时间：
2006-08-01
影响因子：
7.3
通讯作者：
Gorgoulis, V. G.
中科院分区：
文献类型：
--
作者：
Koutsami, M. K.;Tsantoulis, P. K.;Gorgoulis, V. G.
在人类癌症中观察到中心体异常，并且与非整倍性相关，非整倍性是肿瘤进展的驱动力。然而，在人类肿瘤中导致中心体异常的确切途径尚未完全阐明。使用一系列 68 个非小细胞肺癌和一系列体外实验，研究了中心体异常、非整倍性和参与中心体复制调节的关键 G1 到 S 相转变细胞周期分子的状态之间的关系。中心体扩增和结构异常很常见（53%），与非整倍性密切相关，令人惊讶的是，甚至在邻近的增生区域也可见到，这表明这些可能是肺癌发生的早期病变。据观察，细胞周期蛋白 E 和 E2F1 过表达（而非 p53 突变）与体内中心体异常相关（分别为 p = 0.029 和 p = 0.015）。通过观察到细胞周期蛋白 E 特异性存在于含有中心体畸变的细胞的细胞核和/或细胞质中，这一点得到了进一步加强。细胞质细胞周期蛋白 E 信号可能部分归因于细胞周期蛋白 E 的截短低分子量亚型的存在。为了分离细胞周期蛋白 E 对中心体异常出现的影响，使用默认情况下具有正常中心体特征的 U20S 四环素抑制型细胞周期蛋白 E 细胞系。通过该系统，体外证实持续的细胞周期蛋白E过度表达足以导致中心体异常的出现。版权所有 (c) 2006 大不列颠及爱尔兰病理学会。由约翰·威利父子有限公司出版
Centrosome abnormalities are observed in human cancers and have been associated with aneuploidy, a driving force in tumour progression. However, the exact pathways that tend to cause centrosome abnormalities have not been fully elucidated in human tumours. Using a series of 68 non-small-cell lung carcinomas and an array of in vitro experiments, the relationship between centrosome abnormalities, aneuploidy, and the status of key G1 to S-phase transition cell-cycle molecules, involved in the regulation of centrosome duplication, was investigated. Centrosome amplification and structural abnormalities were common (53%), were strongly related to aneuploidy, and, surprisingly, were even seen in adjacent hyperplastic regions, suggesting the possibility that these are early lesions in lung carcinogenesis. Cyclin E and E2F1 overexpression, but not p53 mutation, was observed to correlate with centrosome abnormalities in vivo (p = 0.029 andp = 0.015, respectively). This was further strengthened by the observation that cyclin E was specifically present in the nucleus and/or cytoplasm of the cells that contained centrosome aberrations. The cytoplasmic cyclin E signal may be attributed, in part, to the presence of truncated low-molecularweight isoforms of cyclin E. In order to isolate the effect of cyclin E on the appearance of centrosome abnormalities, a U20S tetracycline-repressible cyclin E cell line that has a normal centrosome profile by default was used. With this system, it was confirmed in vitro that persistent cyclin E overexpression is sufficient to cause the appearance of centrosome abnormalities. Copyright (c) 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.