Overexpression of the mitotic checkpoint genes BUB1, BUBR1, and BUB3 in gastric cancer -: association with tumour cell proliferation
Overexpression of the mitotic checkpoint genes BUB1, BUBR1, and BUB3 in gastric cancer -: association with tumour cell proliferation
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DOI：
10.1002/path.1324
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发表时间：
2003-05-01
影响因子：
7.3
通讯作者：
Mueller, W
中科院分区：
文献类型：
--
作者：
Grabsch, H;Takeno, S;Mueller, W
有丝分裂纺锤体组装检查点调节后期启动的时间，以响应中期平板上染色体的不正确排列。Bub基因家族编码的蛋白质是一个大型多蛋白动粒复合体的一部分，被认为是检查点调控途径的关键组成部分。这一监测系统的失败可能导致基因组不稳定，并可能导致胃癌中非整倍体发生率的增加。由于迄今为止在胃癌中尚未发现bub基因的突变，因此bub表达水平的改变可能会显著损害有丝分裂检查点功能。为探讨这一可能性，采用逆转录聚合酶链式反应(RT-PCR)检测了43例胃癌及相应正常胃粘膜中Bub1、BubR1和Bub3的表达水平。将基因表达水平与组织病理学参数、DNA倍体以及增殖活性进行比较，通过Ki-67mRNA表达来衡量。据作者所知，这是第一次研究有丝分裂检查点基因在胃癌中的表达水平以及DNA倍体。Bub1在84%的胃癌中高表达，Bub1在68%的胃癌中高表达，Bub3在79%的胃癌中高表达。这项研究还发现，在61%的肿瘤中，这三个基因同时过表达，并且Bub1、Bubr1或Bub3的过度表达与Ki-67的表达之间存在统计学上的显著正相关(p<；0.001)。81%的肿瘤被归类为非整倍体。然而，倍性和BUB转录表达水平之间没有相关性。这些结果表明，通过表观遗传沉默使有丝分裂检查点基因Bub1、BUBR1和Bub3失活似乎在胃癌的发生中没有作用。BUB表达水平与肿瘤细胞增殖密切相关，提示BUB过度表达在胃癌中是一种增殖依赖的现象。然而，由于缺乏正常的BUB蛋白功能或由于未知的额外BUB功能而导致的过度表达必须被考虑。版权所有(C)2003 John Wiley&Sons，Ltd.
The mitotic spindle assembly checkpoint modulates the timing of anaphase initiation in response to improper alignment of chromosomes at the metaphase plate. The BUB gene family encodes proteins which are part of a large multi-protein kinetochore complex and which are believed to be key components of the checkpoint regulatory pathway. Failure of this surveillance system can lead to genomic instability and could be responsible for the increased incidence of aneuploidy in gastric cancer. Since mutations of BUB genes have not been identified in gastric cancer to date, altered BUB expression levels may significantly impair mitotic checkpoint function. To explore this possibility, the expression levels of BUB1, BUBR1, and BUB3 were determined in 43 gastric carcinomas and corresponding normal gastric mucosa by reverse transcription-polymerase chain reaction (RT-PCR). Gene expression levels were compared with histopathological parameters and DNA ploidy, as well as with proliferative activity, measured by Ki-67 mRNA expression. To the authors' knowledge, this is the first study to investigate the expression levels of mitotic checkpoint genes together with DNA ploidy in gastric cancer. BUB1 was overexpressed in 84%, BUBR1 in 68%, and BUB3 in 79% of gastric cancers. This study also revealed that all three genes were simultaneously overexpressed in 61% of the tumours and that there was a statistically significant positive correlation between overexpression of BUB1, BUBR1 or BUB3 and Ki-67 expression (p < 0.001). Eighty-one per cent of the tumours were classified as aneuploid. However, no correlation was found between ploidy and BUB transcript expression levels. These results suggest that inactivation of the mitotic checkpoint genes BUB1, BUBR1, and BUB3 by epigenetic silencing does not seem to play a role in gastric carcinogenesis. The strong correlation of BUB expression level and tumour cell proliferation suggests that BUB overexpression is a proliferation-dependent phenomenon in gastric cancer. However, overexpression due to lack of normal BUB protein function or due to a yet unknown additional BUB function has to be considered. Copyright (C) 2003 John Wiley & Sons, Ltd.