Centromere protein H is up-regulated in primary human colorectal cancer and its overexpression induces aneuploidy
Centromere protein H is up-regulated in primary human colorectal cancer and its overexpression induces aneuploidy
复制标题
DOI：
10.1158/0008-5472.can-04-3613
复制
发表时间：
2005-06-01
期刊：
影响因子：
11.2
通讯作者：
Nomura, F
中科院分区：
文献类型：
--
作者：
Tomonaga, T;Matsushita, K;Nomura, F
染色体不稳定性（CIN）已被认为是人类癌症的标志，是由有丝分裂期间连续的染色体错误分离引起的。正确的染色体分离需要纺锤体微管和着丝粒DNA之间的物理连接，这种连接发生在称为动粒的蛋白质结构上。CENP-A和CENP-H等着丝粒蛋白是人类活动着丝粒的基本组成部分，其不适当表达可能是CIN的主要原因。我们先前已经证明CENP-A在原发性人结直肠癌中过表达。在这项研究中，我们发现CENP-H在所有15种原发性人结直肠癌组织以及CIN肿瘤细胞系中也上调。令人惊讶的是，将CENP-H表达质粒瞬时转染到二倍体细胞系HCT 116中显着诱导非整倍体。此外，小鼠胚胎成纤维细胞/3 T3细胞系的CENP-H稳定转染子显示异常间期微核，这是染色体错误分离的特征。在这些CENP-H过表达的细胞中，CENP-H完全从有丝分裂染色体的着丝粒消失，这可能是染色体分离缺陷的原因。这些结果表明，着丝粒蛋白CENP-H的异常表达和定位在结直肠癌中经常观察到的非整倍体中起着重要作用。
Chromosomal instability (CIN) has been recognized as a hallmark of human cancer and is caused by continuous chromosome missegregation during mitosis. Proper chromosome segregation requires a physical connection between spindle microtubules and centromeric DNA and this attachment occurs at proteinaceous structures called kinetochore. Several centromere proteins such as CENP-A and CENP-H are the fundamental components of the human active kinetochore, and inappropriate expression of the centromere proteins could be a major cause of CIN. We have previously shown that CENP-A was overexpressed in primary human colorectal cancer. In this study, we show that CENP-H was also up-regulated in all of 15 primary human colorectal cancer tissues as well as in CIN tumor cell lines. Surprisingly, transient transfection of CENP-H expression plasmid into the diploid cell line HCT116 remarkably induced aneupoidy. Moreover, CENP-H stable transfectant of mouse embryonic fibroblast/3T3 cell lines showed aberrant interphase micronuclei, characteristic of chromosome missegregation. In these CENP-H overexpressed cells, CENP-H completely disappeared from the centromere of mitotic chromosomes, which might be the cause of the chromosome segregation defect. These results suggest that the aberrant expression and localization of a kinetochore protein CENP-H plays an important role in the aneuploidy frequently observed in colorectal cancers.