Tomonaga Takeshi, Matsushita Kazuyuki, Ishibashi Masumi, Nezu Masahiko, Shimada Hideaki, Ochiai Takenori, Yoda Kinya, Nomura Fumio
Department of Molecular Diagnosis (F8), Graduate School of Medicine, Chiba University, Inohana, Chuo-ku, Chiba, Japan.
Cancer Res. 2005 Jun 1;65(11):4683-9. doi: 10.1158/0008-5472.CAN-04-3613.
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.
染色体不稳定（CIN）已被公认为人类癌症的一个标志，它是由有丝分裂期间持续的染色体错分离引起的。正确的染色体分离需要纺锤体微管与着丝粒DNA之间建立物理连接，这种连接发生在称为动粒的蛋白质结构上。几种着丝粒蛋白，如CENP - A和CENP - H，是人类活性动粒的基本组成部分，着丝粒蛋白的不适当表达可能是CIN的主要原因。我们之前已经表明CENP - A在原发性人类结直肠癌中过表达。在本研究中，我们发现CENP - H在15例原发性人类结直肠癌组织以及CIN肿瘤细胞系中均上调。令人惊讶的是，将CENP - H表达质粒瞬时转染到二倍体细胞系HCT11后，显著诱导了非整倍体的产生。此外，小鼠胚胎成纤维细胞/3T3细胞系的CENP - H稳定转染体显示出异常的间期微核，这是染色体错分离的特征。在这些CENP - H过表达的细胞中，CENP - H从有丝分裂染色体的着丝粒上完全消失，这可能是染色体分离缺陷的原因。这些结果表明，动粒蛋白CENP - H的异常表达和定位在结直肠癌中频繁观察到的非整倍体中起重要作用。
