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A large fraction of human cancers have an abnormal number of chromosomes called aneuploidy. This aneuploidy has recently been explained by chromosomal instability (CIN), that is, an accelerated rate of gain or loss of whole or large portions of chromosomes. Recent compelling data has strongly suggested that chromosome missegregation during mitosis is the main cause of CIN and contributes to oncogenesis. Proper chromosome segregation requires a physical connection between spindle microtubules and centromeric DNA and this attachment occurs at proteinaceous structures called kinetochore. Although its malfunction could be a major cause of aneuploidy, there is no direct relationship between kinetochore defects and tumorigenesis. 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. Here, we demonstrate that CENP-H was also upregulated in all of 15 primary human colorectal cancer tissues as well as in CIN tumor cell lines. Surprisingly, transfection of the diploid cell line HCT116 with an expression plasmid for CENP-H induced aneupoidy in cells overexpressing CENP-H. Ectopic expression of CENP-A, although not as significant as CENP-H, also induced aneuploidy. CENP-A was localized to the entire chromosome when it was overexpressed. In contrast, CENP-H completely disappeared from the centromere in CENP-H-overexpressing mitotic chromosomes. These results suggest that the aberrant expression of kinetochore proteins plays an important role in the CIN commonly observed in colorectal cancers.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]