Downregulation of kinetochore-associated 1 gene increases lagging chromosomes and contributes to chromosomal instability in gastric cancer cells.

Abstract

Gastric cancer (GC) is classified into four molecular subtypes according to the Epstein-Barr virus-positive status, microsatellite instability, genomic stability and chromosomal instability (CIN). The CIN subtype is characterized by a high frequency of gene amplifications in receptor tyrosine kinases (RTKs) and a poor prognosis. In addition, the CIN subtype often exhibits intratumoral heterogeneity and indicates insensitivity to targeted drugs. Elucidating the molecular mechanisms of CIN in GC is therapeutically crucial; however, the molecular mechanisms involved are not yet fully understood. The kinetochore-associated 1 (KNTC1) gene encodes kinetochore-associated protein 1 (KNTC1), a major component of the outer kinetochore. The downregulation of KNTC1 causes a high frequency of lagging chromosomes and consequent aneuploidy and CIN in Drosophila and Caenorhabditis elegans. However, the association between KNTC1 and CIN in GC has not yet been clarified. Therefore, the present study investigated the role of KNTC1 in GC CIN. It was found that GC cell lines with a high frequency of lagging chromosomes had a low KNTC1 mRNA expression. Notably, KNTC1 knockdown increased the frequency of lagging chromosomes in GC cell lines. In particular, GC cell lines with the amplification of RTK genes exhibited a significant increase in the frequency of lagging chromosomes. On the whole, the findings of the present study suggest that the suppression of KNTC1 expression may contribute to CIN in GC and may be involved in the generation of intratumoral genetic heterogeneity in GC.