To study the effect of NEK2 on chromosome instability in hepatocellular carcinoma

Abstract

Extra centrosomes have long been observed in cancer cells and it has been shown that extra centrosomes are able to mechanistically promote chromosome instability, aneuploidy and cancer invasiveness. However, extra centrosomes without tumourigenesis have been observed in normal polyploid hepatocytes. Polyploidy has been described in the liver for over a century. About 50% of the adult hepatocytes in humans and up to 90% in mice are polyploid naturally. The mechanisms that allow hepatocytes to divide with extra centrosomes and aneuploidy normally or develop hepatocellular carcinoma (HCC) are poorly understood. NIMA-related kinase 2 (NEK2) expression is found to be elevated in tissues of HCC patients and is associated with poor prognosis and drug resistance. NEK2 is a conserved serine / threonine kinase important for centrosome regulation and mitotic spindle formation during cell cycle. It is involved in multiple cellular functions and is able to interact with different binding partners. It regulates centrosome separation by directly phosphorylating the linker components C-NAP1 and ROOTLETIN, which are proteins constituting the basal bodies of specific cell types. Several reports have shown that NEK2 is associated with multiple pathways including Hippo, NFkB and Wnt. Yet, the molecular function of NEK2 in HCC progression remains unknown. Our evidence showed NEK2 mRNA and protein levels were elevated in liver cancer cells. Overexpression of NEK2 promotes HCC cell growth and cell migration. Cell cycle analysis showed an increased content of DNA in NEK2 overexpressing cell lines suggesting NEK2 contribute to aneuploidy in HCC cells. NEK2 overexpression drove early centrosome splitting in a proportion of both HepG2 and SMMC-7721 inducible cell lines. We found that a ROOTLETIN isoform, called TAX1BP2 and which is a putative tumor suppressor in HCC, is a substrate of NEK2. Hence, I am interested to understand the pathogenic roles of NEK2 in cancer, and to develop better therapeutic strategy for HCC.