Abstract
Kinesin family member 4A (KIF4A) was found to be implicated in the regulation of chromosome condensation and segregation during mitotic cell division, which is essential for eukaryotic cell proliferation. However, little is known about the role of KIF4A in colorectal carcinoma (CRC). This study explored the biological function of KIF4A in CRC progression and investigated the potential molecular mechanisms involved. Here, we found that KIF4A was remarkably upregulated in primary CRC tissues and cell lines compared with paired non-cancerous tissues and normal colorectal epithelium. Elevated expression of KIF4A in CRC tissues was significantly correlated with clinicopathological characteristics in patients as well as with shorter overall and disease-free cumulative survival. Multivariate Cox regression analysis revealed that KIF4A was an independent prognostic factor for poor survival in human CRC patients. Functional assays, including a CCK-8 cell proliferation assay, colony formation analysis, cancer xenografts in nude mice, cell cycle and apoptosis analysis, indicated that KIF4A obviously enhanced cell proliferation by promoting cell cycle progression in vitro and in vivo. Furthermore, gene set enrichment analysis, Luciferase reporter assays, and ChIP assays revealed that KIF4A facilitates cell proliferation via regulating the p21 promoter, whereas KIF4A had no effect on cell apoptosis. In addition, Transwell analysis indicated that KIF4A promotes migration and invasion in CRC. Taken together, these findings not only demonstrate that KIF4A contributes to CRC proliferation via modulation of p21-mediated cell cycle progression but also suggest the potential value of KIF4A as a clinical prognostic marker and target for molecular treatments.
Highlights
Colorectal carcinoma (CRC) remains one of the most common malignancies and leading causes of cancerrelated death worldwide[1]
kinesin family member 4A (KIF4A) is frequently upregulated in CRC tissues and cell lines To investigate the role of KIF4 in CRC development, we first detected the expression of KIF4A at the protein level in five CRC cell lines using western blotting
In a CCK-8 cell proliferation assay, we found that cell proliferation was drastically decreased in both cell lines transfected with KIF4A small interfering RNAs (siRNAs) compared to the control groups (Fig. 2c)
Summary
Colorectal carcinoma (CRC) remains one of the most common malignancies and leading causes of cancerrelated death worldwide[1]. Members of the kinesin superfamily play a key role in cell division, for different stages of mitosis and cytokinesis, which can regulate the formation, orientation, and elongation of the mitotic spindle and the segregation of chromosomes in mitosis[7]. One of the KIFs, kinesin family member 4A (KIF4A), an essential chromosome-associated molecular motor, maps to Xq13.1 in the human genome and encodes a 140-kDa protein that is composed of 1232 amino acids[8] and is dominantly localized in the nucleus[9]. Previous studies have reported that KIF4A is involved in multiple significant cellular processes, especially in the regulation of chromosome condensation and segregation during mitotic cell division[10], and dysregulation of KIF4A is considered to be involved in the DNA damage response[11], abnormal spindle separation, and aneuploidy of daughter cells[12], which further produces abnormal distribution of genetic materials. The expression profile and the function of KIF4A in CRC remain unknown
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