Cancer Institute, Xuzhou Medical University, Jiangsu, 221002, Xuzhou, China.
Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Jiangsu, 221002, Xuzhou, China.
Cell Death Dis. 2018 May 1;9(5):477. doi: 10.1038/s41419-018-0550-9.
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.
驱动蛋白家族成员 4A（KIF4A）被发现参与有丝分裂细胞分裂过程中染色体的浓缩和分离的调节，这对于真核细胞的增殖是必不可少的。然而，关于 KIF4A 在结直肠癌（CRC）中的作用知之甚少。本研究探讨了 KIF4A 在 CRC 进展中的生物学功能，并研究了涉及的潜在分子机制。在这里，我们发现与配对的非癌组织和正常结肠上皮相比，KIF4A 在原发性 CRC 组织和细胞系中显著上调。CRC 组织中 KIF4A 的高表达与患者的临床病理特征以及总生存和无病生存累积时间明显相关。多变量 Cox 回归分析显示，KIF4A 是 CRC 患者不良生存的独立预后因素。包括 CCK-8 细胞增殖测定、集落形成分析、裸鼠癌症异种移植、细胞周期和细胞凋亡分析在内的功能测定表明，KIF4A 明显通过促进体外和体内细胞周期进程来增强细胞增殖。此外，基因集富集分析、荧光素酶报告测定和 ChIP 测定表明，KIF4A 通过调节 p21 启动子促进细胞增殖，而 KIF4A 对细胞凋亡没有影响。此外，Transwell 分析表明 KIF4A 促进 CRC 中的迁移和侵袭。总之，这些发现不仅表明 KIF4A 通过调节 p21 介导的细胞周期进程促进 CRC 的增殖，而且还表明 KIF4A 作为临床预后标志物和分子治疗靶点的潜在价值。
