NEK2, a significant mitotic kinase, could promote mitosis though phosphorylation of the mitotic component, and acted an important role in participating in cell cycle process through promoting centrosome splitting decomposition of mitosis. Furthermore, NEK2 has been identified as an oncogene associated with the development of various cancers, such as, overexpression of NEK2 promoted hepatocellular carcinoma cell proliferation, migration, invasion and drug resistance via activating Akt and Wnt signaling pathways . Knockdown of NEK2 inhibited cell growth and migration through mediating β-catenin/Myc/KDM5B/H3K4me3 pathway in gastric cancer. Down-regulation of NEK2 suppressed breast cancer cell proliferation, clone formation, invasion, and increased cell apoptosis via ERK/MAPK pathway. Indeed, deregulation of NEK2 also associated with prognosis of various types of cancer. Prostate cancer patients with high expression of NEK2 were significantly associated with poor recurrence free survival . The overall survival and disease-free survival of hepatocellular carcinoma patients with high expression of NEK2 was shorter than those patients with low expression of NEK2. Therefore, NEK2 may be a novel and promising biomarker.
In this work, ONCOMINE database showed NEK2 had higher expression in most cancer tissues compared with the corresponding adjacent tissues, except kidney cancer and prostate cancer. Indeed, NEK2 was significantly up-regulated in bladder urothelial carcinoma, breast cancer, cholangiocarcinoma, colorectal cancer, esophageal carcinoma, head and neck squamous cell carcinoma, kidney cancer, liver cancer, lung cancer, prostate adenocarcinoma, stomach adenocarcinoma, thyroid carcinoma, uterine corpus endometrial carcinoma by TIMER database analysis. However, this results showed the opposite trend of NEK expression in kidney cancer and prostate adenocarcinoma, then we further look for other databases to confirm NEK2 expression. It was exhibited NEK2 was up-regulated in kidney renal clear cell carcinoma, kidney renal papillary cell carcinoma and prostate cancer by UALCAN analysis. Therefore, these findings suggest that NEK2 could almost act as an oncogene in cancers. Moreover, Kaplan-Meier Plotter survival analysis demonstrated that high expression of NEK2 was significantly correlated with worse prognosis in breast cancer, lung cancer, liver cancer, renal carcinoma, pancreatic ductal adenocarcinoma, sarcoma and thyroid carcinoma. Besides, NEK2 expression was also involved in pathological cancer stages, and NEK2 expression in patients with early-stages cancers was lower than late-stage cancers, such as, breast cancer, lung adenocarcinoma, liver cancer, kidney renal papillary cell carcinoma and kidney renal clear cell carcinoma. Therefore, NEK2 was not only an important indicator of assessing tumor prognosis, but also a pivotal basis for determining staging.
Tumor microenvironment has been acted an important role in tumor immunology, and regarded as potential prognostic biomarker in numerous cancers, among them, infiltrating immune cells account for a large proportion. CCL14 was significantly associated with immune infiltration in 39 types of cancer, moreover, low expression of CCL14 was associated with higher infiltration of the majority of immune cell and worse prognosis in hepatocellular carcinoma . In our study, it showed that NEK2 was associated with purity, B cells, CD8 + T cells, CD4 + T cells, macrophages, neutrophils and dendritic cells in 2 cancer types with a valuable prognosis. Additionally, NEK2 expression was significant correlated with tumor purity in 7 cancer types, B cells in 6 cancer types, CD4 + T cells in 8 cancer types, CD8 + T cells in 4 cancer types, macrophages in 6 cancer types, neutrophils in 5 cancer types, and dendritic cells in 4 cancer types. Besides, the regulation trend of NEK2 on immune infiltration cell varies with different tumors. Therefore, NEK2 has a potential role in regulating tumor immunology and it can act as a tumor prognosis biomarker.
Although we studied and integrated information from different databases on NEK2, and proved that NEK2 could act as an oncogene to regulate the initiation and progression of cancers. Currently, research on NEK2 was still in the basic stage, so there were still great restrictions and insufficient research on NEK2. It demonstrated that NEK2 was correlated with CDC family gene, FZR1, CDK1, FOXM1, PLK4, DEPDC1, et al. CDC20 was also an oncogene that accelerated promotes anaphase and mitotic progression, promoting cell proliferation. CDC27 was one of the pivotal components of the anaphase promoting complex, which could control mitosis and chromosomal separation via regulating APC/C (Anaphase Promoting Complex or Cyclosome) activity in cyclin degradation, and then regulated the cell cycle transition in cell division. FZR1, a co-activator of the APC/C, was sensitized by dephosphorylation of inactivated CDK1 in anaphase of mitosis, thus mediating cell cycle and apoptosis . PLK4 has been confirmed to mediate centriole duplication through interacting with various central somatic proteins in the cell cycle. These genes were correlated with cell cycle or cell proliferation. Indeed, NEK2 was primarily enriched for CDK-mediated phosphorylation and removal of Cdc6, or cell cycle by path enrichment analysis, therefore, NEK2 could mediate cell biological function by regulating related genes or pathways. In addition, NEK2 was all correlated with cell cycle, DNA damage and proliferation in LUAD, BRCA and CRC, and was associated with invasion or metastasis in LUAD or BRCA through single-cell level analysis. Overall, NEK2 acted as an important role in cell cycle and proliferation in various cancers, which needs to be confirmed by subsequent experiments.