Li Jiachen, Wang Yaojie, Wei Sisi, Xu Shi, Dai Suli, Zhang Li, Tian Ziqiang, Zhao Lianmei, Lv Huilai
Department of Thoracic Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
Mol Carcinog. 2025 Feb;64(2):244-259. doi: 10.1002/mc.23839. Epub 2024 Nov 6.
Never in mitosis gene A (NIMA)-related kinase 2 (NEK2) is a crucial serine-threonine kinase involved in the process of cell mitosis. However, the precise relationship between NEK2 and esophageal squamous cell carcinoma (ESCC) remains inadequately understood. NEK2 expression in ESCC tissues was assessed through bioinformatics analysis, reverse transcription-quantitative PCR (RT-qPCR) and immunohistochemistry, revealing a correlation with ESCC patient prognosis. Cultured ESCC cells and human normal esophageal epithelial cells (HEEC) were used to investigate the effects of NEK2 knockdown on the development and progression of ESCC by integrated confluence algorithm, colony formation, wound-healing, transwell, and ESCC xenograft tumor model, in vitro and in vivo. In ESCC tissues, NEK2 was found to be significantly upregulated, and its expression correlated with poor prognosis in ESCC patients. NEK2 may facilitate ESCC development by regulating cell proliferation, migration, and invasion. Additionally, results from in vivo experiments suggested that NEK2 knockdown can inhibit tumor growth. Moreover, forkhead box M1 (FOXM1) was identified as a potential downstream target of NEK2 in the regulation of ESCC, with its overexpression reversing the effects of NEK2 knockdown on ESCC. Mechanistic studies also indicated that NEK2 may promote the malignant progression of ESCC by inhibiting cellular senescence through the activation of the FOXM1/c-Myc/p27 signaling pathways, which may provide a novel perspective for the management of ESCC.
有丝分裂相关基因A（NIMA）相关激酶2（NEK2）是一种参与细胞有丝分裂过程的关键丝氨酸 - 苏氨酸激酶。然而，NEK2与食管鳞状细胞癌（ESCC）之间的确切关系仍未得到充分了解。通过生物信息学分析、逆转录定量PCR（RT-qPCR）和免疫组织化学评估了ESCC组织中NEK2的表达，发现其与ESCC患者的预后相关。使用培养的ESCC细胞和人正常食管上皮细胞（HEEC），通过整合汇合算法、集落形成、伤口愈合、Transwell实验以及ESCC异种移植肿瘤模型，在体外和体内研究了NEK2敲低对ESCC发生发展的影响。在ESCC组织中，发现NEK2显著上调，其表达与ESCC患者的不良预后相关。NEK2可能通过调节细胞增殖、迁移和侵袭促进ESCC的发展。此外，体内实验结果表明，NEK2敲低可抑制肿瘤生长。此外，叉头框M1（FOXM1）被确定为NEK2在ESCC调节中的潜在下游靶点，其过表达可逆转NEK2敲低对ESCC的影响。机制研究还表明，NEK2可能通过激活FOXM1/c-Myc/p27信号通路抑制细胞衰老，从而促进ESCC的恶性进展，这可能为ESCC的治疗提供新的视角。
