Cui Facai, Chen Yu, Wu Xiaoyu, Zhao Weifeng
Department of Clinical Laboratory, Henan Provincial People's Hospital, Zhengzhou, China.
Department of Pathology, Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou, China.
Discov Oncol. 2025 Mar 28;16(1):417. doi: 10.1007/s12672-025-02154-6.
Never-in-mitosis gene A-related-kinase-2 (NEK2) plays a pivotal role in malignant progression and chemotherapy sensitivity. This study aimed to elucidate the role of NEK2 in colorectal cancer (CRC) and its potential contribution to 5-fluorouracil (5‑FU) resistance mechanisms.
Quantitative real-time PCR (qRT‑PCR), western blotting, and immunohistochemical (IHC) staining were used to assess the expression of NEK2 in CRC tissues and cells. The effects of NEK2 and 5‑FU on the proliferation, apoptosis, migration, and invasion of cancer cells were investigated via Cell Counting Kit-8 (CCK-8), colony formation, flow cytometry, wound healing, and transwell assays, respectively. Methyl 3-(4-methylphenylsulfonamido) benzoate (MSAB) was used as a Wnt/beta (β)-catenin pathway inhibitor in this study.
NEK2 expression was significantly upregulated in CRC tissues and cells compared to normal controls. High NEK2 expression in CRC tissues was correlated with advanced tumor-node-metastasis (TNM) stage, lymph node metastasis, distant metastasis, and a poor tumor prognosis. NEK2 overexpression promoted the proliferation, migration, and invasion of CRC cells. NEK2 overexpression inhibited the cytotoxic effect of 5-FU on CRC cells. NEK2 overexpression promoted the nuclear accumulation of β-catenin and activated the Wnt/β-catenin signaling pathway. MSAB reversed the stimulatory effect of NEK2 upregulation on proliferation and resistance to 5-FU in CRC cells.
In summary, NEK2 promotes cell survival and decreases sensitivity to 5-FU in CRC by activating the Wnt/β-catenin signaling pathway. Consequently, NEK2 holds promise as a potential therapeutic target for CRC management.
有丝分裂阻滞缺陷型蛋白激酶2（NEK2）在恶性进展和化疗敏感性中起关键作用。本研究旨在阐明NEK2在结直肠癌（CRC）中的作用及其对5-氟尿嘧啶（5-FU）耐药机制的潜在影响。
采用定量实时聚合酶链反应（qRT-PCR）、蛋白质免疫印迹法和免疫组织化学（IHC）染色评估NEK2在CRC组织和细胞中的表达。分别通过细胞计数试剂盒-8（CCK-8）、集落形成、流式细胞术、伤口愈合和Transwell实验研究NEK2和5-FU对癌细胞增殖、凋亡、迁移和侵袭的影响。本研究中使用3-（4-甲基苯磺酰胺基）苯甲酸甲酯（MSAB）作为Wnt/β-连环蛋白信号通路抑制剂。
与正常对照相比，CRC组织和细胞中NEK2表达显著上调。CRC组织中NEK2高表达与肿瘤-淋巴结-转移（TNM）分期较晚、淋巴结转移、远处转移及不良肿瘤预后相关。NEK2过表达促进CRC细胞的增殖、迁移和侵袭。NEK2过表达抑制5-FU对CRC细胞的细胞毒性作用。NEK2过表达促进β-连环蛋白的核内积累并激活Wnt/β-连环蛋白信号通路。MSAB逆转了NEK2上调对CRC细胞增殖和对5-FU耐药的刺激作用。
总之，NEK2通过激活Wnt/β-连环蛋白信号通路促进CRC细胞存活并降低对5-FU的敏感性。因此，NEK2有望成为CRC治疗的潜在靶点。
