Zhang Shouhua, Meng Xiaozhen, Xiang Deng, Huang Hui, Ge Yangfan, Zhan Yishan, Li Kehao, Tan Xiaoyun
Department of General Surgery, The Affiliated Children's Hospital of Nanchang Medical College, JXHC Key Laboratory of Jiangxi Provincial Children's Hospital, Jiangxi Provincial Children's Hospital, Nanchang, 330006, China.
Jiangxi Medical College, Nanchang University, Nanchang, 330006, China.
Neurochem Res. 2025 Jul 22;50(4):245. doi: 10.1007/s11064-025-04488-7.
Cyclin-dependent kinases regulatory subunit 2 (CKS2) is a key regulator of the cell cycle, but its role in neuroblastoma remains poorly understood. This study investigates the function and mechanisms of CKS2 in neuroblastoma through bioinformatics analyses, as well as in vitro and in vivo experiments. Data from the GEO and TCGA databases indicate that elevated CKS2 expression is associated with poor prognosis in neuroblastoma. Analysis of clinical tumor samples and cell lines further confirmed that CKS2 was significantly overexpressed, particularly in high-risk neuroblastoma patient-derived tissues. Functional studies revealed that CKS2 knockdown reduced cell proliferation and invasion, induced apoptosis, and caused cell cycle arrest in neuroblastoma cells. In vivo, tumors formed from CKS2-silenced cells showed markedly reduced growth. Mechanistically, CKS2 knockdown decreased the phosphorylation of CDK1 (Thr161) and Cyclin B1 (Ser126), suggesting impaired cell division signaling. Treatment with importazole, an importin-β inhibitor, caused CKS2 to accumulate in the cytoplasm rather than in the nucleus, inhibiting proliferation and increasing apoptosis of neuroblastoma cells. Notably, the combination of CKS2 knockdown and importazole treatment produced a stronger anti-tumor effect than either intervention alone. These findings demonstrate that CKS2 promotes neuroblastoma progression by facilitating cell division via the CDK1/Cyclin B1 complex. Targeting CKS2, especially in combination with nuclear import inhibition, offers a promising therapeutic strategy for neuroblastoma.
细胞周期蛋白依赖性激酶调节亚基2（CKS2）是细胞周期的关键调节因子，但其在神经母细胞瘤中的作用仍知之甚少。本研究通过生物信息学分析以及体外和体内实验，探讨了CKS2在神经母细胞瘤中的功能和机制。来自GEO和TCGA数据库的数据表明，CKS2表达升高与神经母细胞瘤的不良预后相关。对临床肿瘤样本和细胞系的分析进一步证实，CKS2显著过表达，尤其是在高危神经母细胞瘤患者来源的组织中。功能研究表明，敲低CKS2可降低神经母细胞瘤细胞的增殖和侵袭能力，诱导细胞凋亡，并导致细胞周期停滞。在体内，由CKS2沉默细胞形成的肿瘤生长明显减缓。机制上，敲低CKS2可降低CDK1（Thr161）和细胞周期蛋白B1（Ser126）的磷酸化水平，提示细胞分裂信号受损。用输入蛋白-β抑制剂importazole处理可使CKS2在细胞质而非细胞核中积累，从而抑制神经母细胞瘤细胞的增殖并增加其凋亡。值得注意的是，敲低CKS2与importazole处理联合使用产生的抗肿瘤作用比单独使用任何一种干预措施都更强。这些发现表明，CKS2通过CDK1/细胞周期蛋白B1复合物促进细胞分裂，从而推动神经母细胞瘤的进展。靶向CKS2，特别是与核输入抑制联合使用，为神经母细胞瘤提供了一种有前景的治疗策略。
