Diallo Maladho Tanta, Chen Bangquan, Yan Zhang, Sun Qiannan, Liu Guanghao, Wang Yong, Ren Jun, Wang Daorong
Northern Jiangsu People's Hospital, Yangzhou 225001, China; Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225001, China; General Surgery Institute of Yangzhou, Yangzhou University, Yangzhou 225001, China; Yangzhou Key Laboratory of Basic and Clinical Transformation of Digestive and Metabolic Diseases, Yangzhou, 225001, China.
Northern Jiangsu People's Hospital, Yangzhou 225001, China; Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225001, China; General Surgery Institute of Yangzhou, Yangzhou University, Yangzhou 225001, China.
Cell Signal. 2025 Jan;125:111514. doi: 10.1016/j.cellsig.2024.111514. Epub 2024 Nov 21.
KIF3C serves as a motor protein that facilitates axonal transport in neuronal cells. It belongs to the kinesin superfamily and plays a crucial role in the development of various cancers. However, the role of KIF3C in gastric cancer (GC) the third-highest cause of cancer-related deaths remains unclear. To investigate the regulatory mechanisms and expression patterns of KIF3C in GC and their implications for GC progression, we conducted a series of in vitro and in vivo experiments.
We employed bioinformatics tools, including GEPIA, Kaplan-Meier plotter, and cBioPortal, to examine the role of KIF3C in GC, with a focus on its prognostic significance and associated signaling pathways. Furthermore, we conducted immunohistochemistry, real-time polymerase chain reaction (RT-PCR), western blot analyses, cell function and signaling pathway experiments. We further assessed the impact of combination therapy with afatinib and MT-DC (ac) phosphoramidite alongside KIF3C knockdown and overexpression in GC cells and a xenograft mouse model experiment.
Kaplan-Meier and Cox regression analyses revealed that high KIF3C expression in GC is significantly associated with poor prognosis. Genomic alteration and immune microenvironment analyses provided insights into the underlying causes of abnormal KIF3C expression. We observed that KIF3C knockdown decreased the proliferation of GC tumor cells. Additionally, KIF3C was overexpressed in GC and elevated expression was significantly correlated with tumor prognosis. We demonstrated that KIF3C knockdown and overexpression could significantly inhibit and promote tumor cell proliferation, respectively, through the combination therapy by modulating PI3K, AKT, and cell cycle signaling pathways. Notably, tumor size and the number of GC nodules were significantly reduced in the Sh-KIF3C group compared to the Sh-ctrl group.
Our findings highlight the potential of KIF3C as a biomarker for tumor progression diagnosis, establishing it as a pivotal therapeutic target for combating tumor advancement in GC.
驱动蛋白家族成员3C（KIF3C）作为一种驱动蛋白，促进神经元细胞中的轴突运输。它属于驱动蛋白超家族，在多种癌症的发展中起关键作用。然而，KIF3C在胃癌（GC）（癌症相关死亡的第三大原因）中的作用仍不清楚。为了研究KIF3C在GC中的调控机制、表达模式及其对GC进展的影响，我们进行了一系列体外和体内实验。
我们使用了包括GEPIA、Kaplan-Meier Plotter和cBioPortal在内的生物信息学工具，研究KIF3C在GC中的作用，重点关注其预后意义和相关信号通路。此外，我们进行了免疫组织化学、实时聚合酶链反应（RT-PCR）、蛋白质免疫印迹分析、细胞功能和信号通路实验。我们还评估了阿法替尼和亚磷酰胺修饰的甘露糖基-β-环糊精（MT-DC（ac））联合治疗以及KIF3C敲低和过表达对GC细胞和异种移植小鼠模型实验的影响。
Kaplan-Meier和Cox回归分析显示，GC中KIF3C高表达与预后不良显著相关。基因组改变和免疫微环境分析为KIF3C异常表达的潜在原因提供了见解。我们观察到KIF3C敲低降低了GC肿瘤细胞的增殖。此外，KIF3C在GC中过表达，其表达升高与肿瘤预后显著相关。我们证明，通过调节PI3K、AKT和细胞周期信号通路的联合治疗，KIF3C敲低和过表达分别可以显著抑制和促进肿瘤细胞增殖。值得注意的是，与对照短发夹RNA（Sh-ctrl）组相比，短发夹RNA干扰KIF3C（Sh-KIF3C）组的肿瘤大小和GC结节数量显著减少。
我们的研究结果突出了KIF3C作为肿瘤进展诊断生物标志物的潜力，使其成为对抗GC肿瘤进展的关键治疗靶点。
