Targeted therapy for KIF3C: A study on the mechanism of combined therapy with KIF3C signaling pathway, afatinib, and MT-DC (ac)phosphoramide in regulating gastric cancer cell proliferation.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.