KIF4A Promotes Glioblastoma Malignant Progression and Transmission of Temozolomide Resistance in the Tumor Microenvironment via the HIF1A/VEGFA Axis.

BACKGROUND: Glioblastoma (GBM) represents the most prevalent primary malignant brain tumor. Temozolomide (TMZ) is the primary chemotherapeutic agent administered following surgical resection. However, the emergence of TMZ resistance in patients undergoing chemotherapy significantly diminishes its efficacy. To date, the majority of preclinical studies have been unsuccessful in effectively overcoming TMZ resistance. Prior research has suggested that the KIF4A gene may serve as a prognostic indicator for patients with GBM. Nevertheless, the precise mechanism by which KIF4A contributes to TMZ resistance remains to be elucidated. METHODS: In order to simulate the in vivo growth environment of glioblastoma, transwell co-culture and hypoxia induction were employed. Functional experiments were then conducted in order to verify the effects of KIF4A and HIF1A on the proliferation, migration, invasion, and angiogenic ability of GBM cells. Western blot analysis was employed to determine the protein levels of KIF4A, HIF1A, and VEGFA in GBM cells. ELISA was employed to determine the secreted protein levels of VEGFA and MMP9 in GBM cells. A prognostic model was utilized to assess the clinical utility of the pathway. The intercellular resistance to temozolomide was determined through the use of colony formation assays, flow cytometry, and immunofluorescence. The intercellular communication medium and its mechanism were analyzed by electron microscopy, particle size measurement, and WB experiments. Finally, a xenograft tumor model was utilized to investigate the in vivo function of KIF4A. RESULTS: KIF4A promotes the malignant progression of glioblastoma by regulating the HIF1A/VEGFA axis. GBM cells secrete exosomes to regulate the temozolomide resistance of astrocytes and the expression level of HIF1A/VEGFA protein, thereby making glioblastoma more resistant. CONCLUSION: This study provides a new idea for antagonizing temozolomide resistance in glioblastoma. KIF4A promotes malignant progression of glioblastoma and transmission of TMZ resistance in the tumor microenvironment through the HIF1A/VEGFA axis.