Abstract
How selectively increase blood-tumor barrier (BTB) permeability is crucial to enhance the delivery of chemotherapeutic agents to brain tumor tissues. In this study, we established in vitro models of the blood-brain barrier (BBB) and BTB using endothelial cells (ECs) co-cultured with human astrocytes (AECs) and glioma cells (GECs), respectively. The findings revealed high expressions of the RNA-binding protein FXR1 and SNORD63 in GECs, where FXR1 was found to bind and stabilize SNORD63. Knockdown of FXR1 resulted in decreased expression of tight-junction-related proteins and increased BTB permeability by down-regulating SNORD63. SNORD63 played a role in mediating the 2'-O-methylation modification of POU6F1 mRNA, leading to the downregulation of POU6F1 protein expression. POU6F1 showed low expression in GECs and acted as a transcription factor to regulate BTB permeability by binding to the promoter regions of ZO-1, occludin, and claudin-5 mRNAs and negatively regulating their expressions. Finally, the targeted regulation of FXR1, SNORD63, and POU6F1 expressions, individually or in combination, effectively enhanced doxorubicin passage through the BTB and induced apoptosis in glioma cells. This study aims to elucidate the underlying mechanism of the FXR1/SNORD63/POU6F1 axis in regulating BTB permeability, offering a novel strategy to improve the efficacy of glioma chemotherapy.