Abstract
The existence of blood–tumor barrier (BTB) severely restricts the efficient delivery of antitumor drugs to cranial glioma tissues. Various strategies have been explored to increase BTB permeability. RNA-binding proteins and circular RNAs have recently emerged as potential regulators of endothelial cells functions. In this study, RNA-binding protein KH RNA-binding domain containing, signal transduction associated 3 (KHDRBS3) and circular RNA DENND4C (cDENND4C) were enriched in GECs. KHDRBS3 bound to cDENND4C and increased its stability. The knockdown of cDENND4C increased the permeability of BTB via downregulating the expressions of tight junction-related proteins. The miR-577 was lower expressed in GECs. The overexpressed miR-577 increased the permeability of BTB by reducing the tight junction-related protein expressions, and vice versa. Furthermore, cDENND4C acted as a molecular sponge of miR-577, which bound to miR-577 and inhibited its negative regulation of target genes ZO-1, occludin and claudin-1 to regulate BTB permeability. Single or combined treatment of KHDRBS3, cDENND4C, and miR-577 effectively promoted antitumor drug doxorubicin (DOX) across BTB to induce apoptosis of glioma cells. Collectively, the present study indicated that KHDRBS3 could regulate BTB permeability through the cDENND4C/miR-577 axis, which enhanced doxorubicin delivery across BTB. These findings may provide a novel strategy for chemotherapy of brain tumors.
Highlights
Glioma is the most-common malignant central nervous system tumor[1]
The results showed that compared with the sh-KHDRBS3-NC group, the expressions of ZO-1, occludin, and claudin-1 in the sh-KHDRBS3 group were significantly reduced
The results showed that cDENND4C and miR-577 double knockdown could significantly reverse the decreased Transendothelial electric resistance (TEER) value and increased horseradish peroxidase (HRP) flux induced by cDENND4C knockdown (Fig. 5c, d)
Summary
KHDRBS3 was highly expressed in GECs, and silencing of KHDRBS3 increased BTB permeability. In order to explore the mechanism of miR-577 involved in regulating BTB permeability, the effects of miR-577 knockdown or overexpression on tight junction-related protein ZO-1, occludin, and claudin-1 in GECs were detected. The results showed that cDENND4C and miR-577 double knockdown could significantly reverse the decreased TEER value and increased HRP flux induced by cDENND4C knockdown (Fig. 5c, d).
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