KHDRBS3 regulates the permeability of blood–tumor barrier via cDENND4C/miR-577 axis

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.

TRA2A-induced upregulation of LINC00662 regulates blood-brain barrier permeability by affecting ELK4 mRNA stability in Alzheimer’s microenvironment

“…One of the mechanisms is that RBPs alter the stability of non-coding RNAs and regulate vascular endothelial function. For example, Wu et al [ 51] have reported that RBP KHDRBS3 binds to circRNA DENND4C, increases the circRNA's stability and upregulates the expression of tight junction-related proteins, thereby reducing the permeability of blood tumor barrier. Li et al [ 15] have reported that RBP ZRANB2 binds to the lncRNA and increases the lncRNA's stability, thereby affecting the functions of vascular ECs.…”

RETRACTED ARTICLE: Circ-DENND4C up-regulates TCF4 expression to modulate hepatocellular carcinoma cell proliferation and apoptosis via activating Wnt/β-catenin signal pathway

“…MiR-203 is upregulated in breast cancer and regulates cell growth and stemness via targeting SOCS3 [ 10 ]. Previously, a circRNA derived from DENN domain containing 4C (circ-DENND4C) has been newly recognized [ 13 ]. As a hypoxia-associated RNA, circ-DENND4C exhibited a high level and promoted cell proliferation in breast cancer [ 14 ].…”

“…As a hypoxia-associated RNA, circ-DENND4C exhibited a high level and promoted cell proliferation in breast cancer [ 14 ]. It was also reported that circ-DENND4C was involved in the regulation of blood-tumor barrier in glioma [ 13 ]. However, the function and mechanism of circ-DENND4C in HCC remain largely unknown.…”

TRA2A-induced upregulation of LINC00662 regulates blood-brain barrier permeability by affecting ELK4 mRNA stability in Alzheimer’s microenvironment

“…One of the mechanisms is that RBPs alter the stability of non-coding RNAs and regulate vascular endothelial function. For example, Wu et al [49] have reported that RBP KHDRBS3 binds to circRNA DENND4C, increases the circRNA's stability and upregulates the expression of tight junction-related proteins, thereby reducing the permeability of blood tumor barrier. Li et al [15] have reported that RBP ZRANB2 binds to the lncRNA and increases the lncRNA's stability, thereby affecting the functions of vascular ECs.…”