ABSTRACT

Blood-tumour barrier (BTB) has been known to significantly attenuate the efficacy of chemotherapy for glioma. In this report, we identified that insulin-like grown factor 2 mRNA-binding protein 2 (IGF2BP2) was over-expressed in glioma microvessel and glioma endothelial cells (GECs). Knockdown of IGF2BP2 decreased the expression of lncRNA FBXL19-AS1 and tight junction-related proteins, thereby promoting BTB permeability. FBXL19-AS1 was over-expressed and more enriched in the cytoplasm of GECs. In addition, FBXL19-AS1 could bind to 3ʹ-UTR of ZNF765 mRNA and down-regulate ZNF765 mRNA expression through STAU1-mediated mRNA decay (SMD). The low expression of ZNF765 was discovered in GECs and verified to increase BTB permeability by inhibiting the promoter activities of tight junction-related proteins. Meanwhile, ZNF765 also inhibited the transcriptional activity of IGF2BP2, thereby forming a feedback loop in regulating the BTB permeability. Single or combined application of silenced IGF2BP2 and FBXL19-AS1 improved the delivery and antitumor efficiency of doxorubicin (DOX). In general, our study revealed the regulation mechanism of IGF2BP2/FBXL19-AS1/ZNF765 axis on BTB permeability, which may provide valuable insight into treatment strategy for glioma.

摘要

众所周知，血肿瘤屏障 (BTB) 会显着减弱化疗对胶质瘤的疗效。在本报告中，我们发现胰岛素样生长因子 2 mRNA 结合蛋白 2 (IGF2BP2) 在神经胶质瘤微血管和神经胶质瘤内皮细胞 (GEC) 中过度表达。敲除 IGF2BP2 会降低 lncRNA FBXL19-AS1 和紧密连接相关蛋白的表达，从而促进 BTB 通透性。FBXL19-AS1 在 GEC 的细胞质中过度表达并更加富集。此外，FBXL19-AS1 可以与 ZNF765 mRNA 的 3ʹ-UTR 结合，并通过 STAU1 介导的 mRNA 衰减 (SMD) 下调 ZNF765 mRNA 的表达。在 GEC 中发现了 ZNF765 的低表达，并证实通过抑制紧密连接相关蛋白的启动子活性来增加 BTB 通透性。同时，ZNF765 还抑制 IGF2BP2 的转录活性，从而形成调节 BTB 通透性的反馈回路。单独或联合应用沉默的 IGF2BP2 和 FBXL19-AS1 提高了阿霉素 (DOX) 的递送和抗肿瘤效率。总的来说，我们的研究揭示了 IGF2BP2/FBXL19-AS1/ZNF765 轴对 BTB 通透性的调节机制，这可能为胶质瘤的治疗策略提供有价值的见解。