RBFOX1 Regulates the Permeability of the Blood-Tumor Barrier via the LINC00673/MAFF Pathway.,Molecular Therapy: Oncology

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RBFOX1 Regulates the Permeability of the Blood-Tumor Barrier via the LINC00673/MAFF Pathway.
Molecular Therapy: Oncology ( IF 5.3 ) Pub Date : 2020-03-30 , DOI: 10.1016/j.omto.2020.03.014
Shuyuan Shen _{1,

2,

3} , Chunqing Yang _{4,

5,

6} , Xiaobai Liu _{4,

5,

6} , Jian Zheng _{4,

5,

6} , Yunhui Liu _{4,

5,

6} , Libo Liu _{1,

2,

3} , Jun Ma _{1,

2,

3} , Teng Ma _{1,

2,

3} , Ping An _{1,

2,

3} , Yang Lin _{1,

2,

3} , Heng Cai _{4,

5,

6} , Di Wang _{4,

5,

6} , Zhen Li _{4,

5,

6} , Lini Zhao ₇ , Yixue Xue _{1,

2,

3}

Affiliation

The blood-tumor barrier limits the delivery of therapeutic drugs to brain tumor tissues. Selectively opening the blood-tumor barrier is considered crucial for effective chemotherapy of glioma. RNA-binding proteins have emerged as crucial regulators in various biologic processes. This study found that RNA-binding Fox-1 homolog 1 (RBFOX1) was downregulated in glioma vascular endothelial cells derived from glioma tissues, and in glioma endothelial cells obtained by co-culturing endothelial cells with glioma cells. Overexpression of RBFOX1 impaired the integrity of the blood-tumor barrier and increased its permeability. Additionally, RBFOX1 overexpression decreased the expression of tight junction proteins ZO-1, occludin, and claudin-5. Subsequent analysis of the mechanism indicated that the overexpression of RBFOX1 increased musculoaponeurotic fibrosarcoma protein basic leucine zipper [bZIP] transcription factor F (MAFF) expression by downregulating LINC00673, which stabilized MAFF messenger RNA (mRNA) through Staufen1-mediated mRNA decay. Moreover, MAFF could bind to the promoter region and inhibit the promoter activities of ZO-1, occludin, and claudin-5, which reduced its expression. The combination of RBFOX1 upregulation and LINC00673 downregulation promoted doxorubicin delivery across the blood-tumor barrier, resulting in apoptosis of glioma cells. In conclusion, this study indicated that overexpression of RBFOX1 increased blood-tumor barrier permeability through the LINC00673/MAFF pathway, which might provide a new useful target for future enhancement of blood-tumor barrier permeability.

中文翻译：

RBFOX1通过LINC00673 / MAFF通路调节血液肿瘤屏障的通透性。

血液肿瘤屏障限制了治疗药物向脑肿瘤组织的输送。选择性地打开血液肿瘤屏障被认为是有效治疗神经胶质瘤的关键。RNA结合蛋白已成为各种生物学过程中的关键调节剂。这项研究发现，RNA结合的Fox-1同源物1（RBFOX1）在源自神经胶质瘤组织的神经胶质瘤血管内皮细胞以及通过将内皮细胞与神经胶质瘤细胞共同培养获得的神经胶质瘤内皮细胞中被下调。RBFOX1的过表达损害血液肿瘤屏障的完整性并增加其通透性。此外，RBFOX1过表达降低了紧密连接蛋白ZO-1，occludin和claudin-5的表达。随后对该机制的分析表明，RBFOX1的过表达通过下调LINC00673来增加肌腱膜纤维化肉瘤蛋白碱性亮氨酸拉链[bZIP]转录因子F（MAFF）的表达，该蛋白通过Staufen1介导的mRNA衰变来稳定MAFF信使RNA（mRNA）。此外，MAFF可以绑定到启动子区域并抑制ZO-1，occludin和claudin-5的启动子活性，从而降低其表达。RBFOX1上调和LINC00673下调的组合促进了阿霉素跨血肿瘤屏障的传递，导致神经胶质瘤细胞凋亡。总之，这项研究表明RBFOX1的过表达通过LINC00673 / MAFF途径增加了血液肿瘤屏障通透性，

更新日期：2020-03-30

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