Shen Shuyuan, Yu Hai, Liu Xiaobai, Liu Yunhui, Zheng Jian, Wang Ping, Gong Wei, Chen Jiajia, Zhao Lini, Xue Yixue
Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang 110122, People's Republic of China; Key Laboratory of Cell Biology, Ministry of Public Health of China, China Medical University, Shenyang 110122, People's Republic of China; Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang 110122, People's Republic of China.
Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China; Liaoning Research Center for Clinical Medicine in Nervous System Disease, Shenyang 110004, People's Republic of China; Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang 110004, People's Republic of China.
Mol Ther Nucleic Acids. 2018 Mar 2;10:412-425. doi: 10.1016/j.omtn.2017.12.020. Epub 2017 Dec 30.
The blood-tumor barrier (BTB) restricts the efficient delivery of anti-glioma drugs to cranial glioma tissues. Increased BTB permeability may allow greater delivery of the therapeutic agents. Increasing evidence has revealed that PIWI proteins and PIWI-interacting RNAs (piRNAs) play an important role in tumor progression. However, whether PIWI proteins and piRNAs regulate BTB permeability remains unclear. In the present study, we demonstrated that the PIWIL1/piRNA-DQ593109 (piR-DQ593109) complex was the predominant regulator of BTB permeability. Briefly, PIWIL1 was upregulated in glioma endothelial cells (GECs). Furthermore, piR-DQ593109 was also overexpressed in GECs, as revealed via a piRNA microarray. Downregulation of PIWIL1 or piR-DQ593109 increased the permeability of the BTB. Moreover, PIWIL1 and piR-DQ593109, which formed a piRNA-induced silencing complex, degraded the long non-coding RNA maternally expressed 3 (MEG3) in a sequenced-dependent manner. Furthermore, restoring MEG3 released post-transcriptional inhibition of Runt related transcription factor 3 (RUNX3) by sponging miR-330-5p. In addition, RUNX3 bounded to the promoter regions and reduced the promoter activities of ZO-1, occludin, and claudin-5, which significantly impaired the expression levels of ZO-1, occludin, and claudin-5. In conclusion, downregulating PIWIL1 and piR-DQ593109 increased BTB permeability through the MEG3/miR-330-5p/RUNX3 axis. These data may provide insight into glioma treatment.
血脑肿瘤屏障（BTB）限制了抗胶质瘤药物向颅内胶质瘤组织的有效递送。BTB通透性的增加可能会使治疗药物的递送量更大。越来越多的证据表明，PIWI蛋白和PIWI相互作用RNA（piRNA）在肿瘤进展中起重要作用。然而，PIWI蛋白和piRNA是否调节BTB通透性仍不清楚。在本研究中，我们证明PIWIL1/piRNA-DQ593109（piR-DQ593109）复合物是BTB通透性的主要调节因子。简而言之，PIWIL1在胶质瘤内皮细胞（GECs）中上调。此外，通过piRNA微阵列检测发现，piR-DQ593109在GECs中也过表达。PIWIL1或piR-DQ593109的下调增加了BTB的通透性。此外，PIWIL1和piR-DQ593109形成了一个piRNA诱导沉默复合物，以序列依赖的方式降解长链非编码RNA母系表达基因3（MEG3）。此外，恢复MEG3可通过海绵吸附miR-330-5p释放对 runt相关转录因子3（RUNX3）的转录后抑制。此外，RUNX3与启动子区域结合并降低了紧密连接蛋白1（ZO-1）、闭合蛋白和Claudin-5的启动子活性，这显著损害了ZO-1、闭合蛋白和Claudin-5的表达水平。总之，下调PIWIL1和piR-DQ593109通过MEG3/miR-330-5p/RUNX3轴增加了BTB通透性。这些数据可能为胶质瘤治疗提供思路。
