PIWIL1/piRNA-DQ593109 Regulates the Permeability of the Blood-Tumor Barrier via the MEG3/miR-330-5p/RUNX3 Axis

Shuyuan Shen; Hai Yu; Xiaobai Liu; Yunhui Liu; Jian Zheng; Ping Wang; Wei Gong; Jiajia Chen; Lini Zhao; Yixue Xue

doi:10.1016/j.omtn.2017.12.020

PIWIL1/piRNA-DQ593109 Regulates the Permeability of the Blood-Tumor Barrier via the MEG3/miR-330-5p/RUNX3 Axis

Mol Ther Nucleic Acids. 2018 Mar 2:10:412-425. doi: 10.1016/j.omtn.2017.12.020. Epub 2017 Dec 30.

Authors

Shuyuan Shen¹, Hai Yu², Xiaobai Liu², Yunhui Liu², Jian Zheng², Ping Wang¹, Wei Gong¹, Jiajia Chen¹, Lini Zhao¹, Yixue Xue³

Affiliations

¹ 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.
² 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.
³ 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. Electronic address: xueyixue888@163.com.

Abstract

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.

Keywords: MEG3; PIWIL1; RUNX3; blood-tumor barrier; miR-330-5p; piR-DQ593109.