IGF2BP2 stabilized FBXL19-AS1 regulates the blood-tumour barrier permeability by negatively regulating ZNF765 by STAU1-mediated mRNA decay

Xiaobai Liu; Peiqi Wu; Rui Su; Yixue Xue; Chunqing Yang; Di Wang; Xuelei Ruan; Jian Zheng; Yang Yang; Zhen Li; Yunhui Liu

doi:10.1080/15476286.2020.1795583

IGF2BP2 stabilized FBXL19-AS1 regulates the blood-tumour barrier permeability by negatively regulating ZNF765 by STAU1-mediated mRNA decay

RNA Biol. 2020 Dec;17(12):1777-1788. doi: 10.1080/15476286.2020.1795583. Epub 2020 Jul 25.

Authors

Xiaobai Liu^{1

2

3}, Peiqi Wu^{4

5

6}, Rui Su^{4

5

6}, Yixue Xue^{4

5

6}, Chunqing Yang^{1

2

3}, Di Wang^{1

2

3}, Xuelei Ruan^{4

5

6}, Jian Zheng^{1

2

3}, Yang Yang^{1

2

3}, Zhen Li^{1

2

3}, Yunhui Liu^{1

2

3}

Affiliations

¹ Department of Neurosurgery, Shengjing Hospital of China Medical University , Shenyang, China.
² Liaoning Clinical Medical Research Center in Nervous System Disease , Shenyang, China.
³ Key Laboratory of Neuro-oncology in Liaoning Province , Shenyang, China.
⁴ Department of Neurobiology, School of Life Sciences, China Medical University , Shenyang, China.
⁵ Key Laboratory of Cell Biology, Ministry of Public Health of China, China Medical University , Shenyang, China.
⁶ Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University , Shenyang, China.

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 3'-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.

Keywords: FBXL19-AS1; IGF2BP2; blood-tumour barrier; stau1-mediated decay.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Cytoskeletal Proteins / metabolism*
DNA-Binding Proteins / genetics*
Endothelial Cells / metabolism
F-Box Proteins / genetics*
Gene Expression Regulation, Neoplastic*
Gene Knockdown Techniques
Humans
Nonsense Mediated mRNA Decay
Permeability
Protein Binding
RNA Stability
RNA, Long Noncoding / genetics*
RNA-Binding Proteins / genetics*
RNA-Binding Proteins / metabolism*
Transcriptome
Tumor Microenvironment* / genetics

Substances

Cytoskeletal Proteins
DNA-Binding Proteins
F-Box Proteins
FBXL19 protein, human
IGF2BP2 protein, human
RNA, Long Noncoding
RNA-Binding Proteins
STAU1 protein, human

Grants and funding

This work was supported by grants from the Natural Science Foundation of China (81872073, 81672511, 81872503), China Postdoctoral Science Foundation (2019M661172), Liaoning Science and Technology Plan Project (2020-BS-097, 2017225020), Project of Key Laboratory of Neuro-oncology in Liaoning Province (112-2400017005) and outstanding scientific fund of Shengjing hospital (No. 201802).