# The RNA-binding protein MSI2 controls blood-tumor barrier permeability via LINC00667-Mediated IRF6 mRNA decay

## TL;DR

This study reveals how the RNA-binding protein MSI2 influences blood-tumor barrier permeability in glioblastoma through a pathway involving LINC00667 and IRF6, potentially offering new therapeutic targets.

## Contribution

The study identifies a novel MSI2/LINC00667/IRF6 pathway that modulates blood-tumor barrier permeability in glioblastoma.

## Key findings

- MSI2 stabilizes LINC00667, and its knockdown increases blood-tumor barrier permeability.
- LINC00667 promotes IRF6 mRNA degradation, leading to reduced tight junction protein expression.
- Modulating MSI2, LINC00667, and IRF6 enhances doxorubicin permeability and GB cell apoptosis.

## Abstract

Increasing evidence shows that RNA-binding proteins play crucial roles in modulating the blood-tumor barrier (BTB) permeability in glioblastoma (GB). In this study, we identified elevated expression of Musashi RNA-binding protein 2 (MSI2) and Long intergenic nonprotein coding RNA 667 (LINC00667) in glioma co-cultured endothelial cells. MSI2 enhanced the stability of LINC00667, and its knockdown elevated the BTB permeability. In contrast, transcription factor interferon regulatory factor 6 (IRF6) exhibited reduced expression in glioma co-cultured endothelial cells, and its over-expression elevated the BTB permeability. Mechanistically, LINC00667 facilitated IRF6 mRNA degradation through Staufen1-mediated mRNA decay pathway. IRF6 inhibited the transcriptions of key tight junction associated proteins (ZO-1, occludin, and claudin-5) through promoter binding. That is, MSI2 knockdown down-regulated the expression of LINC00667, thereby diminishing its ability to degrade IRF6 through the Staufen1-mediated mRNA decay pathway. This led to IRF6 accumulation, which transcriptionally suppressed ZO-1, occludin and claudin-5 expression, ultimately increasing BTB permeability. Furthermore, both individual and combined modulation of MSI2 knockdown, LINC00667 knockdown and IRF6 over-expression enhanced BTB permeability to doxorubicin, thereby increasing the apoptosis rate of GB cells. Collectively, the MSI2/LINC00667/IRF6 pathway plays an important role in modulating BTB permeability, offering potential targets for new molecular therapies in GB.