Abstract
Antiangiogenic therapy plays a significant role in combined glioma treatment. However, poor permeability of the blood–tumor barrier (BTB) limits the transport of chemotherapeutic agents, including antiangiogenic drugs, into tumor tissues. Long non-coding RNAs (lncRNAs) have been implicated in various diseases, especially malignant tumors. The present study found that lncRNA X-inactive-specific transcript (XIST) was upregulated in endothelial cells that were obtained in a BTB model in vitro. XIST knockdown increased BTB permeability and inhibited glioma angiogenesis. The analysis of the mechanism of action revealed that the reduction of XIST inhibited the expression of the transcription factor forkhead box C1 (FOXC1) and zonula occludens 2 (ZO-2) by upregulating miR-137. FOXC1 decreased BTB permeability by increasing the promoter activity and expression of ZO-1 and occludin, and promoted glioma angiogenesis by increasing the promoter activity and expression of chemokine (C–X–C motif) receptor 7b (CXCR7). Overall, the present study demonstrates that XIST plays a pivotal role in BTB permeability and glioma angiogenesis, and the inhibition of XIST may be a potential target for the clinical management of glioma.
Highlights
Glioblastoma (GBM) is the most lethal brain tumor, which is generally incurable
The western blot assays showed that glioma endothelial cells (GECs) in the X-inactive-specific transcript (XIST)( − ) group presented group compared with the XIST( − ) negative control (NC) group, lower expression of zonula occludens (ZO)-1, zonula occludens 2 (ZO-2) and occludin compared with the indicating that XIST inhibition impaired blood–tumor barrier (BTB) integrity
Consistent with the western peroxidase (HRP) flux was much higher in the XIST( − ) group than blot results, immunofluorescence confirmed that XIST inhibition in the XIST( − )NC group (Figure 1c), indicating that XIST inhibition suppressed ZO-1, ZO-2 and occludin expression, with disincreased BTB permeability
Summary
Glioblastoma (GBM) is the most lethal brain tumor, which is generally incurable. Surgical resection combined with postoperative radiochemotherapy is a common treatment strategy for the tumors, but the median survival time for patients with GBM remains disheartening.[1] GBM is characterized by the elevated expression of proangiogenic factors and heightened tumor angiogenesis,[2] which makes antiangiogenic therapy promising for GBM treatment. The blood–tumor barrier (BTB) mainly consists of highly specialized endothelial cells (ECs). It restricts the delivery of most antitumor drugs to the brain tumor,[3] which mitigates the effects of chemotherapy. Increasing BTB permeability in parallel with inhibiting glioma angiogenesis may be a more efficient treatment strategy for glioma
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