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  2. Programmed cell death 10 increased blood-brain barrier permeability through HMGB1/TLR4 mediated downregulation of endothelial ZO-1 in glioblastoma

Programmed cell death 10 increased blood-brain barrier permeability through HMGB1/TLR4 mediated downregulation of endothelial ZO-1 in glioblastoma

  • Cell Signal. 2023 Apr 17;110683. doi: 10.1016/j.cellsig.2023.110683.
Sisi Wu 1 Junwen Wang 1 Jingdian Liu 1 Hongtao Zhu 1 Ran Li 1 Xueyan Wan 1 Jin Lei 1 Yu Li 1 Chao You 1 Feng Hu 1 Suojun Zhang 1 Kai Zhao 2 Kai Shu 3 Ting Lei 1
Affiliations

Affiliations

  • 1 Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, PR China.
  • 2 Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, PR China. Electronic address: zhaokai@tjh.tjmu.edu.cn.
  • 3 Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, PR China. Electronic address: kshu@tjh.tjmu.edu.cn.
Abstract

Dysfunction of blood brain barrier (BBB) contributes to the development of peritumoral edema (PTE) and GBM progression. Programmed cell death 10 (PDCD10) exerts various influence on cancers, especially in glioblastoma (GBM). We previously found that PDCD10 expression was positively correlated with PTE extent in GBM. Thus, the present study aims to investigate the emerging role of PDCD10 in regulating BBB permeability in GBM. Here we found that in vitro indirect co-culture of ECs with Pdcd10-overexpressed GL261 cells resulted in a significant increase of FITC-Dextran (MW, 4000) leakage by reducing endothelial zonula occluden-1 (ZO-1) and Claudin-5 expression in ECs respectively. Overexpression of Pdcd10 in GBM cells (GL261) triggered an increase of soluble high mobility group box 1 (HMGB1) release, which in turn activated endothelial toll like receptor 4 (TLR4) and downstream NF-κB, ERK1/2 and Akt signaling in ECs through a paracrine manner. Moreover, Pdcd10-overexpressed GL261 cells facilitated a formation of abnormal vasculature and increased the BBB permeability in vivo. Our present study demonstrates that upregulation of PDCD10 in GBM triggered HMGB1/TLR4 signaling in ECs and significantly decreased endothelial ZO-1 expression, which in turn dominantly increased BBB permeability and contributed to tumor progression in GBM.

Keywords

Blood brain barrier (BBB); Glioblastoma (GBM); High mobility group box 1 (HMGB1); Programmed cell death 10 (PDCD10); Tight junction (TJ); Toll like receptor 4 (TLR4).

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