Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Jiangsu, Suzhou 215006, China; Department of Neurosurgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an 710054, Shaanxi Province, China.
Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Jiangsu, Suzhou 215006, China.
Exp Cell Res. 2024 Jun 1;439(1):114091. doi: 10.1016/j.yexcr.2024.114091. Epub 2024 May 11.
Resatorvid (TAK-242), a small-molecule inhibitor of Toll-like receptor 4 (TLR4), has the ability to cross the blood-brain barrier (BBB). In this study, we explored the role of TAK-242 on glioblastoma (GBM) invasion, migration, and proneural-mesenchymal transition (PMT). RNA sequencing (RNA-Seq) data and full clinical information of glioma patients were downloaded from the Chinese Glioma Genome Atlas (CGGA) and the Cancer Genome Atlas (TCGA) cohorts and then analyzed using R language; patients were grouped based on proneural (PN) and mesenchymal (MES) subtypes. Bioinformatics analysis was used to detect the difference in survival and TLR4-pathway expression between these groups. Cell viability assay, wound-healing test, and transwell assay, as well as an intracranial xenotransplantation mice model, were used to assess the functional role of TAK-242 in GBM in vitro and in vivo. RNA-Seq, Western blot, and immunofluorescence were employed to investigate the possible mechanism. TLR4 expression in GBM was significantly higher than in normal brain tissue and upregulated the expression of MES marker genes. Moreover, TAK-242 inhibited GBM progression in vitro and in vivo via linking with PMT, which could be a novel treatment strategy for inhibiting GBM recurrence.
Resatorvid（TAK-242）是一种 Toll 样受体 4（TLR4）的小分子抑制剂，能够穿透血脑屏障（BBB）。在这项研究中，我们探讨了 TAK-242 对神经胶质瘤（GBM）侵袭、迁移和神经前-间质转化（PMT）的作用。从中国脑胶质瘤基因组图谱（CGGA）和癌症基因组图谱（TCGA）队列中下载了胶质瘤患者的 RNA 测序（RNA-Seq）数据和完整的临床信息，并使用 R 语言进行分析；根据神经前体（PN）和间质（MES）亚型对患者进行分组。生物信息学分析用于检测这些组之间生存和 TLR4 通路表达的差异。细胞活力测定、划痕愈合试验和 Transwell 分析以及颅内异种移植小鼠模型用于评估 TAK-242 在体外和体内对 GBM 的功能作用。RNA-Seq、Western blot 和免疫荧光用于研究可能的机制。GBM 中的 TLR4 表达明显高于正常脑组织，并上调了 MES 标记基因的表达。此外，TAK-242 通过与 PMT 结合抑制了 GBM 在体外和体内的进展，这可能是抑制 GBM 复发的一种新的治疗策略。
