Ye Cuifang, Li Huan, Li Yachao, Zhang Yang, Liu Guohao, Mi Hailong, Li Honglian, Xiao Qungen, Niu Li, Yu Xingjiang
Department of Histology and Embryology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China.
Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China.
iScience. 2022 Aug 4;25(9):104872. doi: 10.1016/j.isci.2022.104872. eCollection 2022 Sep 16.
Glioma stem cells (GSCs) in the hypoxic niches contribute to tumor initiation, progression, and recurrence in glioblastoma (GBM). Hypoxia induces release of high-mobility group box 1 (HMGB1) from tumor cells, promoting the development of tumor. Here, we report that HMGB1 is overexpressed in human GBM specimens. Hypoxia promotes the expression and secretion of HMGB1 in GSCs. Furthermore, silencing HMGB1 results in the loss of stem cell markers and a reduction in self-renewal ability of GSCs. Additionally, HMGB1 knockdown inhibits the activation of RAGE-dependent ERK1/2 signaling pathway and arrests the cell cycle in GSCs. Consistently, FPS-ZM1, an inhibitor of RAGE, downregulates HMGB1 expression and the phosphorylation of ERK1/2, leading to a reduction in the proliferation of GSCs. In xenograft mice of GBM, HMGB1 knockdown inhibits tumor growth and promotes mouse survival. Collectively, these findings uncover a vital function for HMGB1 in regulating GSC self-renewal potential and tumorigenicity.
缺氧微环境中的胶质瘤干细胞（GSCs）有助于胶质母细胞瘤（GBM）的肿瘤起始、进展和复发。缺氧诱导肿瘤细胞释放高迁移率族蛋白B1（HMGB1），促进肿瘤发展。在此，我们报告HMGB1在人类GBM标本中过表达。缺氧促进GSCs中HMGB1的表达和分泌。此外，沉默HMGB1会导致干细胞标志物丢失以及GSCs自我更新能力降低。另外，HMGB1基因敲低抑制RAGE依赖的ERK1/2信号通路的激活，并使GSCs细胞周期停滞。同样，RAGE抑制剂FPS-ZM1下调HMGB1表达和ERK1/2的磷酸化，导致GSCs增殖减少。在GBM异种移植小鼠中，HMGB1基因敲低抑制肿瘤生长并延长小鼠生存期。总体而言，这些发现揭示了HMGB1在调节GSC自我更新潜能和致瘤性方面的重要作用。
