Hypoxia-induced HMGB1 promotes glioma stem cells self-renewal and tumorigenicity via RAGE

Cuifang Ye; Huan Li; Yachao Li; Yang Zhang; Guohao Liu; Hailong Mi; Honglian Li; Qungen Xiao; Li Niu; Xingjiang Yu

doi:10.1016/j.isci.2022.104872

Hypoxia-induced HMGB1 promotes glioma stem cells self-renewal and tumorigenicity via RAGE

iScience. 2022 Aug 4;25(9):104872. doi: 10.1016/j.isci.2022.104872. eCollection 2022 Sep 16.

Authors

Cuifang Ye¹, Huan Li¹, Yachao Li¹, Yang Zhang¹, Guohao Liu², Hailong Mi¹, Honglian Li¹, Qungen Xiao², Li Niu³, Xingjiang Yu¹

Affiliations

¹ Department of Histology and Embryology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China.
² Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China.
³ Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan 430071, P.R. China.

Abstract

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.

Keywords: Biological sciences; Cancer; Cell biology; Microenvironment; Molecular biology.