1. Academic Validation
  2. Temozolomide Treatment Induces HMGB1 to Promote the Formation of Glioma Stem Cells via the TLR2/NEAT1/Wnt Pathway in Glioblastoma

Temozolomide Treatment Induces HMGB1 to Promote the Formation of Glioma Stem Cells via the TLR2/NEAT1/Wnt Pathway in Glioblastoma

  • Front Cell Dev Biol. 2021 Feb 1;9:620883. doi: 10.3389/fcell.2021.620883.
Xiang-Yu Gao 1 2 Jian Zang 1 Min-Hua Zheng 3 Yu-Fei Zhang 1 Kang-Yi Yue 1 2 Xiu-Li Cao 3 Yuan Cao 1 2 Xin-Xin Li 4 Hua Han 1 Xiao-Fan Jiang 2 Liang Liang 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China.
  • 2 Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
  • 3 Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, China.
  • 4 Institute of Medical Research, Northwestern Polytechnical University, Xi'an, China.
Abstract

Formation of glioma stem cells (GSCs) is considered as one of the main reasons of temozolomide (TMZ) resistance in glioma patients. Recent studies have shown that tumor microenvironment-derived signals could promote GSCs formation. But the critical molecule and underlying mechanism for GSCs formation after TMZ treatment is not entirely identified. Our study showed that TMZ treatment promoted GSCs formation by glioma cells; TMZ treatment of biopsy-derived glioblastoma multiforme cells upregulated HMGB1; HMGB1 altered gene expression profile of glioma cells with respect to mRNA, lncRNA and miRNA. Furthermore, our results showed that TMZ-induced HMGB1 increased the formation of GSCs and when HMGB1 was downregulated, TMZ-mediated GSCs formation was attenuated. Finally, we showed that the effect of HMGB1 on glioma cells was mediated by TLR2, which activated Wnt/β-catenin signaling to promote GSCs. Mechanistically, we found that HMGB1 upregulated NEAT1, which was responsible for Wnt/β-catenin activation. In conclusion, TMZ treatment upregulates HMGB1, which promotes the formation of GSCs via the TLR2/NEAT1/Wnt pathway. Blocking HMGB1-mediated GSCs formation could serve as a potential therapeutic target for preventing TMZ resistance in GBM patients.

Keywords

NEAT1; TLR2; Wnt; glioma stem cell; high mobility group box 1; temozolomide.

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