Treatment Induces HMGB1 to Promote the Formation of Glioma Stem Cells

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Treatment Induces HMGB1 to Promote the Formation of Glioma Stem Cells (1)

Glioblastoma multiforme (GBM) is the most common primary brain tumor with the average survival of only about 15 months in patients receiving appropriate treatment such as radiotherapy and chemotherapy. Temozolomide (TMZ) is one of the few medicines with a proven efficiency against GBM by inducing tumor cell death via methylating DNA. Cancer stem-like cells (CSCs) the main cause of tumor recurrence after chemotherapy with TMZ. Tumor microenvironment (TME), which is composed of immune cells, perivascular cells, fibroblasts and factors secreted by these cells, can provide extracellular signals for the generation and maintenance of CSCs. High-mobility group box 1 (HMGB1) derived from tumor cells or TME could promote the CSCs phenotype in lung, colon, pancreatic cancer cells. TMZ treatment upregulates HMGB1 in GBM cells in vitro. HMGB1 mediates the effect of TMZ in inducing the formation of GSCs via TLR2/NEAT1/Wnt/β-catenin signaling, thus might promote the resistance to TMZ in GBM patients.

TMZ upregulated HMGB1 from biopsy-derived GBM cells from patients at both mRNA and protein levels. The release of HMGB1 protein was significantly increased in the culture supernatants after TMZ treatment. A total of 115 upregulated and 104 downregulated encoding genes were still detected in GBM cells treated with HMGB1.

Cultured GBM cells with different concentrations of HMGB1 showed that the number and size of tumor spheres under the neural sphere culture condition increased proportionally with increasing HMGB1 concentrations. These tumor spheres were able to differentiate into MAP2+ neurons, O4+ oligodendrocytes and GFAP+ astrocytes, and the expression of GSCs marker CD133 and pluripotency factors including SOX2, OCT4 and NANOG were upregulated proportionally in GBM cells treated with increasing HMGB1 concentrations.

The effect of HMGB1 on the expression of different receptors in GBM cells was evaluated by qRT-PCR. The data showed that TLR2, TLR4, TLR9 and RAGE were accumulated in GBM cells treated with HMGB1 at a concentration of 800 ng/ml, and the expression of TLR2 increased most remarkably. Consistently, the protein level of TLR2 was upregulated when GBM cells were treated with HMGB1. In GBM cells, which were transfected with TLR2 siRNAs, simulated by HMGB1, the mRNA and protein levels of CD133, SOX2, OCT4, and NANOG were downregulated when TLR2 was knocked down. Consistently, the number and the size of tumor spheres decreased significantly by TLR2 siRNAs compared with the negative control.

Extracellular HMGB1 could enhance and maintain the stemness of CSCs in breast cancer, colorectal cancer and pancreatic cancer. Glioblastoma cells released HMGB1 into extracellular space after TMZ treatment and HMGB1 in TME could increase the formation of GSCs. Activation of TLR2 promotes tumor invasion by upregulating MMPs in glioma stem cells, and affects cancer cell behaviors by activating several downstream signaling pathways, including NF-kB, PI3K/Akt and Wnt/β-catenin pathways.

Combining TMZ and an HMGB1 inhibitor may be considered as a future therapeutic strategy.

1. X.-Y. Gao, J. Zang, M.-H. Zheng, Y.-F. Zhang, K.-Y. Yue, X.-L. Cao, Y. Cao, X.-X. Li, H. Han, X.-F. Jiang, L. Liang, Temozolomide Treatment Induces HMGB1 to Promote the Formation of Glioma Stem Cells via the TLR2/NEAT1/Wnt Pathway in Glioblastoma. Front Cell Dev Biol. 9, 620883 (2021).

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