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

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.

Long Non-Coding RNAs in Diagnosis, Treatment, Prognosis, and Progression of Glioma: A State-of-the-Art Review

“…Multiple studies reported increased expression and an oncogenic effect for NEAT1 in glioma (147)(148)(149)(150)(151)(152)(153)(154)(155)(156)(157)(158)(159)(160). NEAT1 increased the activity of several signaling pathways with key roles in the cell cycle, including WNT/b-Catenin and mTOR signaling, leading to increased proliferation, invasion, and metastasis and decreased apoptosis.…”

“…Determining treatment response : lncRNAs modulate treatment response by affecting sensitivity to chemotherapy drugs, mainly TMZ or cisplatin, or altering radiosensitivity. Higher NEAT1 ( 151 , 160 ), XIST ( 172 ), FOXD2-AS1 ( 189 , 192 ), TP73-AS1 ( 251 ), CCAT2 ( 252 ), and lncSBF2-AS1 ( 241 ) were associated with TMZ-resistance. These effects are mediated via several mechanisms.…”

“…These effects are mediated via several mechanisms. For instance, NEAT1 promoted glioma stem cell formation, which is critical for chemoresistance, via activating the Wnt/β-catenin pathway ( 160 ). In another example, FOXD2-AS1 reduced methylation and increased activity of O 6 -methylguanine-DNA methyltransferase (MGMT), which is a treatment response predictor in glioma ( 192 ).…”

Long, Noncoding RNA Dysregulation in Glioblastoma

“…It was later found that miR-370-3p is downregulated in GBM, which contributes to the increased expression of NEAT1 by reducing its inhibition [105]. The effect of NEAT1 on β-catenin activity also contributes to therapeutic resistance-TMZ induces the expression of the HMGB1 protein, which, via TLR2, increases NEAT1 expression [106]. The HOTAIRM1 lncRNA is expressed within the HOXA gene cluster and promotes DNA looping by scaffolding with the HOXA9 gene to form a topologically associated domain.…”

Ivacaftor Inhibits Glioblastoma Stem Cell Maintenance and Tumor Progression

“…However, more than 50% of glioma patients received TMZ treatment show resistance to TMZ therapy ( Lee, 2016 ). This is attributed to GSCs recalcitrance to TMZ therapy due to their enhanced DNA repair ability or/and high methyl guanine methyl transferase expression ( Hu et al, 2019 ; Gao et al, 2021 ). Small molecule compounds, including clofoctol ( Hu et al, 2019 ), LLP-3 ( Guvenc et al, 2013 ), gboxin ( Shi Y. F. et al, 2019 ), inhibitor of dopamine receptor D4 ( Dolma et al, 2016 ), and inhibitor of STAT3 ( Shi et al, 2018 ), have been documented to inhibit GSCs self-renewal ability.…”