SHF Acts as a Novel Tumor Suppressor in Glioblastoma Multiforme by Disrupting STAT3 Dimerization

Wang, Jingjing; Huang, Zixuan; Li, Ji; Chen, Cheng; Wan, Quan; Xin, Yu; Pu, Zhening; Li, Koukou; Jiao, Jiantong; Yin, Ying; Hu, Yaling; Gong, Lingli; Zhang, Rui; Yang, Xusheng; Fang, Xiangming; Wang, Mei; Zhang, Bo; Shao, Jianghua; Zou, Jian

doi:10.1002/advs.202200169

Cited by 8 publications

(5 citation statements)

References 50 publications

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“…STAT3 has been shown to have the potential as a therapeutic target for glioma [12]. The continuous activation of STAT3 in glioma cell can promote proliferation and migration and inhibit apoptosis [13,14]. This study found that bergaptol treatment significantly reduced p-STAT3 phosphorylation ratio and Bcl-2 protein levels and increased Caspase-3 expression dose dependently (Fig.…”

Section: Resultsmentioning

confidence: 66%

Bergaptol inhibits glioma cell proliferation and induces apoptosis via STAT3/Bcl-2 pathway

Huang,

Zhang,

et al. 2024

Anti-Cancer Drugs

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Glioblastoma (GBM) is the most common primary malignant brain tumour and lacks therapeutic options with significant effects. The aberrant activation of STAT3 is a critical factor in glioma progression via activating multiple signalling pathways that promote glioma. Among them, the antiapoptotic gene Bcl-2 could be upregulated by p-STAT3, which is an important reason for the continuous proliferation of glioma. We previously reported that bergaptol, a natural furanocoumarin widely found in citrus products, exerts antineuroinflammatory effects by inhibiting the overactivation of STAT3. Here, we aimed to evaluate whether bergaptol could promote glioma apoptosis by inhibiting the STAT3/Bcl-2 pathway. This study found that bergaptol inhibited the proliferation and migration of GBM cell lines (U87 and A172) and promoted apoptosis in vitro. We also found that bergaptol significantly inhibited the STAT3/Bcl-2 pathway in GBM cells. U87 cells were implanted intracranially into nude mice to establish a glioma model, and glioma-bearing mice were treated with bergaptol (40 mg/kg). Bergaptol treatment significantly inhibited glioma growth and prolonged the glioma-bearing mice’s survival time. In addition, bergaptol administration also significantly inhibited the STAT3/Bcl-2 pathway of tumour tissue in vivo. Overall, we found that bergaptol could effectively play an antiglioma role by inhibiting STAT3/Bcl-2 pathway, suggesting the potential efficacy of bergaptol in treating glioma.

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Section: Resultsmentioning

confidence: 66%

Bergaptol inhibits glioma cell proliferation and induces apoptosis via STAT3/Bcl-2 pathway

Huang,

Zhang,

et al. 2024

Anti-Cancer Drugs

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“…In a bioinformatics analysis, QI et al,(2023) [98] reported that BHLHE40 was overexpressed in 7 of 33 tumor tissues, including GBM tissues, and predicted worse OS in both high-and low-grade gliomas. Among the genes downregulated with MUC1 expression, SHF plays a tumor suppressor role in GBM by negatively regulating signal transducer and activator of transcription 3 (STAT3) activity, and its low expression predicts worse OS [99]. Additionally, low KLHL23 and MATR3 expression is also associated with poor survival in patients with different tumors [100][101][102][103].…”

Section: Discussionmentioning

confidence: 99%

MUC1andMUC4expression are inversely correlated and trigger immunological response and transport pathways in gliomas

Machado,

Ferrer

2024

Preprint

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Diffuse gliomas are tumors that arise from glial or glial progenitor cells. They are currently classified as astrocytoma isocitrate dehydrogenase (IDH)-mutant or oligodendroglioma IDH-mutant, and chromosome arms 1p/19q-codeleted, both slower-growing tumors, or glioblastoma (GBM), a more aggressive tumor. Despite advances in the diagnosis and treatment of gliomas, the median survival time after diagnosis of GBM remains low, approximately 15 months, with a 5-year overall survival rate of only 6.8%. Therefore, new biomarkers and therapy targets that could support better prognosis of these tumors would be of great value. MUC1 and MUC4, membrane-bound mucins, has been identified as a potential biomarker in several tumors. However, the role of these mucins in adult gliomas has not yet been well explored. Here, we show for the first time, in a retrospective study and byin silicoanalysis, the relevance and correlation of these genes in adult gliomas. Analysis of adult diffuse glioma patient cohorts revealed differential methylation and expression patterns of MUC1 and MUC4 across GBM and non-GBM subtypes. GBM patients exhibited decreased MUC1 methylation and elevated expression (r-0.25, p < 0.0001) whereas increased MUC4 methylation and its lower expression (r-0.13, p = 0.1344). Conversely, in non-GBM patients, MUC1 showed higher methylation levels and low expression (r-0.27, p < 0.0001) whereas MUC4 showed lower methylation levels and high expression (r-0.32, p < 0.0001). The expression levels of these genes influenced overall survival (OS) in gliomas patients (p = 0.0344), with high MUC1 and low MUC4 expression associated with worse OS. MUC1 and MUC4 correlated with MUC20 in both GBM (r = 0.54) and non-GBM (r = 0.53) patients (p < 0.0001). Functional enrichment analysis revealed distinct biological roles for co-expressed genes with MUC1 involvement in innate immunity, antigen processing, pro-inflammatory responses in both non-GBM and GBM cohorts, and integrin-based signaling pathways in GBM patients. MUC4 co-expressed genes were involved in ion transport in GBM patients. Using molecular docking, we observed that MUC1 has domains that are physically capable of interacting with immune response-related proteins such as Receptor for Advanced Glycation End-products (RAGE), Major Histocompatibility Complex II (MHCII), and extracellular matrix receptor integrin alpha 2 (ITGA2). These findings shed light on the molecular mechanisms underlying glioma progression and highlight MUC1 and MUC4 as potential prognostic markers and therapeutic targets in glioma management.

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“…The IHC procedure was performed as described in our previous studies. 56 , 57 The slides were incubated with primary antibodies. Cell nuclei were counterstained lightly with crystal violet.…”

Section: Methodsmentioning

confidence: 99%

“…3D-Spheroid formation and growth assay was performed as described previously. 56 , 57 Briefly, the detached cells were resuspended in GBO medium with a minor modification (without insulin) according to a previously published report. 61 Cells were seeded in the non-adherent 96-well plate (Corning, NY) at 400 cells/well.…”

Section: Methodsmentioning

confidence: 99%

SHF Acts as a Novel Tumor Suppressor in Glioblastoma Multiforme by Disrupting STAT3 Dimerization

Cited by 8 publications

References 50 publications

Bergaptol inhibits glioma cell proliferation and induces apoptosis via STAT3/Bcl-2 pathway

Bergaptol inhibits glioma cell proliferation and induces apoptosis via STAT3/Bcl-2 pathway

MUC1andMUC4expression are inversely correlated and trigger immunological response and transport pathways in gliomas

Acetylation halts missense mutant p53 aggregation and rescues tumor suppression in non-small cell lung cancers

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