Glioblastoma Stem Cell-Derived Exosomes Enhance Stemness and Tumorigenicity of Glioma Cells by Transferring Notch1 Protein

Sun, Zhen; Wang, Li; Zhou, Yongfang; Dong, Liang; Ma, Weichao; Lv, Liang; Zhang, Jie; Wang, Xiu‐Jie

doi:10.1007/s10571-019-00771-8

Cited by 73 publications

(52 citation statements)

References 59 publications

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“…As Notch signaling is important for maintaining stemness of GSCs, 2,21,24 RBPJ, as the cardinal transcription factor of the Notch signaling pathway, may be instrumental for proper GSC function. To investigate this, we first confirmed that RBPJ was expressed in GSCs (Figure 3A).…”

Section: Resultsmentioning

confidence: 99%

RBPJ contributes to the malignancy of glioblastoma and induction of proneural‐mesenchymal transition via IL‐6‐STAT3 pathway

et al. 2020

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Notch signaling plays a pivotal role in many cancers, including glioblastoma (GBM). Recombination signal binding protein for immunoglobulin kappa J region (RBPJ) is a key transcription factor of the Notch signaling pathway. Here, we interrogated the function of RBPJ in GBM. Firstly, RBPJ expression of GBM samples was examined. Then, we knocked down RBPJ expression in 2 GBM cell lines (U251 and T98) and 4 glioblastoma (GBM) stem‐like cell lines derived from surgical samples of GBM (KGS01, KGS07, KGS10 and KGS15) to investigate the effect on cell proliferation, invasion, stemness, and tumor formation ability. Expression of possible downstream targets of RBPJ was also assessed. RBPJ was overexpressed in the GBM samples, downregulation of RBPJ reduced cell proliferation and the invasion ability of U251 and T98 cells and cell proliferation ability and stemness of glioblastoma stem‐like cells (GSC) lines. These were accompanied by reduced IL‐6 expression, reduced activation of STAT3, and inhibited proneural‐mesenchymal transition (PMT). Tumor formation and PMT were also impaired by RBPJ knockdown in vivo. In conclusion, RBPJ promotes cell proliferation, invasion, stemness, and tumor initiation ability in GBM cells through enhanced activation of IL‐6‐STAT3 pathway and PMT, inhibition of RBPJ may constitute a prospective treatment for GBM.

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Section: Resultsmentioning

confidence: 99%

RBPJ contributes to the malignancy of glioblastoma and induction of proneural‐mesenchymal transition via IL‐6‐STAT3 pathway

et al. 2020

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“…It is known that GSCs are responsible for cancer progression and recurrence, and the elimination of GSCs is crucial for treating glioblastoma (38,39). To the best of our knowledge, the association between GASC1 expression and the clinical progression of glioma remains unknown.…”

Section: Discussionmentioning

confidence: 99%

GASC1 promotes glioma progression by enhancing NOTCH1 signaling

et al. 2021

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Recent studies have reported that gene amplified in squamous cell carcinoma 1 (GASC1) is involved in the progression of several types of cancer. However, whether GASC1 promotes glioma progression remains unknown. Therefore, the present study aimed to investigate the effect of GASC1 exposure on glioma tumorigenesis. The western blot demonstrated that grade III and IV glioma tissues exhibited a higher mRNA and protein expression of GASC1. Moreover, CD133 + U87 or U251 cells from magnetic cell separation exhibited a higher GASC1 expression. Invasion Transwell assay, clonogenic assay and wound healing assay have shown that GASC1 inhibition using a pharmacological inhibitor and specific short hairpin (sh)RNA suppressed the invasive, migratory and tumorsphere forming abilities of primary culture human glioma cells. Furthermore, GASC1-knockdown decreased notch receptor (Notch) responsive protein hes family bHLH transcription factor 1 (Hes1) signaling. GASC1 inhibition reduced notch receptor 1 (NOTCH1) expression, and a NOTCH1 inhibitor enhanced the effects of GASC1 inhibition on the CD133 + U87 or U251 cell tumorsphere forming ability, while NOTCH1 overexpression abrogated these effects. In addition, the GASC1 inhibitor caffeic acid and/or the NOTCH1 inhibitor DAPT (a γ-Secretase Inhibitor), efficiently suppressed the human glioma xenograft tumors. Thus, the present results demonstrated the importance of GASC1 in the progression of glioma and identified that GASC1 promotes glioma progression, at least in part, by enhancing NOTCH signaling, suggesting that GASC1/NOTCH1 signaling may be a potential therapeutic target for glioma treatment.

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“…As an information carrier, glioblastoma stem cells (GSC) EVs mediated the dedifferentiation of non-GSC glioma cells into GSCs by activating Notch1 signal to transmit Notch1 protein, thus enhancing the stemness and tumorigenesis of non-GSC glioma cells [83]. The research described that Semaphorin 7A (SEMA7A) was exposed to the surface of patient-derived glioma-associated stem cells (GASC) EVs and increased the activity of GSC through the interaction between integrin β1 and GSC in the microenvironment [84].…”

Section: Role Of Evs In Gbm Microenvironmentmentioning

confidence: 99%

Role of Tumor-Derived Extracellular Vesicles in Glioblastoma

Chen

Jin

2021

Cells

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Glioblastoma (GBM) is the most common primary central nervous system tumor and one of the most lethal cancers worldwide, with morbidity of 5.26 per 100,000 population per year. These tumors are often associated with poor prognosis and terrible quality of life. Extracellular vesicles (EVs) are membrane-bound nanoparticles secreted by cells and contain lipid, protein, DNA, mRNA, miRNA and other bioactive substances. EVs perform biological functions by binding or horizontal transfer of bioactive substances to target cell receptors. In recent years, EVs have been considered as possible targets for GBM therapy. A great many types of research demonstrated that EVs played a vital role in the GBM microenvironment, development, progression, angiogenesis, invasion, and even the diagnosis of GBM. Nevertheless, the exact molecular mechanisms and roles of EVs in these processes are unclear. It can provide the basis for GBM treatment in the future that clarifying the regulatory mechanism and related signal pathways of EVs derived from GBM and their clinical value in GBM diagnosis and treatment. In this paper, the research progress and clinical application prospects of GBM-derived EVs are reviewed and discussed.

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Glioblastoma Stem Cell-Derived Exosomes Enhance Stemness and Tumorigenicity of Glioma Cells by Transferring Notch1 Protein

Cited by 73 publications

References 59 publications

RBPJ contributes to the malignancy of glioblastoma and induction of proneural‐mesenchymal transition via IL‐6‐STAT3 pathway

RBPJ contributes to the malignancy of glioblastoma and induction of proneural‐mesenchymal transition via IL‐6‐STAT3 pathway

GASC1 promotes glioma progression by enhancing NOTCH1 signaling

Role of Tumor-Derived Extracellular Vesicles in Glioblastoma

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