Prosaposin is a biomarker of mesenchymal glioblastoma and regulates mesenchymal transition through the TGF‐β1/Smad signaling pathway

Jiang, Yang; Zhou, Jinpeng; Hou, Dianqi; Luo, Peng; Gao, Huiling; Ma, Yanju; Chen, Yinsheng; Li, Long; Zou, Dan; Zhang, Haiying; Zhang, Ye

doi:10.1002/path.5278

Cited by 46 publications

(37 citation statements)

References 54 publications

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“…Additionally, immunofluorescence also showed that FTY720 treatment significantly inhibited EMT in sacrum chordoma cells. EMT is a common phenomenon in epithelial-derived malignant tumours and is responsible for invasion and radiotherapeutic and chemotherapeutic tolerance of malignant tumours [39][40][41]. Our findings suggest that FTY720 treatment inhibited the invasion of chordoma cells and enhanced the effects of radiotherapy and chemotherapy by altering EMT.…”

Section: Discussionmentioning

confidence: 58%

Fingolimod inhibits proliferation and epithelial–mesenchymal transition in sacral chordoma by inactivating IL-6/STAT3 signalling

Wang

et al. 2020

Bioscience Reports

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Purpose: To explore the sensitivity of the immunosuppressive agent fingolimod (FTY720) in chordoma and determine whether it can serve as an appropriate alternate treatment for unresectable tumours in patients after incomplete surgery. Methods: Cell viability assays, colony formation assays and EdU assays were performed to evaluate the sensitivity of chordoma cell lines to FTY720. Transwell invasion assays, wound healing assays, flow cytometry, cell cycle analysis, immunofluorescence analysis, Western blotting analysis and enzyme-linked immunosorbent assays (ELISAs) were performed to evaluate cell invasion, epithelial–mesenchymal transition (EMT) and activation of related pathways after treatment with FTY720. The effect of FTY720 was also evaluated in vivo in a xenograft model. Results: We found that FTY720 inhibited the proliferation, invasion and metastasis of sacral chordoma cells (P < 0.01). FTY720 also inhibited the proliferation of tumour cells in a xenograft model using sacral chordoma cell lines (P < 0.01). The mechanism was related to the EMT and apoptosis of chordoma cells and inactivation of IL-6/STAT3 signalling in vitro and in vivo. Conclusions: Our findings indicate that FTY720 may be an effective therapeutic agent against chordoma. These findings suggest that FTY720 is a novel agent that can treat locally advanced and metastatic chordoma.

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Section: Discussionmentioning

confidence: 58%

Fingolimod inhibits proliferation and epithelial–mesenchymal transition in sacral chordoma by inactivating IL-6/STAT3 signalling

Wang

et al. 2020

Bioscience Reports

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“…PSAP is a highly conserved glycoprotein and precursor of lysosomal proteins (saposins A–D) that is integral to the intracellular degradation of sphingolipids [ 64 ]. Previously, we showed that PSAP levels in GBM-EVs have a significant, positive correlation to in vitro GBM cell invasion [ 29 ] and multiple studies have reported high PSAP expression in clinical glioma specimens, glioma-stem cells and cell-lines [ 65 , 66 ]. PSAP was not confidently identified in EVs captured directly from diffuse glioma (II–IV) microenvironments [ 24 , 25 ], and here we report significantly lower PSAP levels in GBM plasma-EVs relative to controls.…”

Section: Discussionmentioning

confidence: 99%

A Comprehensive Proteomic SWATH-MS Workflow for Profiling Blood Extracellular Vesicles: A New Avenue for Glioma Tumour Surveillance

Hallal

Azimi

Wei

et al. 2020

IJMS

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Improving outcomes for diffuse glioma patients requires methods that can accurately and sensitively monitor tumour activity and treatment response. Extracellular vesicles (EV) are membranous nanoparticles that can traverse the blood–brain-barrier, carrying oncogenic molecules into the circulation. Measuring clinically relevant glioma biomarkers cargoed in circulating EVs could revolutionise how glioma patients are managed. Despite their suitability for biomarker discovery, the co-isolation of highly abundant complex blood proteins has hindered comprehensive proteomic studies of circulating-EVs. Plasma-EVs isolated from pre-operative glioma grade II–IV patients (n = 41) and controls (n = 11) were sequenced by Sequential window acquisition of all theoretical fragment ion spectra mass spectrometry (SWATH-MS) and data extraction was performed by aligning against a custom 8662-protein library. Overall, 4054 proteins were measured in plasma-EVs. Differentially expressed proteins and putative circulating-EV markers were identified (adj. p-value < 0.05), including those reported in previous in-vitro and ex-vivo glioma-EV studies. Principal component analysis showed that plasma-EV protein profiles clustered according to glioma histological-subtype and grade, and plasma-EVs resampled from patients with recurrent tumour progression grouped with more aggressive glioma samples. The extensive plasma-EV proteome profiles achieved here highlight the potential for SWATH-MS to define circulating-EV biomarkers for objective blood-based measurements of glioma activity that could serve as ideal surrogate endpoints to assess tumour progression and allow more dynamic, patient-centred treatment protocols.

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“…EMT is a key event driving the invasion of glioma cells [43,44]. In addition, several EMT-related factors are associated with increased invasion and poor prognosis in gliomas [45][46][47]. Here, we observed that CUL7 depletion significantly reversed EMT features and decreased invasiveness in glioma cells.…”

Section: Discussionmentioning

confidence: 57%

Cullin-7 (CUL7) is overexpressed in glioma cells and promotes tumorigenesis via NF-κB activation

Zhang

Qian

et al. 2020

J Exp Clin Cancer Res

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Background: Cullin-7 (CUL7) is a member of the DOC domain-containing cullin family and is involved in the regulation of cell transformation. However, the clinical significance, potential mechanism and upstream regulators of CUL7 in malignant gliomas remain to be determined. Methods:Expression level data and clinical information were obtained via the Cancer Genome Atlas (TCGA) database, the Chinese Glioma Genome Atlas (CGGA) database, immunohistochemistry (IHC) and western blot analysis. Gene set enrichment analysis (GSEA) was used to explore the potential molecular mechanisms of CUL7. RNA silencing was performed using siRNA or lentiviral constructs in U87MG and U251 glioma cell lines and GSC267 glioma stem cells. CUL7 overexpression was performed using the GV141-CUL7 plasmid construct. In addition, overexpression of miR-3940-5p was performed and validated by quantitative real-time PCR (qRT-PCR). Cells were characterized in vitro or in vivo to evaluate their molecular status, cell proliferation, invasion, and migration by Cell Counting Kit (CCK)-8, EdU, flow cytometry, colony formation, Transwell and 3D tumour spheroid invasion assays. Coimmunoprecipitation (co-IP) and western blotting were performed to test the mechanisms of activation of the NF-κB signalling pathway.Results: High CUL7 expression was associated with a high tumour grade, a mesenchymal molecular glioma subtype and a poor prognosis in patients. Gene silencing of CUL7 in U87MG and U251 cells significantly inhibited tumour growth, invasion and migration in vitro and in vivo. Western blot analysis revealed that cyclin-dependent kinase inhibitors and epithelial-mesenchymal transition (EMT) molecular markers changed under CUL7 silencing conditions. In contrast, CUL7 overexpression promoted tumour growth, invasion and migration. Gene set enrichment analysis (GSEA) and western blot analysis revealed that CUL7 was positively associated with the NF-κB pathway. Moreover, with coimmunoprecipitation assays, we discovered that CUL7 physically associated with MST1, which further led to ubiquitin-mediated MST1 protein degradation, which promoted activation of the NF-κB signalling pathway. Finally, CUL7 was found to be downregulated by miR-3940-5p, which suppressed the development of gliomas.(Continued on next page)

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Prosaposin is a biomarker of mesenchymal glioblastoma and regulates mesenchymal transition through the TGF‐β1/Smad signaling pathway

Cited by 46 publications

References 54 publications

Fingolimod inhibits proliferation and epithelial–mesenchymal transition in sacral chordoma by inactivating IL-6/STAT3 signalling

Fingolimod inhibits proliferation and epithelial–mesenchymal transition in sacral chordoma by inactivating IL-6/STAT3 signalling

A Comprehensive Proteomic SWATH-MS Workflow for Profiling Blood Extracellular Vesicles: A New Avenue for Glioma Tumour Surveillance

Cullin-7 (CUL7) is overexpressed in glioma cells and promotes tumorigenesis via NF-κB activation

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