Prosaposin promotes the proliferation and tumorigenesis of glioma through toll-like receptor 4 (TLR4)-mediated NF-κB signaling pathway

Abstract

BackgroundAs a neurotrophic factor, prosaposin (PSAP) can exert neuroprotective and neurotrophic effects. It is involved in the occurrence and development of prostate and breast cancer. However, there is no research about the role of PSAP in glioma.MethodsThe PSAP overexpressed or silenced glioma cells or glioma stem cells were established based on Lentiviral vector transfection. Cell viability assay, Edu assay, neurosphere formation assay and xenograft experiments were used to detect the proliferative ability. Western blot, Elisa and luciferase reporter assays were used to detect the possible mechanism.FindingsOur study firstly found that PSAP was highly expressed and secreted in clinical glioma specimens, glioma stem cells, and glioma cell lines. It was associated with poor prognosis. We found that PSAP significantly promoted the proliferation of glioma stem cells and cell lines. Moreover, PSAP promoted tumorigenesis in subcutaneous and orthotopic models of this disease. Furthermore, GSEA and KEGG analysis predicted that PSAP acts through the TLR4 and NF-κB signaling pathways, which was confirmed by western blot, immunoprecipitation, immunofluorescence, and use of the TLR4-specific inhibitor TAK-242.InterpretationThe findings of this study suggest that PSAP can promote glioma cell proliferation via the TLR4/NF-κB signaling pathway and may be an important target for glioma treatment.FundThis work was funded by (Nos. 81101917, 81270036, 81201802, 81673025), (No. LR2014023), and (Nos. 20170541022, 20172250290). The funders did not play a role in manuscript design, data collection, data analysis, interpretation nor writing of the manuscript.

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

“…In our previous study, we demonstrated that PSAP can bind to TLR4, mediating activation of the NF‐κB signaling pathway . In addition, several studies have reported that NF‐κB can directly regulate the expression and secretion of TGF‐β1.…”

“…It is mainly involved in the metabolism of sphingomyelin and ceramide and acts as a neurotrophic factor [7,8]. Our previous studies found that the overexpression and secretion of PSAP in glioma can promote the proliferation and tumorigenesis of glioma cells and lead to poor prognosis [9]. It is also reported that PSAP is overexpressed in prostate cancer.…”

Tracking intratumoral heterogeneity in glioblastoma via regularized classification of single-cell RNA-Seq data

“…PSAP, which together with CHCHD2 presented the lowest weights (Fig. 4), has been pointed as a target for glioma treatment, by promoting glioma cell proliferation via the TLR4/NF-κB signaling pathway [28]. PREX1 and ABHD2 have also shown to promote tumor invasion and progression in glioblastoma [29,30], while the tumor sup-pressor BIN1 was found to be regulated by HNRNPA2B1, a putative proto-oncogene in GBM [31].…”

A comprehensive proteomic SWATH-MS workflow for profiling blood extracellular vesicles: a new avenue for glioma tumour surveillance

“…PSAP is a highly conserved glycoprotein and precursor of lysosomal proteins (saposins A-D) that plays substantial roles in intracellular degradation of sphingolipids [78]. Previously, we showed that PSAP levels in GBM-EVs have a significant, positive correlation to in vitro GBM cell invasion [25] and multiple studies have reported high PSAP expression in clinical glioma specimens, glioma-stem cells and cell-lines [79,80] with elevated serum levels in advanced-stage prostate cancer patients [81]. While PSAP was not confidently identified in EVs purified from glioma (II-IV) neurosurgical fluids [24,25], here PSAP levels are significantly lower in GBM plasma-EVs relative to controls.…”