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The invasion ability of glioblastoma (GBM) causes tumor cells to infiltrate the surrounding brain parenchyma and leads to poor outcomes. Transient receptor potential vanilloid 4 (TRPV4) exhibits a remarkable role in cancer cell motility, but the contribution of TRPV4 to glioblastoma metastasis is not fully understood. Here, we reported that TRPV4 expression was significantly elevated in malignant glioma compared to normal brain and low-grade glioma, and TRPV4 expression was negatively correlated with the prognosis of glioma patients. Functionally, stimulation of TRPV4 promoted glioblastoma cell migration and invasion, and repression of TRPV4 hindered the migration and invasion of glioblastoma cells in vitro. Molecularly, TRPV4 strongly colocalized and interacted with skeletal protein-F-actin at cellular protrusions, and TRPV4 regulated the formation of invadopodia and filopodia in glioblastoma cells. Furthermore, the Cdc42/N-wasp axis mediated the effect of TRPV4-regulated cellular protrusions and invasion. Foremost, TRPV4 inhibitor treatment or downregulation of TRPV4 significantly reduced the invasion-growth of subcutaneously and intracranially transplanted glioblastoma in mice. In conclusion, the TRPV4/Cdc42/wasp signaling axis regulates cellular protrusion formation in glioblastoma cells and influences the invasion-growth phenotype of glioblastoma in vivo. TRPV4 may serve as a prognostic factor and specific therapeutic target for GBM patients.

Glioblastoma (GBM) has been regarded as the most aggressive disease in the nervous system. Accumulating literatures have illustrated the crucial role of competing endogenous RNAs (ceRNAs) network in the pathogenesis and progression of various tumors. The promoting effect of LEF1-AS1 on GBM development has been previously identified. This study attempted to explore the underlying mechanism of LEF1-AS1 in GBM. Data of clinical GBM patients was downloaded from TCGA and GEO databases. The proliferative ability, clonogenic vitality, invasive, and migratory capabilities of GBM cells were measured using Cell counting kit-8 (CCK-8), colony formation and transwell assays. Luciferase reporter gene analysis was performed to verify the correlations between LEF1-AS1/EN2 and miR-543. qRT-PCR and western blotting were implemented to evaluate the mRNA and protein levels, respectively. Our results consolidated that LEF1-AS1 was highly expressed in GBM tissue specimens and its up-regulation induced unfavorable prognosis. The loss/gain-of-function analyses verified that LEF1-AS1 promoted the GBM cell malignant behaviors. Mechanically, LEF1-AS1 acted as a ceRNA for miR-543 and positively regulated engrailed homeobox 2 (EN2) expression. Down-regulation of miR-543 elevated GBM cell malignant behaviors, which was reversed by LEF1-AS1 knockdown. Meanwhile, the LEF1-AS1 inhibition could arrest the promoting effect of high-regulated EN2 on GBM cell aggressiveness and vice versa. In conclusion, our findings identified LEF1-AS1 as a ceRNA for miR-543 and showed that EN2 was positively regulated by LEF1-AS1. The LEF1-AS1/miR-543/EN2, as a novel ceRNA network, was implicated in the progression of GBM, which provided a novel insight for GBM treatment., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Glioblastoma and Alzheimer's disease (AD) are the most common and devastating diseases in the central nervous system. The dysfunction of Presenilin1 is the main reason for AD pathogenesis. However, the molecular function of Presenilin1 and its relative mechanism in glioblastoma remain unclear., Methods: Expression of presenilin1 in glioma was determined by IHC. CCK-8, colony formation, Flow cytometry, Edu staining were utilized to evaluate functions of presenilin1 on glioblastoma proliferation. The mechanism of above process was assessed by Western blotting and cell immunofluorescence. Mouse transplanting glioblastoma model and micro-MRI detection were used to verified presenilin1 function in vivo., Results: In this study, we found that all grades of glioma maintained relatively low Presenilin1 expression and that the expression of Presenilin1 in high-grade glioma was significantly lower than that in low-grade glioma. Moreover, the Presenilin1 level had a positive correlation with glioma and glioblastoma patient prognosis. Next, we determined that Presenilin1 inhibited the growth and proliferation of glioblastoma cells by downregulating CDK6, C-myc and Cyclin D1 to arrest the cell cycle at the G1/S phase. Mechanistically, Presenilin1 promoted the direct phosphorylation of β-catenin at the 45 site and indirect phosphorylation at the 33/37/41 site, then decreased the stabilized part of β-catenin and hindered its translocation from the cytoplasm to the nucleus. Furthermore, we found that Presenilin1 downregulation clearly accelerated the growth of subcutaneous glioblastoma, and Presenilin1 overexpression significantly repressed the subcutaneous and intracranial transplantation of glioblastoma by hindering β-catenin-dependent cell proliferation., Conclusion: Our data implicate the antiproliferative effect of Presenilin1 in glioblastoma by suppressing Wnt/β-catenin signaling, which may provide a novel therapeutic agent for glioblastoma. Video Abstract.

High aggressiveness is a hallmark of glioblastoma and predicts poor prognosis of patients with glioblastoma. The expression level of sortilin has been preliminarily reported to be elevated in high-grade glioma; however, the potential significance of sortilin in glioblastoma progression has not been elucidated. In this study, we investigated the oncogenic effect of sortilin in glioblastoma. Increased levels of sortilin were noted in the mesenchymal subtype of glioblastoma and highly aggressive subtypes of glioblastoma tissues and cell lines. In addition, high levels of sortilin predicted poor prognoses in patients with glioblastoma. Sortilin knockdown or inhibition with AF38469 (an orally bioavailable inhibitor of sortilin) significantly suppressed migration and invasion by inhibiting EMT-like mesenchymal transition in glioblastoma cells. Furthermore, we proved that sortilin promoted cell invasion mainly via Glycogen synthase kinase 3 beta (GSK-3β)/β-catenin/Twist-induced EMT-like mesenchymal transition in glioblastoma. Taken together, our results demonstrate a critical role of sortilin in glioblastoma invasion and EMT-like mesenchymal transition, indicating that sortilin contributes to glioblastoma progression. These data also highlight the dramatic antitumor effects of AF38469 in glioblastoma, suggesting that AF38469 is a potentially powerful antitumor agent for sortilin-overexpressing human glioblastoma.