BRMS1 Suppresses Glioma Progression by Regulating Invasion, Migration and Adhesion of Glioma Cells

Abstract Background: Glioma is a fatal malignancy caused by dysregulation of cellular signal transduction. Internalization plays a key role in maintaining signalling balance. SorCS3 is involved in nerve cell receptor internalization. However, the impact of SorCS3 on the biological processes involved in glioma has not yet been reported. Here, we highlight the potential of SorCS3-mediated regulation of signalling receptor internalization as a rational target for therapeutic intervention in glioma.Methods: SorCS3 expression was analysed in the TCGA and CGGA databases and in tissue microarrays. The effects of SorCS3 on the proliferation and metastasis of glioma cells were examined in vitro and in vivo with Transwell, wound healing, EdU incorporation and nude mouse tumorigenicity assays. Fluorescent 5-FAM, SE-labelled proteins were used to detect the internalization of SorCS3 in glioma cells. Immunofluorescence and Co-IP assays were conducted to investigate the downstream effector of SorCS3. Moreover, Dynasore and Ro 08-2750, inhibitors of internalization and NGF binding to p75NTR, respectively, were used to validate the biological functions of SorCS3 in glioma.Results: Our data demonstrated that SorCS3 was downregulated in glioma tissues and closely related to favourable prognosis. Overexpression of SorCS3 inhibited the proliferation and metastasis of glioma cells in vitro and in vivo, while silencing of SorCS3 exerted the opposite effects. Mechanistic investigations showed that SorCS3 bound to p75NTR, which subsequently increased the internalization of p75NTR, and then transported p75NTR to the lysosome for degradation, ultimately contributing to inhibition of glioma progression.Conclusions: Our work suggests that SorSC3 is a marker of promising prognosis in glioma patients and suggests that SorCS3 regulates internalization, which plays an important role in inhibiting glioma progression.

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TMIC-58. THE CELLULAR AND MOLECULAR BASIS FOR MESENCHYMAL TRANSFORMATION IN GLIOMAS

Neuro-Oncology ◽

10.1093/neuonc/noz175.1092 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi260-vi260

Author(s):

Andrea Comba ◽

Patrick J Dunn ◽

Anna E Argento ◽

Padma Kadiyala ◽

Sebastien Motsch ◽

...

Keyword(s):

Tumor Progression ◽

Tumor Cells ◽

Smooth Muscle Actin ◽

Glioma Cells ◽

Time Lapse ◽

Mesenchymal Cells ◽

Genetically Engineered ◽

Normal Brain ◽

Mesenchymal Transformation ◽

Glioma Progression

Abstract Mesenchymal gliomas are the most aggressive tumors that carry the worst prognosis. The origins of mesenchymal cells within brain tumors, remains poorly understood. They could originate either from invading mesenchymal cells, from perivascular smooth muscle actin+ cells, or from a mesenchymal transformation of tumor cells. Identifying the origin and function of mesenchymal cells within gliomas is essential as these cells contribute to increased glioma aggressiveness and tumor progression. In this study we used human biopsies and implantable and genetically engineered mouse models (GEMM) of GBM to study tumor mesenchymal transformation. GBM implantable models were used to analyze the molecular landscape by laser microdissection followed by RNA-Seq and bioinformatics analysis. Time lapse confocal imagining was implemented to analyze GBM cells dynamics. Our results indicate the existence of a complex intratumoral and peritumoral dynamic organization of glioma cells (i.e., Oncostreams). Multicellular structures of elongated cells compatible with mesenchymal differentiation. These structures play important roles in intratumoral movements, peritumoral invasion of normal brain, and overall glioma progression. We also show that oncostreams are molecularly distinct and display increased expression of mesenchymal genes such as Col1a1. Knocking down of Col1a1 in a GEMM of aggressive gliomas reduced tumor progression and significantly increased animal survival. Histological examination confirmed absence of Col1a1, and absence of morphologically identifiable oncostreams. Our results show that tumor cells, especially within oncostreams, display a fibroblastic-like morphology and express proteins typical of mesenchymal cells. The knockout of Col1a1 from tumoral cells eliminated oncostreams from tumors and delayed tumor progression. These data suggest that tumor cells expressing mesenchymal genes regulate the organization of mesenchymal multicellular structures, and determine glioma progression. We propose that inhibiting mesenchymal transformation of glioma cells will assist in the treatment of glioblastoma.

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Tumor-Suppressive Function of lncRNA-MEG3 in Glioma Cells by Regulating miR-6088/SMARCB1 Axis

BioMed Research International ◽

10.1155/2020/4309161 ◽

2020 ◽

Vol 2020 ◽

pp. 1-15 ◽

Cited By ~ 1

Author(s):

Xin Gong ◽

Meng-Yi Huang

Keyword(s):

Cell Proliferation ◽

Epithelial Mesenchymal Transition ◽

Glioma Cells ◽

Luciferase Reporter ◽

Favorable Effect ◽

Mesenchymal Transition ◽

Gene Assay ◽

And Migration ◽

Proliferation And Migration ◽

Glioma Progression

Objective. Mounting evidence has elaborated the implication of long noncoding RNAs (lncRNAs) in tumorigenesis of several cancers, including glioma. However, little was known about the mechanism of lncRNA maternally expressed gene 3 (MEG3) in the development and progression of glioma. This work is designed to explore the effect of MEG3 on glioma progression and its possible mechanism. Methods. Expressions of lncRNA-MEG3 and SMARCB1 were detected in human glioblastoma U87 and U251 cell lines. Gain and loss of function of MEG3 or/and miR-6088 was performed in U87 and U251 cells to observe its effect on cell proliferation and migration as well as on epithelial-mesenchymal transition (EMT) related markers. Luciferase reporter gene assay was employed to inspect the interactions among MEG3, miR-6088, and SMARCB1. Results. MEG3 and SMARCB1 expressions were downregulated in glioma cells. Transfection of pcDNA3.1-MEG3 or pcDNA3.1-SMARCB1 plasmids could clearly block cell proliferation, migration, and EMT progression. MEG3 functions as a sponge for miR-6088, while SMARCB1 is a downstream protein of miR-6088. Transfection of miR-6088 mimic or si-SMARCB1 could obviously reverse the favorable effect of pcDNA3.1-MEG3 on glioma progression. Conclusion. Collectively, the evidence in this study indicated that MEG3 was downregulated in glioma cells and inhibited proliferation and migration of glioma cells via regulating miR-6088/SMARCB1 axis.

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On the Impact of Chemo-Mechanically Induced Phenotypic Transitions in Gliomas

Cancers ◽

10.3390/cancers11050716 ◽

2019 ◽

Vol 11 (5) ◽

pp. 716 ◽

Cited By ~ 1

Author(s):

Pietro Mascheroni ◽

Juan Carlos López Alfonso ◽

Maria Kalli ◽

Triantafyllos Stylianopoulos ◽

Michael Meyer-Hermann ◽

...

Keyword(s):

Glioma Cells ◽

Blood Perfusion ◽

Mechanical Compression ◽

Therapy Outcomes ◽

Stress Alleviation ◽

Therapeutic Outcomes ◽

The Impact ◽

New Strategies ◽

Glioma Microenvironment ◽

Glioma Progression

Tumor microenvironment is a critical player in glioma progression, and novel therapies for its targeting have been recently proposed. In particular, stress-alleviation strategies act on the tumor by reducing its stiffness, decreasing solid stresses and improving blood perfusion. However, these microenvironmental changes trigger chemo–mechanically induced cellular phenotypic transitions whose impact on therapy outcomes is not completely understood. In this work we analyze the effects of mechanical compression on migration and proliferation of glioma cells. We derive a mathematical model of glioma progression focusing on cellular phenotypic plasticity. Our results reveal a trade-off between tumor infiltration and cellular content as a consequence of stress-alleviation approaches. We discuss how these novel findings increase the current understanding of glioma/microenvironment interactions and can contribute to new strategies for improved therapeutic outcomes.

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miR-381-3p Involves in Glioma Progression by Suppressing Tumor-Promoter Factor ANTXR1

Computational and Mathematical Methods in Medicine ◽

10.1155/2021/4883509 ◽

2021 ◽

Vol 2021 ◽

pp. 1-7

Author(s):

Zhiqiang Dong ◽

Jinglong Zhang ◽

Liang Niu ◽

Guokuo Hou ◽

Zhenshan Gao ◽

...

Keyword(s):

Glioma Cells ◽

Molecular Target ◽

Anthrax Toxin ◽

Tumor Promoter ◽

Biological Functions ◽

Toxin Receptor ◽

Glioma Progression

Accumulating studies revealed association between development of glioma and miRNA dysregulation. A case in point is miR-381-3p, but its mechanism in glioma is unclear yet. In this work, we confirmed that overexpressed miR-381-3p repressed biological functions of glioma cells. Additionally, we also discovered that upregulated anthrax toxin receptor 1 (ANTXR1) was negatively mediated by miR-381-3p. We further proved that miR-381-3p-targeted ANTXR1 was able to counteract the suppression of miR-381-3p on biological functions of glioma. We concluded that miR-381-3p and ANTXR1 were both important factors in modulating glioma progression. miR-381-3p/ANTXR1 axis is expected to be a molecular target for glioma.

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Tumor associated macrophages and its nanovesicles: Immunological insights in cerebral glioma

Journal of Solid Tumors ◽

10.5430/jst.v10n1p14 ◽

2020 ◽

Vol 10 (1) ◽

pp. 14

Author(s):

Turano E ◽

Farinazzo A ◽

El Mously S ◽

Calabria F ◽

Jugerson I ◽

...

Keyword(s):

Glioma Cells ◽

Annexin V ◽

Low Grade ◽

Cerebral Glioma ◽

Tumor Associated Macrophages ◽

Cellular Activation ◽

Protein Assay ◽

Glioma Progression

Purpose: The immune system has a key role in glioma progression, especially the tumor associated macrophages (TAMs). In-vivo, we aimed to study the total TAMs and differential M1 and M2 TAM infiltration in low grade (LGG) versus high grade gliomas (HGG). Also, we investigated the implication of total TAMs and differential M1 and M2 TAMs infiltration on glioma progression. In-vitro, we studied the effect of soluble factors present in nanovesicles (NV) released from M1 TAMs on the fate of glioma cells.Methods: In-vivo, we performed immunohistochemistry using iNOS and CD163 (markers for M1 and M2 respectively). In-vitro, we polarized the human monocytes U937 cell line into M1, we isolated the NV from the M1-conditioned medium (CM) by centrifugation and filtration; then, the protein content of the NV was quantified by the protein assay. We added M1-NV on U251 glioma cells and we studied the cellular activation of glioma cells using the MTT assay. To assess the apoptosis of U251, we used the flow-cytometry. Apoptotic cells were identified by annexin V and Propidium Iodide (markers for early and late apoptosis respectively).Results: in-vivo, there is an M1/M2 imbalance in early stages of glioma which is associated with earlier progression to high malignancy. Also, the higher M2 infiltration, the earlier is the progression. In-vitro, M1-NV had a more potent anti-tumor effect compared to its corresponding CM. We assume that our experimental results can be a future treatment for the cerebral glioma.

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Opticalin vivoandex vivoimaging of glioma cells migration via the cerebral vessels: Prospective clinical application of the beta2-adrenoreceptors blockade for glioma treatment

Journal of Innovative Optical Health Sciences ◽

10.1142/s1793545818500256 ◽

2018 ◽

Vol 11 (04) ◽

pp. 1850025 ◽

Cited By ~ 3

Author(s):

Olga Pavlova ◽

Alexander Shirokov ◽

Alexander Fomin ◽

Nikita Navolokin ◽

Andrey Terskov ◽

...

Keyword(s):

Ex Vivo ◽

Malignant Gliomas ◽

Glioma Cells ◽

Cerebral Vessels ◽

Limited Information ◽

Glioma Growth ◽

Slow Progress ◽

Pharmacological Blockade ◽

Glioma Progression

Malignant gliomas are highly invasive tumors that use the cerebral vessels for invasion due to high vascular fragility of the blood–brain barrier (BBB). On one hand, glioma is characterized by the BBB disruption, on the other hand, drug brain delivery via the BBB is a big challenge in glioma therapy. The limited information about vascular changes associated with glioma growth is a reason of slow progress in prevention of glioma development.Here, we present in vivo and ex vivo study of the BBB disruption and glioma cells (GCs) migration in rats using fluorescence and confocal microscopy. We uncovered a local breach in the BBB in the main tumor mass but not within the border of normal and malignant cells, where the BBB was impermeable for high weight molecules. The migration of GCs were observed via the cerebral vessels with the intact BBB that was associated with macrophages infiltration.The mechanisms underlying glioma progression remain unknown but there is an evidence that the sympathetic nervous system (SNS) via activation of vascular beta2-adrenoreceptors (B2-ADRs) can play an important role in tumor metastasis. Our results clearly show an increase in the expression of vascular B2-ADRs and production of the beta-arrestin-1 — co-factor of B2-ADRs signaling pathway in rats with glioma. Pharmacological blockade of B2-ADRs reduces the BBB disruption, macrophages infiltration, GCs migration and increases survival rate.These data suggest that the blockade of B2-ADRs may be a novel adjuvant therapeutic strategy to reduce glioma progression and prevent metastasis.

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Pristimerin inhibits glioma progression by targeting AGO2 and PTPN1 expression via miR-542-5p

Bioscience Reports ◽

10.1042/bsr20182389 ◽

2019 ◽

Vol 39 (5) ◽

Cited By ~ 3

Author(s):

Zaiyu Li ◽

Cong Hu ◽

Yu Zhen ◽

Bo Pang ◽

Huanfa Yi ◽

...

Keyword(s):

Target Genes ◽

Process Analysis ◽

Glioma Cells ◽

Functional Enrichment ◽

High Recurrence Rate ◽

High Dose ◽

Diffuse Glioma ◽

Compound Target ◽

Glioma Progression

Abstract Glioblastoma multiform is the most common and malignant primary tumor of the central nervous system in adults, the high recurrence rate and poor prognosis are critical priorities. Pristimerin is a naturally occurring quinone methide triterpenoid isolated from the Celastraceae and Hippocrateaceae families. Its anticancer effects have garnered considerable attention; nonetheless, the mechanisms of action remain unknown. To predict the hub genes of pristimerin, PharmMapper and the Coremine database were used to identify 13 potential protein targets; protein–protein interaction, for which functional enrichment analyses were performed. Compound-target, target-pathway, and compound-target-pathway networks were constructed using Cytoscape. Biological process analysis first revealed that enrichment of these target genes correlated with negative regulation of symbiont growth in the host, and regulation of chronic inflammatory response to antigenic stimulus. Survival analysis in cBioPortal showed that protein tyrosine phosphatase, non-receptor type 1 (PTPN1) and Argonaute 2 (AGO2) might be involved in the carcinogenesis, invasion, or recurrence of diffuse glioma. In addition, we observed that low-dose pristimerin inhibited the viability of glioma cells, while miR-542-5p in vitro; and reduced PTPN1 expression. Notably, high-dose pristimerin induced apoptosis. Furthermore, miR-542-5p silence with siRNA in glioma cells lead to the elevation in AGO2, and decreased PTPN1 level. The effect was obviously post pristimerin treatment and miR-542-5p suppression. In conclusion, pristimerin inhibited glioma progression through AGO2 and PTPN1 expression via a canonical miRNA-mediated mechanism.

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LAP3 promotes glioma progression by regulating proliferation, migration and invasion of glioma cells

International Journal of Biological Macromolecules ◽

10.1016/j.ijbiomac.2014.10.021 ◽

2015 ◽

Vol 72 ◽

pp. 1081-1089 ◽

Cited By ~ 6

Author(s):

Xiaojuan He ◽

Qingfeng Huang ◽

Xiaojun Qiu ◽

Xianchen Liu ◽

Guan Sun ◽

...

Keyword(s):

Glioma Cells ◽

Migration And Invasion ◽

Glioma Progression

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Double-Targeted Knockdown of miR-21 and CXCR4 Inhibits Malignant Glioma Progression by Suppression of the PI3K/AKT and Raf/MEK/ERK Pathways

BioMed Research International ◽

10.1155/2020/7930160 ◽

2020 ◽

Vol 2020 ◽

pp. 1-17

Author(s):

Feijiao Liu ◽

Bo Yang

Keyword(s):

Tumor Volume ◽

Xenograft Model ◽

Glioma Cells ◽

Erk Signaling ◽

Combined Effects ◽

Inhibition Effect ◽

Transplanted Tumor ◽

Tumor Tissues ◽

Two Factors ◽

Glioma Progression

Currently, miR-21 and CXCR4 are being extensively investigated as two key regulators in glioma malignancy. In this study, we investigated the combined effects of these two factors on glioma progression. Herein, the expression of miR-21 and CXCR4 was increased in tumor tissues and cell lines. Inhibition of miR-21, CXCR4, and miR-21 and CXCR4 together all reduced the migration, invasiveness, proliferation, and enhanced apoptosis in glioma cells, as well as reduced tumor volume and mass in xenograft model. The inhibition effect was strongest in double-targeted knockdown of miR-21 and CXCR4 group, whose downstream pathways involved in AKT axis and ERK axis activation. In conclusion, our findings reported that double-targeted knockdown of miR-21 and CXCR4 could more effectively inhibit the proliferation, migration, invasion, and growth of transplanted tumor and promote cell apoptosis, which were involved in the PI3K/AKT and Raf/MEK/ERK signaling pathways.

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