Microglia-Specific Expression of HEXA and HEXB Leads to Poor Prognosis in Glioblastoma Patients

Glioblastoma multiforme (GBM) is one of the deadliest cancers in brain. There have been few treatment advances for GBM despite increasing scientific understanding of this disease. β-hexosaminidase (Hex) is an important enzyme system in human body, encoded by two genes, HEXA and HEXB, are closely related to central nervous system (CNS) diseases such as Sandhoff disease (SD) and Tay-Sachs disease (TSD). However, the expression pattern and function of HEXA and HEXB in GBM remains unclear. Here, we found that both the mRNA and protein expression levels of HEXA and HEXB were significantly upregulated in GBM patient samples. The results from single-cell RNA-sequencing (scRNA-seq) database and double immunostaining showed that HEXA and HEXB were specifically expressed in microglia in GBM patient samples. Furthermore, our in vitro experiments revealed that conditioned media from HEXA and HEXB knockdown-microglia cells could inhibit the proliferation and migration of GBM cells. Finally, according to survival analysis based on online database, higher expression of HEXA and HEXB was associated with poor prognosis in GBM patients. In conclusion, these results suggest that microglial HEXA and HEXB play fundamental role in GBM progression, and they will be potential biomarkers for GBM.

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GNG5 is a novel oncogene associated with cell migration, proliferation, and poor prognosis in glioma

10.21203/rs.3.rs-49192/v2 ◽

2021 ◽

Author(s):

Wang Zhang ◽

Zhendong Liu ◽

Binchao Liu ◽

Miaomiao Jiang ◽

Shi Yan ◽

...

Keyword(s):

Signaling Pathways ◽

Clinical Data ◽

Poor Prognosis ◽

Glioma Cells ◽

Diagnosis And Treatment ◽

And Migration ◽

The Relationship ◽

Proliferation And Migration

Abstract Background: Although many biomarkers have been reported for detecting glioma, the prognosis for the disease remains poor, and therefore, new biomarkers need to be identified. GNG5, which is part of the G-protein family, has been associated with different malignant tumors, though the role of GNG5 in glioma has not been studied. Therefore, we aimed to identify the relationship between GNG5 and glioma prognosis and identify a new biomarker for the diagnosis and treatment of gliomas.Methods: We used data on more than a thousand gliomas from multiple databases and clinical data to determine the expression of GNG5 in glioma. Based on clinical data and CGGA database, we identified the correlation between GNG5 and multiple molecular and clinical features and prognosis using various analytical methods. Co-expression analysis and GSEA were performed to detect GNG5-related genes in glioma and possible signaling pathways involved. ESTIMATE, ssGSEA, and TIMER were used to detect the relationship between GNG5 and the immune microenvironment. Functional experiments were performed to explore the function of GNG5 in glioma cells.Results: GNG5 is highly expressed in gliomas, and its expression level is positively correlated with pathological grade, histological type, age, and tumor recurrence and negatively correlated with isocitrate dehydrogenase mutation, 1p/19 co-deletion, and chemotherapy. Moreover, GNG5 as an independent risk factor was negatively correlated with the overall survival time. GSEA revealed the potential signaling pathways involved in GNG5 function in gliomas, including cell adhesion molecules signaling pathway. The ssGSEA, ESTIMATE, and TIMER based analysis indicated a correlation between GNG5 expression and various immune cells in glioma. In vivo and in vitro experiments showed that GNG5 could participate in glioma cell proliferation and migration.Conclusions: Based on the large data platform and the use of different databases to corroborate results obtained using various datasets, as well as in vitro and in vivo experiments, our study reveals for the first time that GNG5, as an oncogene, is overexpressed in gliomas and can inhibit the proliferation and migration of glioma cells and lead to poor prognosis of patients. Thus, GNG5 is a potential novel biomarker for the clinical diagnosis and treatment of gliomas.

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GNG5 is a novel oncogene associated with cell migration, proliferation, and poor prognosis in glioma

Cancer Cell International ◽

10.1186/s12935-021-01935-7 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Wang Zhang ◽

Zhendong Liu ◽

Binchao Liu ◽

Miaomiao Jiang ◽

Shi Yan ◽

...

Keyword(s):

Signaling Pathways ◽

Clinical Data ◽

Poor Prognosis ◽

Glioma Cells ◽

Diagnosis And Treatment ◽

And Migration ◽

The Relationship ◽

Proliferation And Migration

Abstract Background Although many biomarkers have been reported for detecting glioma, the prognosis for the disease remains poor, and therefore, new biomarkers need to be identified. GNG5, which is part of the G-protein family, has been associated with different malignant tumors, though the role of GNG5 in glioma has not been studied. Therefore, we aimed to identify the relationship between GNG5 and glioma prognosis and identify a new biomarker for the diagnosis and treatment of gliomas. Methods We used data on more than a thousand gliomas from multiple databases and clinical data to determine the expression of GNG5 in glioma. Based on clinical data and CGGA database, we identified the correlation between GNG5 and multiple molecular and clinical features and prognosis using various analytical methods. Co-expression analysis and GSEA were performed to detect GNG5-related genes in glioma and possible signaling pathways involved. ESTIMATE, ssGSEA, and TIMER were used to detect the relationship between GNG5 and the immune microenvironment. Functional experiments were performed to explore the function of GNG5 in glioma cells. Results GNG5 is highly expressed in gliomas, and its expression level is positively correlated with pathological grade, histological type, age, and tumor recurrence and negatively correlated with isocitrate dehydrogenase mutation, 1p/19 co-deletion, and chemotherapy. Moreover, GNG5 as an independent risk factor was negatively correlated with the overall survival time. GSEA revealed the potential signaling pathways involved in GNG5 function in gliomas, including cell adhesion molecules signaling pathway. The ssGSEA, ESTIMATE, and TIMER based analysis indicated a correlation between GNG5 expression and various immune cells in glioma. In vivo and in vitro experiments showed that GNG5 could participate in glioma cell proliferation and migration. Conclusions Based on the large data platform and the use of different databases to corroborate results obtained using various datasets, as well as in vitro and in vivo experiments, our study reveals for the first time that GNG5, as an oncogene, is overexpressed in gliomas and can inhibit the proliferation and migration of glioma cells and lead to poor prognosis of patients. Thus, GNG5 is a potential novel biomarker for the clinical diagnosis and treatment of gliomas.

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Fibronectin precoating wound bed enhances the therapeutic effects of autologous epidermal basal cell suspension for full-thickness wounds by improving epidermal stem cells’ utilization

Stem Cell Research & Therapy ◽

10.1186/s13287-019-1236-7 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 6

Author(s):

Peng Wang ◽

Zhicheng Hu ◽

Xiaoling Cao ◽

Shaobin Huang ◽

Yunxian Dong ◽

...

Keyword(s):

Wound Healing ◽

In Vitro Study ◽

Epidermal Stem Cells ◽

Full Thickness ◽

Collagen Formation ◽

And Migration ◽

And Function ◽

Proliferation And Migration

Abstract Background Autologous epidermal basal cell suspension therapy has been proven to be one of the most effective treatments for full-thickness wounds. However, we found there remain obvious defects that significantly confined the utilization and function of the epidermal basal cells (EBCs), especially the epidermal stem cells (ESCs) in it. This study investigated whether precoating fibronectin (FN) on the wound bed before spraying EBCs could overcome these defects and further explored its possible mechanisms. Methods In the in vitro study, EBCs were isolated from the donor skin of patients who needed skin grafting. Different concentrations of FN were used to precoat culture dishes before cell culture; the adherent efficiency, proliferation and migration ability of ESCs were analyzed and compared with traditional collagen IV precoating. In the in vivo study, Sprague–Dawley (SD) rats with full-thickness skin wounds were selected as full-thickness wounds’ model. For the experiment groups, 20 μg/ml FN was precoated on the wound bed 10 min before EBC spray. The quality of wound healing was estimated by the residual wound area rate, wound healing time, and hematoxylin and eosin (H&E) staining. Expression of ESC markers, neovascular markers, inflammation markers, and collagen formation and degradation markers was elucidated by immunohistochemistry (IHC), immunofluorescence (IF), western blot (WB), and RT-qPCR analysis. Results The in vitro study showed that the dishes precoated with 20 μg/ml FN had a similar adherent efficiency and colony formation rate with collagen IV, but it could improve the proliferation and migration of ESCs significantly. Similarly, in the in vivo study, precoating FN on wound bed before EBC spray also significantly promote wound healing by improving ESCs’ utilization efficiency, promoting angiogenesis, decreasing inflammations, and regulating collagen formation and degradation. Conclusion FN precoating wound bed before EBC spray could significantly promote full-thickness wound healing by improving the utilization and function of the ESCs and further by promoting angiogenesis, decreasing inflammations, and regulating collagen formation and degradation. Graphical abstract

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RBM8A promotes growth and invasion through the Notch/STAT3 pathway in glioblastoma.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e14038 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e14038-e14038

Author(s):

Yan Lin ◽

Jinyan Zhang ◽

Beiquan Hu ◽

Gang Qin ◽

Rong Liang ◽

...

Keyword(s):

Cell Proliferation ◽

Poor Prognosis ◽

Glioblastoma Cell ◽

Stat3 Pathway ◽

In Vivo Assays ◽

Cell Proliferation And Migration ◽

And Migration ◽

Proliferation And Migration

e14038 Background: Glioblastoma (GBM) is a prevalent brain malignance with an extremely poor prognosis, which is attributable to its invasive biological behaviors. The RNA-binding motif protein 8A (RBM8A) has different effects on various human cancers. However, the implication of RBM8A in glioblastoma progression remains unclear. Methods: Glioblastoma (GBM) data set was downloaded from the Cancer Genome Atlas (TCGA). Differential expression analysis was used to screen the differentially expressed genes (DEGs) between GBM and control, RBM8A high and low expression samples, Gene Ontology (GO) analysis and Kyoto Encyclopedia of Gene Genomes (KEGG) analysis were performed on the co-upregulated DEGs. Additionally, We investigated the expression levels of RBM8A in 94 glioblastoma patients and explored the correlation between the RBM8A expressions with prognosis. Using in vitro and in vivo assays, we addressed the functional impacts of RBM8A on and the underlying mechanisms through which RBM8A contribute to glioblastoma progression. In addition, a comprehensive regulatory network of RBM8A regulation was constructed based on STRING database. Molecular docking model was used to predict the possibility of RBM8A binding to target genes. Combined with TCGA and Chinese glioma genome map (CGGA), gene set variance analysis (GSVA) was used to calculate the GSVA scores of the genes involved in the mechanism. Receiver operator characteristic curve (ROC) curve analysis and survival analysis were performed to explore the prognostic and diagnostic ability of GSVA score for GBM. Results: Our results indicate that higher RBM8A expression in glioblastoma tissues was associated with a poor prognosis. In addition, functional enrichment analysis based on genes related to RBM8A expression showed that RBM8A was related to cell cycle and Notch signaling pathway. RBM8A may promote glioblastoma cell proliferation and migration by activating Notch/STAT3 pathway in glioblastoma cells. In vitro and in vivo assays confirmed that knocking down RBM8A inhibited glioblastoma progression and invasion ability. We also observed that the pro-oncogenic effects of RBM8A in glioblastoma tissues were mediated by activation of the Notch/STAT3 pathway. Finally, it was concluded that the GSVA score has good diagnostic and prognostic value for GBM. Conclusions: RBM8A may promote glioblastoma cell proliferation and migration by activating Notch/STAT3 pathway in glioblastoma cells, suggesting that RBM8A may serve as a potential therapeutic target for the treatment of glioblastoma.

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Effects of Arsenic Trioxide-Loaded PLGA Nanoparticles on Proliferation and Migration of Human Vascular Smooth Muscle Cells

Journal of Nanomaterials ◽

10.1155/2021/5575370 ◽

2021 ◽

Vol 2021 ◽

pp. 1-8

Author(s):

Susu Zhao ◽

Zeqian Yu ◽

Yifen Zhang ◽

Mei Lin

Keyword(s):

Smooth Muscle ◽

Protein Expression ◽

Smooth Muscle Cells ◽

Vascular Smooth Muscle Cells ◽

Inhibitory Effect ◽

Plga Nanoparticles ◽

Mrna And Protein Expression ◽

And Migration ◽

Proliferation And Migration

Backgroud. To evaluate improvement of arsenic trioxide-loaded PLGA nanoparticles (As2O3-PLGA-NPs) to Human Vascular Smooth Muscle Cells (HUVSMCs) in vitro. Methods. As2O3-PLGA-NPs were synthesized and characterized by transmission electron microscopy (TEM), scanning electron microscope (SEM), and energy dispersive spectrometry (EDS), and the cumulative release rates of As2O3-PLGA-NPs were measured in vitro; HUVSMCs were treated with As2O3-PLGA-NPs in vitro. MTT assay and flow cytometry assay (FCM) were performed to examine the inhibitory effect of As2O3-PLGA-NPs on HUVSMCs and compared with As2O3 solution at various concentrations. Optical microscope was used to observe the morphological change of HUVSMCs treated with As2O3-PLGA-NPs. The expression of Bcl-2, Bax, and MMP-9 in HUVSMCs was detected by RT-PCR and Western blot (WB). Results. EDS confirmed that prepared nanoparticles contained elements of arsenic. The surface coating of the eluting stent of As2O3-PLGA-NPs has the same characteristics with our self-prepared As2O3-PLGA-NPs, and it also has a drug sustained-release character. Compared with the control group, cell proliferation and migration cell were significantly suppressed with concentration-dependent ( P < 0.05 , respectively). Meanwhile, in concentration-dependent, As2O3-PLGA-NPs depressed mRNA and protein expression of Bcl-2 and MMP-9 and increased mRNA and protein expression of Bax. Conclusion. As2O3-PLGA-NPs had an inhibitory effect on HUVSMCs’ proliferation and migration, and it may work via regulating Bax, Bcl-2, and MMP-9 expression in vitro.

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Degradation of keratan sulphate by β-N-acetylhexosaminidases A and B

Biochemical Journal ◽

10.1042/bj1930811 ◽

1981 ◽

Vol 193 (3) ◽

pp. 811-818 ◽

Cited By ~ 26

Author(s):

T Ludolph ◽

E Paschke ◽

J Glössl ◽

H Kresse

Keyword(s):

Isoelectric Focusing ◽

Human Liver ◽

Thermal Inactivation ◽

Sandhoff Disease ◽

Chromogenic Substrate ◽

Polymeric Substrate ◽

Keratan Sulphate ◽

Human Enzyme ◽

Tay Sachs Disease

Enzymic cleavage of beta-N-acetylglucosamine residues of keratan sulphate was studied in vitro by using substrate a [3H]glucosamine-labelled desulphated keratan sulphate with N-acetylglucosamine residues at the non-reducing end. Both lysosomal beta-N-acetylhexosaminidases A and B are proposed to participate in the degradation of keratan sulphate on the basis of the following observations. Homogenates of fibroblasts from patients with Sandhoff disease, but not those from patients with Tay–Sachs disease, were unable to release significant amounts of N-acetyl[3H]glucosamine. On isoelectric focusing of beta-N-acetylhexosaminidase from human liver the peaks of keratan sulphate-degrading activity coincided with the activity towards p-nitrophenyl beta-N-acetylglucosaminide. A monospecific antibody against the human enzyme reacted with both enzyme forms and precipitated the keratan sulphate-degrading activity. Both isoenzymes had the same apparent Km of 4mM, but the B form was approximately twice as active as the A form when compared with the activity towards a chromogenic substrate. Differences were noted in the pH–activity profiles of both isoenzymes. Thermal inactivation of isoenzyme B was less pronounced towards the polymeric substrate than towards the p-nitrophenyl derivative.

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Hypoxic glioma-derived exosomes promote M2-like macrophage polarization by enhancing autophagy induction

Cell Death and Disease ◽

10.1038/s41419-021-03664-1 ◽

2021 ◽

Vol 12 (4) ◽

Author(s):

Jianye Xu ◽

Jian Zhang ◽

Zongpu Zhang ◽

Zijie Gao ◽

Yanhua Qi ◽

...

Keyword(s):

Macrophage Polarization ◽

Autophagy Induction ◽

Antitumor Immunotherapy ◽

Novel Biomarkers ◽

And Migration ◽

Immunosuppressive Microenvironment ◽

Proliferation And Migration ◽

Glioma Progression

AbstractExosomes participate in intercellular communication and glioma microenvironment modulation, but the exact mechanisms by which glioma-derived exosomes (GDEs) promote the generation of the immunosuppressive microenvironment are still unclear. Here, we investigated the effects of GDEs on autophagy, the polarization of tumor-associated macrophages (TAMs), and glioma progression. Compared with normoxic glioma-derived exosomes (N-GDEs), hypoxic glioma-derived exosomes (H-GDEs) markedly facilitated autophagy and M2-like macrophage polarization, which subsequently promoted glioma proliferation and migration in vitro and in vivo. Western blot and qRT-PCR analyses indicated that interleukin 6 (IL-6) and miR-155-3p were highly expressed in H-GDEs. Further experiments showed that IL-6 and miR-155-3p induced M2-like macrophage polarization via the IL-6-pSTAT3-miR-155-3p-autophagy-pSTAT3 positive feedback loop, which promotes glioma progression. Our study clarifies a mechanism by which hypoxia and glioma influence autophagy and M2-like macrophage polarization via exosomes, which could advance the formation of the immunosuppressive microenvironment. Our findings suggest that IL-6 and miR-155-3p may be novel biomarkers for diagnosing glioma and that treatments targeting autophagy and the STAT3 pathway may contribute to antitumor immunotherapy.

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Cyr61 promotes Schwann cell proliferation and migration via αvβ3 integrin

BMC Molecular and Cell Biology ◽

10.1186/s12860-021-00360-y ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Zhenghui Cheng ◽

Yawen Zhang ◽

Yinchao Tian ◽

Yuhan Chen ◽

Fei Ding ◽

...

Keyword(s):

Nerve Injury ◽

Peripheral Nerves ◽

Molecular Mechanisms ◽

Αvβ3 Integrin ◽

Promoting Effect ◽

Ccn Family ◽

And Migration ◽

Proliferation And Migration

Abstract Background Schwann cells (SCs) play a crucial role in the repair of peripheral nerves. This is due to their ability to proliferate, migrate, and provide trophic support to axon regrowth. During peripheral nerve injury, SCs de-differentiate and reprogram to gain the ability to repair nerves. Cysteine-rich 61 (Cyr61/CCN1) is a member of the CCN family of matrix cell proteins and have been reported to be abundant in the secretome of repair mediating SCs. In this study we investigate the function of Cyr61 in SCs. Results We observed Cyr61 was expressed both in vivo and in vitro. The promoting effect of Cyr61 on SC proliferation and migration was through autocrine and paracrine mechanisms. SCs expressed αvβ3 integrin and the effect of Cyr61 on SC proliferation and migration could be blocked via αvβ3 integrin. Cyr61 could influence c-Jun protein expression in cultured SCs. Conclusions In this study, we found that Cyr61 promotes SC proliferation and migration via αvβ3 integrin and regulates c-Jun expression. Our study contributes to the understanding of cellular and molecular mechanisms underlying SC’s function during nerve injury, and thus, may facilitate the regeneration of peripheral nerves after injury.

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Effect of Slit/Robo signaling on regeneration in lung emphysema

Experimental & Molecular Medicine ◽

10.1038/s12276-021-00633-8 ◽

2021 ◽

Author(s):

Jin-Soo Park ◽

RyeonJin Cho ◽

Eun-Young Kang ◽

Yeon-Mok Oh

Keyword(s):

Epithelial Cells ◽

Mouse Model ◽

Lung Epithelial Cells ◽

Mouse Lung ◽

Chronic Obstructive ◽

Irreversible Damage ◽

Lung Epithelial ◽

And Migration ◽

Proliferation And Migration

AbstractEmphysema, a pathological component of chronic obstructive pulmonary disease, causes irreversible damage to the lung. Previous studies have shown that Slit plays essential roles in cell proliferation, angiogenesis, and organ development. In this study, we evaluated the effect of Slit2 on the proliferation and migration of mouse lung epithelial cells and its role in regeneration in an emphysema lung mouse model. Here, we have shown that Slit2/Robo signaling contributes to the regeneration of lungs damaged by emphysema. Mouse epithelial lung cells treated with Slit2 exhibited increased proliferation and migration in vitro. Our results also showed that Slit2 administration improved alveolar regeneration in the emphysema mouse model in vivo. Furthermore, Slit2/Robo signaling increased the phosphorylation of ERK and Akt, which was mediated by Ras activity. These Slit2-mediated cellular signaling processes may be involved in the proliferation and migration of mouse lung epithelial cells and are also associated with the potential mechanism of lung regeneration. Our findings suggest that Slit2 administration may be beneficial for alveolar regeneration in lungs damaged by emphysema.

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Cyclooxygenase Inhibition Alters Proliferative, Migratory, and Invasive Properties of Human Glioblastoma Cells In Vitro

International Journal of Molecular Sciences ◽

10.3390/ijms22094297 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4297

Author(s):

Matthew Thomas Ferreira ◽

Juliano Andreoli Miyake ◽

Renata Nascimento Gomes ◽

Fábio Feitoza ◽

Pollyana Bulgarelli Stevannato ◽

...

Keyword(s):

Cell Migration ◽

Cell Biology ◽

Gelatin Zymography ◽

Viable Cell ◽

Cell Counting ◽

Gelatinolytic Activity ◽

Ep4 Receptor ◽

And Migration ◽

Proliferation And Migration

Prostaglandin E2 (PGE2) is known to increase glioblastoma (GBM) cell proliferation and migration while cyclooxygenase (COX) inhibition decreases proliferation and migration. The present study investigated the effects of COX inhibitors and PGE2 receptor antagonists on GBM cell biology. Cells were grown with inhibitors and dose response, viable cell counting, flow cytometry, cell migration, gene expression, Western blotting, and gelatin zymography studies were performed. The stimulatory effects of PGE2 and the inhibitory effects of ibuprofen (IBP) were confirmed in GBM cells. The EP2 and EP4 receptors were identified as important mediators of the actions of PGE2 in GBM cells. The concomitant inhibition of EP2 and EP4 caused a significant decrease in cell migration which was not reverted by exogenous PGE2. In T98G cells exogenous PGE2 increased latent MMP2 gelatinolytic activity. The inhibition of COX1 or COX2 caused significant alterations in MMP2 expression and gelatinolytic activity in GBM cells. These findings provide further evidence for the importance of PGE2 signalling through the EP2 and the EP4 receptor in the control of GBM cell biology. They also support the hypothesis that a relationship exists between COX1 and MMP2 in GBM cells which merits further investigation as a novel therapeutic target for drug development.

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