scholarly journals STUB1-SMYD2 Axis Regulated Drug Resistance in Glioma cells

2021 ◽  
Author(s):  
Kailing Pan ◽  
Bin Hu ◽  
Lude Wang ◽  
Jinyong Fang ◽  
Jianlie Yuan ◽  
...  
Keyword(s):  
Cell Function ◽  
Degradation Mechanism ◽  
Chemotherapy Resistance ◽  
Glioma Cells ◽  
Sequencing Analysis ◽  
Kaplan Meier ◽  
Function Impairment ◽  
Epigenetic Regulator ◽  
And Migration ◽  
And Control

Abstract Aim: SMYD2 is an important epigenetic regulator that methylates histone and non-histone proteins. This study aims to investigate SMYD2 as an oncogene of gliomas and explore its degradation mechanism induced by cisplatin.Methods: Tumor tissue microarray of 441 glioma patients was collected for SMYD2 immunohistochemistry staining. Kaplan-Meier survival curves were constructed by using he overall survival. mRNA-sequencing analysis was detected for understanding the downstream mechanisms mediated by SMYD2. The half-inhibitory concentrations (IC50) of temozolomide and cisplatin in AZ505-treated and control cells were calculated. Thepotential E3 ubiquitin ligase of SMYD2 was predicted in UbiBrowser and confirmed by knockdown test. The effect of SMYD2 and its E3 ligase on gliomas apoptosis and migration were determined via cell-function assays.Results: High SMYD2 expression correlated with a high WHO stage (P=0.004) and a low survival probability (P=0.012). The inhibition of SMYD2 suppressed the process of EMT by downregulating the expression of COL1A1. AZ505 treatment significantly increased drug sensitivity of glioma cells. And the expression of SMYD2 was markedly reduced by cisplatin treatment via STUB1 mediated degradation. The knockdown of STUB1 could partly reverse the cell function impairment induced by cisplatin.Conclusion: These findings suggested that SMYD2 could be a potential drug target for the treatment of gliomas, and STUB1-mediated degradation of SMYD2 plays an important role in reversing chemotherapy resistance in gliomas.

scholarly journals CTR9-Mediated JAK2/STAT3 Pathway Promotes The Proliferation, Migration and Invasion of Human Glioma Cells

2021 ◽  
Author(s):  
Yang Xu ◽  
Jiaguo Chen ◽  
Gao He ◽  
Yuhai Zhang
Keyword(s):  
Protein Modification ◽  
Cell Function ◽  
Glioma Cells ◽  
Migration And Invasion ◽  
Stat3 Pathway ◽  
Invasion And Migration ◽  
The Public ◽  
Significant Difference ◽  
And Migration ◽  
U87 Cells

Abstract Background CTR9 (Cln three requiring 9) has been reported to be implicated in protein modification and oncogenesis of several human cancers. However, the protein expression and mechanism of CTR9 in glioma progression remain unclear. Methods We analyzed mRNA expression of CTR9 and CTR9-related survival curves in the public database. Then we detected CTR9 expression in glioma tissues and constructed U251 and U87 cells with stable silencing or overexpression of CTR9. Cell function tests and Western blot were conducted to explore the effects of CTR9 on glioma proliferation, invasion and migration, as well as the specific mechanism. All the date was presented as means ± SEM. Two-sample t-test and one-way analysis of variance (ANOVA) were used to identify whether there was a significant difference between each group of data. Results We found that CTR9 was overexpressed in glioma and inversely associated with glioma patient survival. The results manifested that knockdown of CTR9 suppressed the proliferation, migration and invasion of glioma cells, while overexpression facilitated them. The underlying molecular mechanism may involve the regulation of JAK2/STAT3 pathway by CTR9. Conclusion Our present study indicates that CTR9 is highly expressed in glioma and related to glioma grading and prognosis. CTR9 regulates malignant behaviors of glioma cells by activating JAK2/STAT3 pathway. Therefore, CTR9 is a promising biomarker for the diagnosis,targeted therapy and prognosis evaluation of glioma.

scholarly journals FAM87A as a Competing Endogenous RNA of miR-424-5p Suppresses Glioma Progression by Regulating PPM1H

2021 ◽  
Vol 2021 ◽  
pp. 1-18
Author(s):  
Hua Xu ◽  
Haiping Zhang ◽  
Lina Tan ◽  
Yang Yang ◽  
Haiyun Wang ◽  
...  
Keyword(s):  
Cell Function ◽  
Glioma Cells ◽  
Vital Role ◽  
Migration And Invasion ◽  
Competing Endogenous Rna ◽  
Qrt Pcr ◽  
Rate Effects ◽  
And Migration ◽  
Proliferation And Migration ◽  
Glioma Progression

Far less has been unveiled about the functions of lncRNAs on cancers yet. Here, we reported that lncRNA FAM87A, as a ceRNA of miR-424-5p, played a vital role in glioma development. qRT-PCR result indicated that FAM87A was abnormally downregulated in glioma tissue and cells. Survival analysis suggested that the FAM87A expression was negatively correlated with the survival rate. Effects of FAM87A on human glioma cell lines were also analyzed by MTT, Edu, and transwell assays. FAM87A hastened proliferation and migration of glioma cells. MiR-424-5p, predicted target of FAM87A, was fostered in glioma, which was examined by qRT-PCR. A negative correlation was indicated between FAM87A and miR-424-5p. Results of bioinformatics, dual luciferase, and RIP assays unveiled that FAM87A and miR-424-5p act upon each other. In addition, miR-424-5p targeted 3 ′ -UTR of PPM1H. Also, effects of miR-424-5p/FAM87A on glioma cells were identified via the cell function experiments. FAM87A suppressed PPM1H by binding to miR-424-5p competitively, thereby restraining cell proliferation, migration, and invasion. Collectively, these findings illuminated a new mechanism for glioma progression. Therefore, FAM87A may act as a feasible target for glioma treatment.

RBM5 Acts as Tumor Suppressor in Medulloblastoma through Regulating Wnt/β-Catenin Signaling

2020 ◽  
Vol 83 (3) ◽  
pp. 242-250
Author(s):  
Jianzhong Yu ◽  
Guangchun Ji ◽  
Wei Shi ◽  
Rui Zhao ◽  
Wenjun Shen ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Expression Patterns ◽  
Suppressor Gene ◽  
Sequencing Analysis ◽  
Mrna Levels ◽  
Breast Cancers ◽  
Kaplan Meier ◽  
Whole Exome ◽  
And Migration

Introduction: RBM5 acts as a tumor suppressor gene in lung and breast cancers; however, its role in the pathogenesis of medulloblastoma (MB) remains unclear. We previously identified 4 RBM5 mutations in whole exome sequencing analysis of 40 MB patients. This study examined the role of RBM5 in MB progression. Methods: The expression patterns of RBM5 in tissues of 40 MB patients were analyzed using immunohistochemistry. Associations between RBM5 expression and overall survival (OS) were evaluated using Kaplan-Meier analysis. The RBM5 role in Daoy cells’ proliferation, migration, and Wnt/β-catenin signaling was analyzed after RBM5 knockdown and overexpression. Results: The expression level of RBM5 mRNA and protein was significantly lower in MB than that in adjacent normal control tissues, and low RBM5 expression was significantly associated with reduced OS (p = 0.034). RBM5 knockdown induced Daoy and ONS-76 cells proliferation, while RBM5 overexpression repressed cell proliferation and migration in vitro (all p < 0.05). β-Catenin, LEF1, and cyclin D1 mRNA levels were upregulated, while DKK1 expression was downregulated in Daoy cells following RBM5 knockdown. Conclusion: RBM5 may function as a tumor suppressor in MB by regulating Wnt/β-catenin signaling, and its reduced expression is associated with lower OS.

Wnt/beta-catenin and PI3K/Akt/mTOR Signaling Pathways in Glioblastoma: Two Main Targets for Drug Design: A Review

2020 ◽  
Vol 26 (15) ◽  
pp. 1729-1741 ◽  
Author(s):  
Seyed H. Shahcheraghi ◽  
Venant Tchokonte-Nana ◽  
Marzieh Lotfi ◽  
Malihe Lotfi ◽  
Ahmad Ghorbani ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Cellular Proliferation ◽  
Chemotherapy Resistance ◽  
Wnt Signaling Pathway ◽  
Therapeutic Interventions ◽  
Beta Catenin ◽  
Clinical Prognosis ◽  
Invasion And Migration ◽  
And Migration

: Glioblastoma (GBM) is the most common and malignant astrocytic glioma, accounting for about 90% of all brain tumors with poor prognosis. Despite recent advances in understanding molecular mechanisms of oncogenesis and the improved neuroimaging technologies, surgery, and adjuvant treatments, the clinical prognosis of patients with GBM remains persistently unfavorable. The signaling pathways and the regulation of growth factors of glioblastoma cells are very abnormal. The various signaling pathways have been suggested to be involved in cellular proliferation, invasion, and glioma metastasis. The Wnt signaling pathway with its pleiotropic functions in neurogenesis and stem cell proliferation is implicated in various human cancers, including glioma. In addition, the PI3K/Akt/mTOR pathway is closely related to growth, metabolism, survival, angiogenesis, autophagy, and chemotherapy resistance of GBM. Understanding the mechanisms of GBM’s invasion, represented by invasion and migration, is an important tool in designing effective therapeutic interventions. This review will investigate two main signaling pathways in GBM: PI3K/Akt/mTOR and Wnt/beta-catenin signaling pathways.

scholarly journals Metagenomic Analysis of the Fecal Archaeome in Suckling Piglets Following Perinatal Tulathromycin Metaphylaxis

Animals ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 1825
Author(s):  
Mohamed Zeineldin ◽  
Ameer Megahed ◽  
Benjamin Blair ◽  
Brian Aldridge ◽  
James Lowe
Keyword(s):  
Sequencing Analysis ◽  
Metagenomic Sequencing ◽  
Post Intervention ◽  
Gastrointestinal Microbiome ◽  
Health And Wellbeing ◽  
Suckling Piglets ◽  
And Function ◽  
Changes Over Time ◽  
And Control ◽  
The Impact

The gastrointestinal microbiome plays an important role in swine health and wellbeing, but the gut archaeome structure and function in swine remain largely unexplored. To date, no metagenomics-based analysis has been done to assess the impact of an early life antimicrobials intervention on the gut archaeome. The aim of this study was to investigate the effects of perinatal tulathromycin (TUL) administration on the fecal archaeome composition and diversity in suckling piglets using metagenomic sequencing analysis. Sixteen litters were administered one of two treatments (TUL; 2.5 mg/kg IM and control (CONT); saline 1cc IM) soon after birth. Deep fecal swabs were collected from all piglets on days 0 (prior to treatment), 5, and 20 post intervention. Each piglet’s fecal archaeome was composed of rich and diverse communities that showed significant changes over time during the suckling period. At the phylum level, 98.24% of the fecal archaeome across all samples belonged to Euryarchaeota. At the genus level, the predominant archaeal genera across all samples were Methanobrevibacter (43.31%), Methanosarcina (10.84%), Methanococcus (6.51%), and Methanocorpusculum (6.01%). The composition and diversity of the fecal archaeome between the TUL and CONT groups at the same time points were statistically insignificant. Our findings indicate that perinatal TUL metaphylaxis seems to have a minimal effect on the gut archaeome composition and diversity in sucking piglets. This study improves our current understanding of the fecal archaeome structure in sucking piglets and provides a rationale for future studies to decipher its role in and impact on host robustness during this critical phase of production.

scholarly journals A85 THE CLINICAL IMPACT OF COVID-19 DELAYS ON PLASTIC BILIARY STENT REMOVAL IN NOVA SCOTIA

2021 ◽  
Vol 4 (Supplement_1) ◽  
pp. 54-56
Author(s):  
D R Lim ◽  
M Tsai ◽  
S E Gruchy ◽  
J Jones ◽  
G Williams ◽  
...  
Keyword(s):  
Survival Analysis ◽  
Nova Scotia ◽  
Stent Placement ◽  
Biliary Stent ◽  
Biliary Stents ◽  
Stent Occlusion ◽  
Stent Removal ◽  
Kaplan Meier ◽  
And Migration

Abstract Background The COVID-2019 pandemic continues to restrict access to endoscopy, resulting in delays or cancellation of non-urgent endoscopic procedures. A delay in the removal or exchange of plastic biliary stents may lead to stent occlusion with consensus recommendation of stent removal or exchange at three-month intervals [1–4]. We postulated that delayed plastic biliary stent removal (DPBSR) would increase complication rates. Aims We aim to report our single-centre experience with complications arising from DPBSR. Methods This was a retrospective, single-center, observational cohort study. All subjects who had ERCP-guided plastic biliary stent placement in Halifax, Nova Scotia between Dec 2019 and June 2020 were included in the study. DPBSR was defined as stent removal &gt;=90 days from insertion. Four endpoints were assigned to patients: 1. Stent removed endoscopically, 2. Died with stent in-situ (measured from stent placement to documented date of death/last clinical encounter before death), 3. Pending removal (subjects clinically well, no liver enzyme elevation, not expired, endpoint 1 Nov 2020), and 4. Complication requiring urgent reintervention. Kaplan-Meier survival analysis was used to represent duration of stent patency (Fig.1). Results 102 (47.2%) had plastic biliary stents placed between 2/12/2019 and 29/6/2020. 49 (48%) were female, and the median age was 68 (R 16–91). Median follow-up was 167.5 days, 60 (58.8%) subjects had stent removal, 12 (11.8%) died before replacement, 21 (20.6%) were awaiting stent removal with no complications (median 230d, R 30–332), 9 (8.8%) had complications requiring urgent ERCP. Based on death reports, no deaths were related to stent-related complications. 72(70.6%) of patients had stents in-situ for &gt;= 90 days. In this population, median time to removal was 211.5d (R 91-441d). 3 (4.2%) subjects had stent-related complications requiring urgent ERCP, mean time to complication was 218.3d (R 94–441). Stent removal &gt;=90 days was not associated with complications such as occlusion, cholangitis, and migration (p=1.0). Days of stent in-situ was not associated with occlusion, cholangitis, and migration (p=0.57). Sex (p=0.275), cholecystectomy (p=1.0), cholangiocarcinoma (p=1.0), cholangitis (p=0.68) or pancreatitis (p=1.0) six weeks prior to ERCP, benign vs. malignant etiology (p=1.0) were not significantly associated with stent-related complications. Conclusions Plastic biliary stent longevity may have been previously underestimated. The findings of this study agree with CAG framework recommendations [5] that stent removal be prioritized as elective (P3). Limitations include small sample size that could affect Kaplan-Meier survival analysis. Despite prolonged indwelling stent time as a result of COVID-19, we did not observe an increased incidence of stent occlusion or other complications. Funding Agencies None

scholarly journals B cell-specific GPR55 deficiency promotes atherosclerosis

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
R Guillamat-Prats ◽  
D Hering ◽  
M Rami ◽  
C Haerdtner ◽  
L Bindila ◽  
...  
Keyword(s):  
Body Weight ◽  
B Cells ◽  
B Cell ◽  
Mrna Expression ◽  
Cell Function ◽  
Metabolic Effects ◽  
Atherosclerotic Plaques ◽  
Funding Source ◽  
Sequencing Analysis ◽  
B Cell Function

Abstract Background Atherosclerosis is accompanied by an imbalance between resolving and pro-inflammatory lipid mediators. Targeting lipid signaling pathways might offer a new anti-inflammatory therapy for improving the clinical outcome in cardiovascular disease patients. We considered lysophosphatidylinositol (LPI) and its receptor G protein-coupled receptor (GPR)55 as a potential modulator of atherosclerosis. Its role in regulating atherosclerosis and B cell function is unknown. Hypothesis We assessed the hypothesis that GPR55 signaling causally affects atherosclerosis and whether it has a specific role in regulating B cell function in this disease. Methods Atherosclerotic plaques were compared between apolipoprotein E deficient (ApoE−/−) and ApoE−/−Gpr55−/− mice after 4 to 16 weeks Western Diet (WD; 0.15% cholesterol; n=12–15 per group). To specifically test the role of B cell GPR55 in atherosclerosis, we generated mixed chimeras by lethally irradiating low density lipoprotein receptor deficient (Ldlr−/−) mice and reconstituting with a mixture of μMT and wildtype (control) or μMT and Gpr55−/− bone marrow cells. Circulating B cells were sorted and bulk RNA sequencing analysis was performed. We performed lipid and immunostainings of murine aortic root plaques, qPCR and ELISA of tissue lysates, as well as multiplex analysis of plasma immunoglobulins. Leukocyte plasma and tissue counts were determined by flow cytometry. Results GPR55 expression in mouse and human atherosclerotic plaques was detected by immunostaining. Furthermore, we confirmed murine Gpr55 mRNA expression on sorted circulating B220+B cells via qPCR, which was higher compared to CD3+ T cells, while CD11+ myeloid cells as well as NK cells had only low Gpr55 mRNA levels. ApoE−/−Gpr55−/− mice had significantly larger plaques after 4&16 weeks WD compared to ApoE−/− controls, with more pronounced body weight increases and higher cholesterol levels at the 16 weeks WD time point. In addition, global Gpr55 deficiency resulted in enhanced aortic pro-inflammatory cytokine mRNA expression (IL-1β, IL-6, TNFα) and a massively upregulated IgG1 plasma levels and increased percentages of splenic germinal center and plasma cells. B-cell RNA-seq analysis showed 460 differential expressed regulated genes in the ApoE−/−Gpr55−/− compared to ApoE−/−. The main pathways affected were calcium ion transport, immunoglobulin production, negative regulation of phosphorylation, and cellular component morphogenesis, suggesting a dsysregulation of B cell function. B cell specific Gpr55 deficiency blunted the metabolic effects on body weight and cholesterol, but still translated in larger atherosclerotic plaques and elevated plasma IgG levels compared to the respective controls. Conclusion Both global and B cell-restricted Gpr55 deficiency promotes atherosclerosis and is associated with a more pro-inflammatory phenotype. Our findings suggest a novel role for GPR55 in regulating B cell development and function. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Deutsche Forschungsgemeinschaft (DFG)

scholarly journals YB-1 Is Altered in Pregnancy-Associated Disorders and Affects Trophoblast in Vitro Properties via Alternation of Multiple Molecular Traits

2021 ◽  
Vol 22 (13) ◽  
pp. 7226
Author(s):  
Violeta Stojanovska ◽  
Aneri Shah ◽  
Katja Woidacki ◽  
Florence Fischer ◽  
Mario Bauer ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Progression ◽  
Cell Function ◽  
Trophoblast Cell ◽  
Mrna Levels ◽  
Trophoblast Cells ◽  
Invasion And Migration ◽  
And Migration ◽  
Apoptosis And Inflammation

Cold shock Y-box binding protein-1 (YB-1) coordinates several molecular processes between the nucleus and the cytoplasm and plays a crucial role in cell function. Moreover, it is involved in cancer progression, invasion, and metastasis. As trophoblast cells share similar characteristics with cancer cells, we hypothesized that YB-1 might also be necessary for trophoblast functionality. In samples of patients with intrauterine growth restriction, YB-1 mRNA levels were decreased, while they were increased in preeclampsia and unchanged in spontaneous abortions when compared to normal pregnant controls. Studies with overexpression and downregulation of YB-1 were performed to assess the key trophoblast processes in two trophoblast cell lines HTR8/SVneo and JEG3. Overexpression of YB-1 or exposure of trophoblast cells to recombinant YB-1 caused enhanced proliferation, while knockdown of YB-1 lead to proliferative disadvantage in JEG3 or HTR8/SVneo cells. The invasion and migration properties were affected at different degrees among the trophoblast cell lines. Trophoblast expression of genes mediating migration, invasion, apoptosis, and inflammation was altered upon YB-1 downregulation. Moreover, IL-6 secretion was excessively increased in HTR8/SVneo. Ultimately, YB-1 directly binds to NF-κB enhancer mark in HTR8/SVneo cells. Our data show that YB-1 protein is important for trophoblast cell functioning and, when downregulated, leads to trophoblast disadvantage that at least in part is mediated by NF-κB.

scholarly journals CD90low glioma-associated mesenchymal stromal/stem cells promote temozolomide resistance by activating FOXS1-mediated epithelial-mesenchymal transition in glioma cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Bing-zhou Xue ◽  
Wei Xiang ◽  
Qing Zhang ◽  
Hao-fei Wang ◽  
Yu-jie Zhou ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Line ◽  
Epithelial Mesenchymal Transition ◽  
Chemotherapy Resistance ◽  
Glioma Cells ◽  
Conditioned Media ◽  
Cell Counting ◽  
Mesenchymal Transition ◽  
Mesenchymal Transformation ◽  
Stromal Stem Cells

Abstract Background The tumour microenvironment contributes to chemotherapy resistance in gliomas, and glioma-associated mesenchymal stromal/stem cells (gaMSCs) are important stromal cell components that play multiple roles in tumour progression. However, whether gaMSCs affect chemotherapy resistance to the first-line agent temozolomide (TMZ) remains unclear. Herein, we explored the effect and mechanism of gaMSCs on resistance to TMZ in glioma cells. Methods Human glioma cells (cell line U87MG and primary glioblastoma cell line GBM-1) were cultured in conditioned media of gaMSCs and further treated with TMZ. The proliferation, apoptosis and migration of glioma cells were detected by Cell Counting Kit-8 (CCK-8), flow cytometry and wound-healing assays. The expression of FOXS1 in glioma cells was analysed by gene microarray, PCR and Western blotting. Then, FOXS1 expression in glioma cells was up- and downregulated by lentivirus transfection, and markers of the epithelial-mesenchymal transformation (EMT) process were detected. Tumour-bearing nude mice were established with different glioma cells and treated with TMZ to measure tumour size, survival time and Ki-67 expression. Finally, the expression of IL-6 in gaMSC subpopulations and its effects on FOXS1 expression in glioma cells were also investigated. Results Conditioned media of gaMSCs promoted the proliferation, migration and chemotherapy resistance of glioma cells. The increased expression of FOXS1 and activation of the EMT process in glioma cells under gaMSC-conditioned media were detected. The relationship of FOXS1, EMT and chemotherapy resistance in glioma cells was demonstrated through the regulation of FOXS1 expression in vitro and in vivo. Moreover, FOXS1 expression in glioma cells was increased by secretion of IL-6 mainly from the CD90low gaMSC subpopulation. Conclusions CD90low gaMSCs could increase FOXS1 expression in glioma cells by IL-6 secretion, thereby activating epithelial-mesenchymal transition and resistance to TMZ in glioma cells. These results indicate a new role of gaMSCs in chemotherapy resistance and provide novel therapeutic targets.

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