scholarly journals ANGI-07. NOVEL FUSION GENE PTPRZ1-MET PROMOTES GLIOMAS ANGIOGENESIS BY UP-REGULATING EXOCRINE PROTEIN IGF2BP3

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi31-vi31
Author(s):  
Yanwei Liu ◽  
Xiaoguang Qiu ◽  
Tao Jiang
Keyword(s):  
Gene Expression ◽  
Candidate Genes ◽  
Kinase Inhibitor ◽  
Fusion Gene ◽  
Vascular Endothelial Cells ◽  
Negative Control ◽  
Fold Change ◽  
Prognostic Analysis ◽  
Stat3 Signaling ◽  
Worse Prognosis

Abstract We previously reported a novel fusion gene PTPRZ1-MET in 15% of secondary GBM (sGBM). Subsequent studies showed that ZM fusion indicates a significantly worse prognosis and promotes glioma progression by increasing MET activity. We have demonstrated hyper-activation of MAPK and STAT3 signaling and elevated angiogenesis activities in patients and subcutaneous tumors with ZM fusion. However, the angiogenesis mechanism regulated by ZM is still unclear. In this study, 66 up-regulated and 66 down-regulated genes were identified on 8 sGBMs with ZM fusion comparing gene expression with 135 negative sGBMs (fold-change >2.5 & p.value < 0.05). ZM-harboring U87 MG xenograft models were conducted and RNA sequencing was performed in 3 subcutaneous tumors with ZM-harboring U87 MG and 3 negative control. 384 up-regulated and 698 down-regulated genes were identified on 3 ZM-harboring samples comparing gene expression with 3 negative control samples (fold-change >2.5 & p.value < 0.05. Three subcutaneous tumors with ZM-harboring U87 MG were treated by a MET kinase inhibitor, PLB-1001. Finally, the expression of 13 up-regulated gene decreased and 10 down-regulated genes increased after treatment by PLB-1001. We overlapped the candidate genes between patient samples and subcutaneous tumors and 5 up-regulated and 4 down-regulated genes was appeared and most associated with ZM fusion. Prognostic analysis of 9 candidate genes on sGBM revealed that a higher expression of IGF2BP3 indicates a worse prognosis. In further study, we found that IGF2BP3 can be secreted out of the gliomas stem cells (GSCs) and promote proliferation of vascular endothelial cells and the expression of CD31. IGF2BP3 siRNA can block this pathway and inhibit the angiogenesis. Conclusion, our study demonstrated a new pathway promoting angiogenesis in gliomas. But the regulating mechanism between ZM fusion gene and IGF2BP3 deserves to do further research.

scholarly journals Flavanoids induce expression of the suppressor of cytokine signalling 3 (SOCS3) gene and suppress IL-6-activated signal transducer and activator of transcription 3 (STAT3) activation in vascular endothelial cells

2013 ◽  
Vol 454 (2) ◽  
pp. 283-293 ◽  
Author(s):  
Jolanta Wiejak ◽  
Julia Dunlop ◽  
Simon P. Mackay ◽  
Stephen J. Yarwood
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Kinase Inhibitor ◽  
Vascular Endothelial Cells ◽  
Janus Kinase ◽  
Vascular Endothelial ◽  
Signal Transducer ◽  
Compound C ◽  
Transcription 3 ◽  
Socs3 Protein

The atherogenic cytokine IL-6 (interleukin-6) induces pro-inflammatory gene expression in VECs (vascular endothelial cells) by activating the JAK (Janus kinase)/STAT3 (signal transducer and activator of transcription 3) signalling pathway, which is normally down-regulated by the STAT3-dependent induction of the E3 ubiquitin ligase component SOCS3 (suppressor of cytokine signalling 3). Novel treatments based on the regulation of SOCS3 protein levels could therefore have value in the treatment of diseases with an inflammatory component, such as atherosclerosis. To this end we carried out a screen of 1031 existing medicinal compounds to identify inducers of SOCS3 gene expression and identified the flavanoids naringenin and flavone as effective inducers of SOCS3 protein, mRNA and promoter activity. This was in contrast with the action of traditional JAK/STAT3 inhibitors and the polyphenol resveratrol, which effectively suppress SOCS3 gene expression. Both naringenin and flavone also effectively suppressed IL-6-stimulated phosphorylation of STAT3 (Tyr705) which led to suppression of IL-6-induction of the atherogenic STAT3 target gene MCP1 (monocyte chemotactic protein-1), suggesting that their ability to induce SOCS3 gene expression is STAT3-independent. Supporting this idea was the observation that the general kinase inhibitor compound C inhibits flavone- and cAMP-dependent, but not JAK-dependent, SOCS3 induction in VECs. Indeed, the ability of flavanoids to induce SOCS3 expression requires activation of the ERK (extracellular-signal-regulated kinase)-dependent transcription factor SP3, and not STAT3. In the present paper we therefore describe novel molecular actions of flavanoids, which control SOCS3 gene induction and suppression of STAT3 signalling in VECs. These mechanisms could potentially be exploited to develop novel anti-atherogenic therapies.

Potentiation of Proopiomelanocortin Gene Expression in Cultured Pituitary Cells by Benzodiazepines

2003 ◽  
Vol 98 (5) ◽  
pp. 1172-1177 ◽  
Author(s):  
Kazuhiko Fukuda ◽  
Nobuo Uetsuki ◽  
Hisatoshi Uga ◽  
Mitsuko Hashiguchi ◽  
Masami Sato ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cyclic Amp ◽  
Kinase Inhibitor ◽  
Fusion Gene ◽  
Benzodiazepine Receptors ◽  
Phosphodiesterase Inhibitor ◽  
Benzodiazepine Receptor ◽  
Pituitary Cells ◽  
Dependent Protein ◽  
Pituitary Adrenal Axis

Background Benzodiazepines are frequently used not only as a part of general anesthesia but also for the purpose of sedation during regional anesthesia. Effects of these drugs on the hypothalamic-pituitary-adrenal axis activity have been studied, but are still controversial. It is not known whether benzodiazepines affect expression of proopiomelanocortin, precursor protein of adrenocorticotropic hormone and related peptides. Methods AtT20PL cell line, a clone of AtT20/D16v mouse corticotroph tumor cells stably transfected with approximately 0.7 kilobases (kb) of the rat proopiomelanocortin 5' promoter-luciferase fusion gene, was used. In the presence or absence of diazepam or midazolam, cells were stimulated by corticotropin-releasing hormone (CRH) or forskolin. Proopiomelanocortin gene expression was estimated by measurement of luciferase activity. Furthermore, to study the mechanism of benzodiazepine effects, cyclic adenosine 3',5'-monophosphate (cyclic AMP) efflux was measured by enzyme immunoassay. Results Diazepam and midazolam dose-dependently increased the proopiomelanocortin gene expression induced by CRH or forskolin. The potentiating effect was not affected by benzodiazepine receptor antagonists flumazenil and PK11195, but was abolished by a cyclic AMP-dependent protein kinase inhibitor H89. Cyclic AMP efflux induced by CRH or forskolin was also enhanced by diazepam and midazolam. In the presence of isobutylmethylxanthine, a nonspecific phosphodiesterase inhibitor, potentiation of proopiomelanocortin gene expression and enhancement of cyclic AMP efflux by benzodiazepines were not observed. Conclusions Benzodiazepines potentiate the effect of CRH or forskolin on proopiomelanocortin gene expression. The potentiating effect is not mediated by the benzodiazepine receptors, but its mechanism probably involves inhibition of phosphodiesterase.

scholarly journals Insulin Inhibits Dexamethasone Effect on Angiotensinogen Gene Expression and Induction of Hypertrophy in Rat Kidney Proximal Tubular Cells in High Glucose

Endocrinology ◽  
2002 ◽  
Vol 143 (12) ◽  
pp. 4627-4635 ◽  
Author(s):  
Shao-Ling Zhang ◽  
Xing Chen ◽  
Chih-Chang Wei ◽  
Janos G. Filep ◽  
Shiow-Shih Tang ◽  
...  
Keyword(s):  
Gene Expression ◽  
High Glucose ◽  
Kinase Inhibitor ◽  
Fusion Gene ◽  
Rat Kidney ◽  
Chloramphenicol Acetyl Transferase ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Proximal Tubular ◽  
Renal Proximal Tubular

Abstract The present studies investigated whether insulin inhibits the stimulatory effect of dexamethasone (DEX) on angiotensinogen (ANG) gene expression and induction of hypertrophy in rat immortalized renal proximal tubular cells (IRPTCs) in a high-glucose milieu. Rat IRPTCs were cultured in monolayer. ANG and ANG mRNA expression in IRPTCs were quantified by a specific RIA for rat ANG and by RT-PCR assay, respectively. A fusion gene containing the full length of the 5′-flanking region of the rat ANG gene linked to a chloramphenicol acetyl transferase reporter gene was introduced into IRPTCs. The level of fusion gene expression was determined by cellular chloramphenicol acetyl transferase enzymatic activity. Cellular hypertrophy was assessed by flow cytometry, cellular p27Kip1 protein expression, and protein assay. Our results showed that high glucose (i.e. 25 mm) and DEX (10−7m) additively stimulated ANG gene expression and induced IRPTC hypertrophy. Insulin inhibited the effect of high glucose and DEX on these parameters. The inhibitory effect of insulin was reversed by PD 98059 (a MAPK inhibitor) but not by wortmannin (a phosphatidylinositol-3-kinase inhibitor). These results demonstrate that insulin is effective in blocking the stimulatory action of high glucose and DEX on ANG gene expression and induction of IRPTC hypertrophy, suggesting its important role in preventing local intrarenal renin-angiotensin system activation and renal proximal tubular cell hypertrophy induced by hyperglycemia and glucocorticoids in vivo.

scholarly journals Regulation of the gonadal transcriptome during sex determination and testis morphogenesis: comparative candidate genes

Reproduction ◽  
2007 ◽  
Vol 134 (3) ◽  
pp. 455-472 ◽  
Author(s):  
Tracy M Clement ◽  
Matthew D Anway ◽  
Mehmet Uzumcu ◽  
Michael K Skinner
Keyword(s):  
Gene Expression ◽  
Sex Determination ◽  
Candidate Genes ◽  
Expression Profiles ◽  
Gonadal Development ◽  
Developmental Period ◽  
Fold Change ◽  
Ovary Development ◽  
Testis Development

Gene expression profiles during sex determination and gonadal differentiation were investigated to identify new potential regulatory factors. Embryonic day 13 (E13), E14, and E16 rat testes and ovaries were used for microarray analysis, as well as E13 testis organ cultures that undergo testis morphogenesis and develop seminiferous cordsin vitro. A list of 109 genes resulted from a selective analysis for genes present in male gonadal development and with a 1.5-fold change in expression between E13 and E16. Characterization of these 109 genes potentially important for testis development revealed that cytoskeletal-associated proteins, extracellular matrix factors, and signaling factors were highly represented. Throughout the developmental period (E13–E16), sex-enriched transcripts were more prevalent in the male with 34 of the 109 genes having testis-enriched expression during sex determination. In ovaries, the total number of transcripts with a 1.5-fold change in expression between E13 and E16 was similar to the testis, but none of those genes were both ovary enriched and regulated during the developmental period. Genes conserved in sex determination were identified by comparing changing transcripts in the rat analysis herein, to transcripts altered in previously published mouse studies of gonadal sex determination. A comparison of changing mouse and rat transcripts identified 43 genes with species conservation in sex determination and testis development. Profiles of gene expression during E13–E16 rat testis and ovary development are presented and candidate genes for involvement in sex determination and testis differentiation are identified. Analysis of cellular pathways did not reveal any specific pathways involving multiple candidate genes. However, the genes and gene network identified influence numerous cellular processes with cellular differentiation, proliferation, focal contact, RNA localization, and development being predominant.

scholarly journals Meta-Analysis-Assisted Detection of Gravity-Sensitive Genes in Human Vascular Endothelial Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Yin Liang ◽  
Mengxue Wang ◽  
Yun Liu ◽  
Chen Wang ◽  
Ken Takahashi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Candidate Genes ◽  
Dna Microarray ◽  
Vascular Endothelial Cells ◽  
Meta Analysis ◽  
Vascular Endothelial Cell ◽  
Expression Level ◽  
Vascular Endothelial ◽  
Microarray Datasets

Gravity affects the function and maintenance of organs, such as bones, muscles, and the heart. Several studies have used DNA microarrays to identify genes with altered expressions in response to gravity. However, it is technically challenging to combine the results from various microarray datasets because of their different data structures. We hypothesized that it is possible to identify common changes in gene expression from the DNA microarray datasets obtained under various conditions and methods. In this study, we grouped homologous genes to perform a meta-analysis of multiple vascular endothelial cell and skeletal muscle datasets. According to the t-distributed stochastic neighbor embedding (t-SNE) analysis, the changes in the gene expression pattern in vascular endothelial cells formed specific clusters. We also identified candidate genes in endothelial cells that responded to gravity. Further, we exposed human umbilical vein endothelial cells (HUVEC) to simulated microgravity (SMG) using a clinostat and measured the expression levels of the candidate genes. Gene expression analysis using qRT-PCR revealed that the expression level of the prostaglandin (PG) transporter gene SLCO2A1 decreased in response to microgravity, consistent with the meta-analysis of microarray datasets. Furthermore, the direction of gravity affected the expression level of SLCO2A1, buttressing the finding that its expression was affected by gravity. These results suggest that a meta-analysis of DNA microarray datasets may help identify new target genes previously overlooked in individual microarray analyses.

scholarly journals The choice of negative control antisense oligonucleotides dramatically impacts downstream analysis depending on the cellular background

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Luca Ducoli ◽  
Saumya Agrawal ◽  
Chung-Chau Hon ◽  
Jordan A. Ramilowski ◽  
Eliane Sibler ◽  
...  
Keyword(s):  
Gene Expression ◽  
Vascular Endothelial Cells ◽  
Cell Types ◽  
Negative Control ◽  
Vascular Endothelial ◽  
Cell Type ◽  
A Cell ◽  
Cell Type Specific ◽  
Downstream Analysis ◽  
Cap Analysis

Abstract Background The lymphatic and the blood vasculature are closely related systems that collaborate to ensure the organism’s physiological function. Despite their common developmental origin, they present distinct functional fates in adulthood that rely on robust lineage-specific regulatory programs. The recent technological boost in sequencing approaches unveiled long noncoding RNAs (lncRNAs) as prominent regulatory players of various gene expression levels in a cell-type-specific manner. Results To investigate the potential roles of lncRNAs in vascular biology, we performed antisense oligonucleotide (ASO) knockdowns of lncRNA candidates specifically expressed either in human lymphatic or blood vascular endothelial cells (LECs or BECs) followed by Cap Analysis of Gene Expression (CAGE-Seq). Here, we describe the quality control steps adopted in our analysis pipeline before determining the knockdown effects of three ASOs per lncRNA target on the LEC or BEC transcriptomes. In this regard, we especially observed that the choice of negative control ASOs can dramatically impact the conclusions drawn from the analysis depending on the cellular background. Conclusion In conclusion, the comparison of negative control ASO effects on the targeted cell type transcriptomes highlights the essential need to select a proper control set of multiple negative control ASO based on the investigated cell types.

scholarly journals Programmed cell death 4 and BCR-ABL fusion gene expression are negatively correlated in chronic myeloid leukemia

2016 ◽  
Vol 12 (4) ◽  
pp. 2976-2981 ◽  
Author(s):  
Xia Zhang ◽  
Riming Liu ◽  
Baohua Huang ◽  
Xiaolu Zhang ◽  
Weijuan Yu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Death ◽  
Chronic Myeloid Leukemia ◽  
Programmed Cell Death ◽  
Myeloid Leukemia ◽  
Fusion Gene ◽  
Programmed Cell Death 4

scholarly journals Gene expression profiling reveals candidate genes for defining spider silk gland types

2021 ◽  
pp. 103594
Author(s):  
R. Crystal Chaw ◽  
Thomas H. Clarke ◽  
Peter Arensburger ◽  
Nadia A. Ayoub ◽  
Cheryl Y. Hayashi
Keyword(s):  
Gene Expression ◽  
Gene Expression Profiling ◽  
Candidate Genes ◽  
Expression Profiling ◽  
Spider Silk ◽  
Silk Gland

scholarly journals Activation of the S100A7/RAGE Pathway by IGF-1 Contributes to Angiogenesis in Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 621
Author(s):  
Maria Grazia Muoio ◽  
Marianna Talia ◽  
Rosamaria Lappano ◽  
Andrew H. Sims ◽  
Veronica Vella ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Endothelial Cells ◽  
Vascular Endothelial Cells ◽  
Bioinformatic Analysis ◽  
Tube Formation ◽  
Endothelial Cell Proliferation ◽  
Diabetic Patients ◽  
Obesity And Diabetes ◽  
Er Positive

Background: Breast cancer (BC) mortality is increased among obese and diabetic patients. Both obesity and diabetes are associated with dysregulation of both the IGF-1R and the RAGE (Receptor for Advanced Glycation End Products) pathways, which contribute to complications of these disorders. The alarmin S100A7, signaling through the receptor RAGE, prompts angiogenesis, inflammation, and BC progression. Methods: We performed bioinformatic analysis of BC gene expression datasets from published studies. We then used Estrogen Receptor (ER)-positive BC cells, CRISPR-mediated IGF-1R KO BC cells, and isogenic S100A7-transduced BC cells to investigate the role of IGF-1/IGF-1R in the regulation of S100A7 expression and tumor angiogenesis. To this aim, we also used gene silencing and pharmacological inhibitors, and we performed gene expression and promoter studies, western blotting analysis, ChIP and ELISA assays, endothelial cell proliferation and tube formation assay. Results: S100A7 expression correlates with worse prognostic outcomes in human BCs. In BC cells, the IGF-1/IGF-1R signaling engages STAT3 activation and its recruitment to the S100A7 promoter toward S100A7 increase. In human vascular endothelial cells, S100A7 activates RAGE signaling and prompts angiogenic effects. Conclusions: In ER-positive BCs the IGF-1 dependent activation of the S100A7/RAGE signaling in adjacent endothelial cells may serve as a previously unidentified angiocrine effector. Targeting S100A7 may pave the way for a better control of BC, particularly in conditions of unopposed activation of the IGF-1/IGF-1R axis.

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