scholarly journals EWS-FLI1 regulates and cooperates with core regulatory circuitry in Ewing sarcoma

2020 ◽  
Vol 48 (20) ◽  
pp. 11434-11451
Author(s):  
Xianping Shi ◽  
Yueyuan Zheng ◽  
Liling Jiang ◽  
Bo Zhou ◽  
Wei Yang ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Ewing Sarcoma ◽  
Gene Mutations ◽  
Mapk Signaling ◽  
Genome Wide ◽  
Regulatory Loop ◽  
Sarcoma Cells

Abstract Core regulatory circuitry (CRC)-dependent transcriptional network is critical for developmental tumors in children and adolescents carrying few gene mutations. However, whether and how CRC contributes to transcription regulation in Ewing sarcoma is unknown. Here, we identify and functionally validate a CRC ‘trio’ constituted by three transcription factors (TFs): KLF15, TCF4 and NKX2-2, in Ewing sarcoma cells. Epigenomic analyses demonstrate that EWS-FLI1, the primary fusion driver for this cancer, directly establishes super-enhancers of each of these three TFs to activate their transcription. In turn, KLF15, TCF4 and NKX2-2 co-bind to their own and each other's super-enhancers and promoters, forming an inter-connected auto-regulatory loop. Functionally, CRC factors contribute significantly to cell proliferation of Ewing sarcoma both in vitro and in vivo. Mechanistically, CRC factors exhibit prominent capacity of co-regulating the epigenome in cooperation with EWS-FLI1, occupying 77.2% of promoters and 55.6% of enhancers genome-wide. Downstream, CRC TFs coordinately regulate gene expression networks in Ewing sarcoma, controlling important signaling pathways for cancer, such as lipid metabolism pathway, PI3K/AKT and MAPK signaling pathways. Together, molecular characterization of the oncogenic CRC model advances our understanding of the biology of Ewing sarcoma. Moreover, CRC-downstream genes and signaling pathways may contain potential therapeutic targets for this malignancy.

scholarly journals EWS-FLI1 regulates and cooperates with core regulatory circuitry in Ewing sarcoma

2020 ◽  
Author(s):  
Xianping Shi ◽  
Yueyuan Zheng ◽  
Liling Jiang ◽  
Bo Zhou ◽  
Wei Yang ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Ewing Sarcoma ◽  
Gene Mutations ◽  
Mapk Signaling ◽  
Genome Wide ◽  
Children And Young Adults ◽  
Regulatory Loop ◽  
Sarcoma Cells

AbstractCore regulatory circuitry (CRC)-dependent transcriptional network is critical for developmental tumors in children and young adults carrying few gene mutations. However, whether and how CRC contributes to transcription regulation in Ewing sarcoma is unknown. Here, we identify and functionally validate a CRC “trio” constituted by three transcription factors (TFs): KLF15, TCF4 and NKX2-2, in Ewing sarcoma cells. Epigenomic analyses demonstrate that EWS-FLI1, the primary fusion driver for this cancer, directly establishes super-enhancers of each of these three TFs to activate their transcription. In turn, KLF15, TCF4 and NKX2-2 co-bind to their own and each other’s super-enhancers and promoters, forming an inter-connected auto-regulatory loop. Functionally, CRC factors contribute significantly to cell proliferation of Ewing sarcoma both in vitro and in vivo, and are all overexpressed in this cancer. Mechanistically, CRC factors exhibit prominent capacity of co-regulating the epigenome in cooperation with EWS-FLI1, occupying 77.2% of promoters and 55.6% of enhancers genome-wide. Downstream, CRC TFs coordinately regulate gene expression networks in Ewing sarcoma, directly controlling important signaling pathways for cancer, such as lipid metabolism pathway, PI3K/AKT and MAPK signaling pathways. Together, molecular characterization of the oncogenic CRC model advances our understanding of the biology of Ewing sarcoma. Moreover, this study identifies CRC-downstream genes and signaling pathways, which may contain potential targets for therapeutic intervention for this malignancy.

scholarly journals Inhibition effects of patchouli alcohol against influenza a virus through targeting cellular PI3K/Akt and ERK/MAPK signaling pathways

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Yunjia Yu ◽  
Yang Zhang ◽  
Shuyao Wang ◽  
Wei Liu ◽  
Cui Hao ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Influenza A ◽  
Plaque Assay ◽  
Mapk Signaling ◽  
Western Blot Assay ◽  
Patchouli Alcohol ◽  
Erk Mapk ◽  
Mapk Signaling Pathways

Abstract Background Patchouli alcohol (PA) is a tricyclic sesquiterpene extracted from Pogostemonis Herba, which is a traditional Chinese medicine used for therapy of inflammatory diseases. Recent studies have shown that PA has various pharmacological activities, including anti-bacterial and anti-viral effects. Methods In this study, the anti-influenza virus (IAV) activities and mechanisms were investigated both in vitro and in vivo. The inhibitory effects of PA against IAV in vitro were evaluated by plaque assay and immunofluorescence assay. The neuraminidase inhibition assay, hemagglutination inhibition (HI) assay, and western blot assay were used to explore the anti-viral mechanisms. The anti-IAV activities in vivo were determined by mice pneumonia model and HE staining. Results The results showed that PA significantly inhibited different IAV strains multiplication in vitro, and may block IAV infection through inactivating virus particles directly and interfering with some early stages after virus adsorption. Cellular PI3K/Akt and ERK/MAPK signaling pathways may be involved in the anti-IAV actions of PA. Intranasal administration of PA markedly improved mice survival and attenuated pneumonia symptoms in IAV infected mice, comparable to the effects of Oseltamivir. Conclusions Therefore, Patchouli alcohol has the potential to be developed into a novel anti-IAV agent in the future.

scholarly journals In Vitro Biophysical and Biological Characterization of Lipid Nanoparticles Co-Encapsulating Oncosuppressors miR-199b-5p and miR-204-5p as Potentiators of Target Therapy in Metastatic Melanoma

2020 ◽  
Vol 21 (6) ◽  
pp. 1930 ◽  
Author(s):  
Luigi Fattore ◽  
Virginia Campani ◽  
Ciro Francesco Ruggiero ◽  
Valentina Salvati ◽  
Domenico Liguoro ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Melanoma Cell ◽  
Biological Fluids ◽  
Target Therapy ◽  
Lipid Nanoparticles ◽  
Mapk Signaling ◽  
Oncogenic Driver

Uncontrolled MAPK signaling is the main oncogenic driver in metastatic melanomas bearing mutations in BRAF kinase. These tumors are currently treated with the combination of BRAF/MEK inhibitors (MAPKi), but this therapy is plagued by drug resistance. In this context we recently discovered that several microRNAs are involved in the development of drug resistance. In particular miR-204-5p and miR-199b-5p were found to function as antagonists of resistance because their enforced overexpression is able to inhibit melanoma cell growth in vitro either alone or in combination with MAPKi. However, the use of miRNAs in therapy is hampered by their rapid degradation in serum and biological fluids, as well as by the poor intracellular uptake. Here, we developed lipid nanoparticles (LNPs) encapsulating miR-204-5p, miR-199b-5p individually or in combination. We obtained LNPs with mean diameters < 200 nm and high miRNA encapsulation efficiency. These formulations were tested in vitro on several melanoma cell lines sensitive to MAPKi or rendered drug resistant. Our results show that LNPs encapsulating combinations of the two oncosuppressor miRNAs are highly efficient in impairing melanoma cell proliferation and viability, affect key signaling pathways involved in melanoma cell survival, and potentiate the efficacy of drugs inhibiting BRAF and MEK. These results warrant further assessment of the anti-tumor efficacy of oncosuppressor miRNAs encapsulating LNPs in in vivo tumor models.

scholarly journals CGRP Regulates Nucleus Pulposus Cell Apoptosis and Inflammation via the MAPK/NF-κB Signaling Pathways during Intervertebral Disc Degeneration

2021 ◽  
Vol 2021 ◽  
pp. 1-19
Author(s):  
Kaiqiang Sun ◽  
Jian Zhu ◽  
Chen Yan ◽  
Fudong Li ◽  
Fanqi Kong ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Signaling Pathways ◽  
Nucleus Pulposus ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Nucleus Pulposus Cell ◽  
Mapk Signaling ◽  
Discogenic Pain

Chronic low back pain (CLBP) has been proved to be the dominating cause of disability in patients with lumbar degenerative diseases. Of the various etiological factors, intervertebral disc degeneration (IVDD) has been the dominating cause. In the past few decades, the role and changes of nerve systems, especially the peripheral sensory fibers and their neurotransmitters, in the induction and progression of IVDD have attracted growing concerns. The expression of many neuropeptides, such as SP, NPY, and CGRP, in the nociceptive pathways is increased during the progression of IVDD and responsible for the discogenic pain. Here, the role of CGRP in the progression of IVDD was firstly investigated both in vitro and in vivo. Firstly, we confirmed that human degenerated intervertebral disc tissue exhibited elevated expression of CGRP and its receptor. Secondly, in vitro experiments suggested that CGRP could inhibit the proliferation and induce apoptosis in human nucleus pulposus (NP) cells, as well as promote inflammation and degenerated phenotypes through activating NF-κB and MAPK signaling pathways. Thirdly, CGRP receptor antagonist, Rimegepant, can ameliorate the adverse effects of CGRP imposed on NP cells, which were confirmed in vitro and in vivo. Our results will bring about a brand-new insight into the roles of neuromodulation in IVDD and related therapeutic attempts.

scholarly journals Berbamine Exerts Anti-Inflammatory Effects via Inhibition of NF-κB and MAPK Signaling Pathways

2017 ◽  
Vol 41 (6) ◽  
pp. 2307-2318 ◽  
Author(s):  
Xiao-Jian Jia ◽  
Xi Li ◽  
Feng Wang ◽  
Han-Qing Liu ◽  
Da-Jun Zhang
Keyword(s):  
Signaling Pathways ◽  
Mapk Signaling ◽  
Inflammatory Factor ◽  
Anti Inflammatory ◽  
Underlying Mechanisms ◽  
Peritonitis Model ◽  
Mapk Signaling Pathways ◽  
Superoxide Release

Background/Aims: This study aimed to investigate the anti-inflammatory activity of Berbamine (BER), a bisbenzylisoquinoline alkaloid extracted from Berberis amurensis (Xiao Bo An), and the underlying mechanisms. Methods: Macrophages and neutrophils were treated with BER in vitro and stimulated with LPS and fMLP. The effects of BER on the expression of pro-inflammatory mediators in macrophages were evaluated with quantitative RT-PCR and ELISA. The effects of BER on the activation and superoxide release of neutrophils were determined with flow cytometry and WST-1 reduction test. The inhibitory effects of BER on the activation of signaling pathways related to inflammatory response in macrophages were evaluated by western blot analysis. In addition, a mouse peritonitis model was made by peritoneal injection of thioglycollate medium and anti-inflammatory effects of BER were investigated in vivo by quantitative analysis of pro-inflammatory factor production and leukocyte exudation. Results: BER significantly inhibited inflammatory factor expression by LPS-stimulated macrophages and suppressed activation and superoxide release of fMLP-stimulated neutrophils. In the mouse peritonitis model, BER significantly inhibited the activation of macrophages and exudation of neutrophils. According to analysis, BER significantly suppressed phosphorylation of NF-κB and MAPK (JNK and ERK1/2) signaling pathways in LPS-stimulated macrophages. Conclusions: Collectively, data from this study suggest that BER has anti-inflammatory potential, which is effected via inhibition of NF-κB and MAPK signaling pathways, and thus holds promise for treatment of inflammatory disease.

scholarly journals Signaling Pathways Regulated by Silica Nanoparticles

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1398
Author(s):  
Shih-Yi Hsu ◽  
Robert Morris ◽  
Feng Cheng
Keyword(s):  
Silica Nanoparticles ◽  
Signaling Pathways ◽  
Drug Targets ◽  
Silica Nanoparticle ◽  
Cell Types ◽  
Mapk Signaling ◽  
Nanoparticle Exposure ◽  
Mechanism Of Toxicity

Silica nanoparticles are a class of molecules commonly used in drug or gene delivery systems that either facilitate the delivery of therapeutics to specific drug targets or enable the efficient delivery of constructed gene products into biological systems. Some in vivo or in vitro studies have demonstrated the toxic effects of silica nanoparticles. Despite the availability of risk management tools in response to the growing use of synthetic silica in commercial products, the molecular mechanism of toxicity induced by silica nanoparticles is not well characterized. The purpose of this study was to elucidate the effects of silica nanoparticle exposure in three types of cells including human aortic endothelial cells, mouse-derived macrophages, and A549 non-small cell lung cancer cells using toxicogenomic analysis. The results indicated that among all three cell types, the TNF and MAPK signaling pathways were the common pathways upregulated by silica nanoparticles. These findings may provide insight into the effects of silica nanoparticle exposure in the human body and the possible mechanism of toxicity.

scholarly journals CircEpc1 Promotes Ricin Toxin-Induced Inflammation via Activation of NF-κB and MAPK Signaling Pathways by Sponging miR-5114

2021 ◽  
Vol 12 ◽  
Author(s):  
Mingxin Dong ◽  
Xiaohao Zhang ◽  
Haotian Yu ◽  
Yan Wang ◽  
Ying Chang ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Suppressive Effect ◽  
Mapk Signaling ◽  
Innate Immune ◽  
Circular Rnas ◽  
Inflammatory Injury ◽  
Ricin Toxin ◽  
Mapk Signaling Pathways

Increasing studies have concentrated on investigating circular RNAs (circRNAs) as pivotal regulators in the progression of numerous diseases and biological processes and abundant evidence shows that circRNAs are participated in the regulation of innate immune responses. Several studies showed that Ricin Toxin (RT) could induce inflammatory injury. There was no research on the particular functions and underlying mechanisms of circRNAs in RT-induced inflammation. In this study, RNA sequencing performed on RT-treated and normal RAW264.7 macrophage cells was used to investigated the differentially expressed circRNAs. Based on the dataset, the expression of circEpc1 (mmu_circ_0,000,842) was identified higher in RT-treated cells. Moreover, gain-and-loss function assays showed that circEpc1 function as a promoter in RT-induced inflammation in vivo and in vitro. Mechanistically, circEpc1 acted as a miR-5114 sponge to relieve the suppressive effect of miR-5114 on its target NOD2 and thereby activating NF-κB and MAPK signaling pathways. Our results illuminated a link between RT-induced inflammation and the circEpc1 regulatory loop and provided novel insight into the functions of circRNA in innate immune, which may emerge as a potential target in immunotherapy to control the RT-induced inflammatory injury.

scholarly journals CircEpc1 Promotes Ricin Toxin-Induced Inflammation Via Activation of NF-κB And MAPK Signaling Pathways By Sponging miR-5114

2021 ◽  
Author(s):  
Mingxin Dong ◽  
Xiaohao Zhang ◽  
Haotian Yu ◽  
Yan Wang ◽  
Ying Chang ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Suppressive Effect ◽  
Mapk Signaling ◽  
Innate Immune ◽  
Circular Rnas ◽  
Inflammatory Injury ◽  
Ricin Toxin ◽  
Mapk Signaling Pathways

Abstract Background: Increasing studies have concentrated on investigating circular RNAs (circRNAs) as pivotal regulators in the progression of numerous diseases and biological processes and abundant evidence shows that circRNAs are participated in the regulation of innate immune responses. Several studies showed that Ricin Toxin (RT) could induce inflammatory injury. There was no research on the particular functions and underlying mechanisms of circRNAs in RT-induced inflammation. Results: In this study, RNA sequencing performed on RT-treated and normal RAW264.7 macrophage cells was used to investigated the differentially expressed circRNAs. Based on the dataset, the expression of circEpc1 (mmu_circ_0000842) was identified higher in RT-treated cells. Moreover, gain-and-loss function assays showed that circEpc1 function as a promoter in RT-induced inflammation in vivo and in vitro. Mechanistically, circEpc1 acted as a miR-5114 sponge to relieve the suppressive effect of miR-5114 on its target NOD2 and thereby activating NF-κB and MAPK signaling pathways. Conclusions: Our results illuminated a link between RT-induced inflammation and the circEpc1 regulatory loop and provided novel insight into the functions of circRNA in innate immune, which may emerge as a potential target in immunotherapy to control the RT-induced inflammatory injury.

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