scholarly journals PPAR-Responsive Elements Enriched with Alu Repeats May Contribute to Distinctive PPARγ–DNMT1 Interactions in the Genome

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 3993
Author(s):  
Amit Sharma ◽  
Fabian Tobar-Tosse ◽  
Tikam Chand Dakal ◽  
Hongde Liu ◽  
Arijit Biswas ◽  
...  
Keyword(s):  
Prognostic Marker ◽  
Dna Methyltransferase ◽  
The Cancer Genome Atlas ◽  
Peroxisome Proliferator ◽  
Additional Contribution ◽  
Peroxisome Proliferator Activated Receptor ◽  
Alu Repeats ◽  
Protein Protein Interaction ◽  
Interaction Sites ◽  
Protein Functions

Background: PPARγ (peroxisome proliferator-activated receptor gamma) is involved in the pathology of numerous diseases, including UM and other types of cancer. Emerging evidence suggests that an interaction between PPARγ and DNMTs (DNA methyltransferase) plays a role in cancer that is yet to be defined. Methods: The configuration of the repeating elements was performed with CAP3 and MAFFT, and the structural modelling was conducted with HDOCK. An evolutionary action scores algorithm was used to identify oncogenic variants. A systematic bioinformatic appraisal of PPARγ and DNMT1 was performed across 29 tumor types and UM available in The Cancer Genome Atlas (TCGA). Results: PPAR-responsive elements (PPREs) enriched with Alu repeats are associated with different genomic regions, particularly the promotor region of DNMT1. PPARγ–DNMT1 co-expression is significantly associated with several cancers. C-terminals of PPARγ and DNMT1 appear to be the potential protein–protein interaction sites where disease-specific mutations may directly impair the respective protein functions. Furthermore, PPARγ expression could be identified as an additional prognostic marker for UM. Conclusions: We hypothesize that the function of PPARγ requires an additional contribution of Alu repeats which may directly influence the DNMT1 network. Regarding UM, PPARγ appears to be an additional discriminatory prognostic marker, in particular in disomy 3 tumors.

scholarly journals Screening of Prognostic Factors in Early-Onset Breast Cancer

2020 ◽  
Vol 19 ◽  
pp. 153303381989367 ◽  
Author(s):  
Zhun Yu ◽  
Qi He ◽  
Guoping Xu
Keyword(s):  
Breast Cancer ◽  
Transcription Factor ◽  
Differentially Expressed Genes ◽  
Early Onset ◽  
Differentially Expressed ◽  
Peroxisome Proliferator ◽  
Early Onset Breast Cancer ◽  
Microrna Target ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Protein Interaction

Background: Gene expression profiles from early-onset breast cancer and normal tissues were analyzed to explore the genes and prognostic factors associated with breast cancer. Methods: GSE109169 and GSE89116 were obtained from the database of Gene Expression Omnibus. We firstly screened the differentially expressed genes between tumor samples and normal samples from patients with early-onset breast cancer. Based on database for annotation, visualization and intergrated discovery (DAVID) tool, functional analysis was calculated. Transcription factor-target regulation and microRNA-target gene network were constructed using the tool of transcriptional regulatory relatitionships unraveled by sentence-based text mining (TRRUST) and miRWalk2.0, respectively. The prognosis-related survival information was compiled based on The Cancer Genome Atlas breast cancer clinical data. Results: A total of 708 differentially expressed genes from GSE109169 data sets and 358 differentially expressed genes from GSE89116 data sets were obtained, of which 122 common differentially expressed genes including 102 uniformly downregulated genes and 20 uniformly upregulated genes were screened. Protein–protein interaction network with a total of 83 nodes and 157 relationship pairs was obtained, and genes in protein–protein interaction, such as peroxisome proliferator-activated receptor γ, FGF2, adiponectin, and PCK1, were recognized as key nodes in protein–protein interaction. In total, 66 transcription factor–target relationship pairs were obtained, and peroxisome proliferator-activated receptor γ was the only one downregulated transcription factor. MicroRNA-target gene network contained 368 microRNA-target relationship pairs. Moreover, 16 differentially expressed genes, including 2 upregulations and 14 downregulations, were related to a significant correlation with the prognosis, including SQLE and peroxisome proliferator-activated receptor γ. Conclusions: SQLE and peroxisome proliferator-activated receptor γ might be important prognostic factors in breast cancers, and adiponectin might be important in breast cancer pathogenesis regulated by peroxisome proliferator-activated receptor γ.

scholarly journals Bioinformatics analysis of different candidate genes involved in hepatocellular carcinoma induced by HepG2 cells or tumor cells of patients

2020 ◽  
Vol 48 (6) ◽  
pp. 030006052093211
Author(s):  
Xiang Zhang ◽  
Songna Yin ◽  
Ke Ma
Keyword(s):  
Hepatocellular Carcinoma ◽  
Hepg2 Cells ◽  
Liver Parenchyma ◽  
Preclinical Study ◽  
Gene Expression Omnibus ◽  
Receptor Interaction ◽  
Peroxisome Proliferator ◽  
Ppi Network ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Protein Interaction

Objective Hepatocellular carcinoma (HCC) is a common cancer with a high mortality rate; the molecular mechanism involved in HCC remain unclear. We aimed to provide insight into HCC induced with HepG2 cells and identify genes and pathways associated with HCC, as well as potential therapeutic targets. Methods Dataset GSE72581 was downloaded from the Gene Expression Omnibus, including samples from mice injected in liver parenchyma with HepG2 cells, and from mice injected with cells from patient tumor explants. Differentially expressed genes (DEGs) between the two groups of mice were analyzed. Then, gene ontology and Kyoto Encyclopedia of Gene and Genomes pathway enrichment analyses were performed. The MCODE plug-in in Cytoscape was applied to create a protein–protein interaction (PPI) network of DEGs. Results We identified 1,405 DEGs (479 upregulated and 926 downregulated genes), which were enriched in complement and coagulation cascades, peroxisome proliferator-activated receptor signaling pathway, and extracellular matrix–receptor interaction. The top 4 modules and top 20 hub genes were identified from the PPI network, and associations with overall survival were determined using Kaplan–Meier analysis. Conclusion This preclinical study provided data on molecular targets in HCC that could be useful in the clinical treatment of HCC.

scholarly journals PPARγ1 attenuates cytosol to membrane translocation of PKCα to desensitize monocytes/macrophages

2007 ◽  
Vol 176 (5) ◽  
pp. 681-694 ◽  
Author(s):  
Andreas von Knethen ◽  
Mathias Soller ◽  
Nico Tzieply ◽  
Andreas Weigert ◽  
Axel M. Johann ◽  
...  
Keyword(s):  
Human Monocyte ◽  
Underlying Mechanism ◽  
Nuclear Factor Κb ◽  
Peroxisome Proliferator ◽  
Membrane Translocation ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Protein Interaction ◽  
Tnf Α ◽  
Dependent Inhibition ◽  
Pparγ Agonists

Recently, we provided evidence that PKCα depletion in monocytes/macrophages contributes to cellular desensitization during sepsis. We demonstrate that peroxisome proliferator–activated receptor γ (PPARγ) agonists dose dependently block PKCα depletion in response to the diacylglycerol homologue PMA in RAW 264.7 and human monocyte–derived macrophages. In these cells, we observed PPARγ-dependent inhibition of nuclear factor-κB (NF-κB) activation and TNF-α expression in response to PMA. Elucidating the underlying mechanism, we found PPARγ1 expression not only in the nucleus but also in the cytoplasm. Activation of PPARγ1 wild type, but not an agonist-binding mutant of PPARγ1, attenuated PMA-mediated PKCα cytosol to membrane translocation. Coimmunoprecipitation assays pointed to a protein–protein interaction of PKCα and PPARγ1, which was further substantiated using a mammalian two-hybrid system. Applying PPARγ1 mutation and deletion constructs, we identified the hinge helix 1 domain of PPARγ1 that is responsible for PKCα binding. Therefore, we conclude that PPARγ1-dependent inhibition of PKCα translocation implies a new model of macrophage desensitization.

scholarly journals DNMT1-mediated PPARα methylation aggravates damage of retinal tissues in diabetic retinopathy mice

2021 ◽  
Vol 54 (1) ◽  
Author(s):  
Ying Zhu ◽  
Xinru Wang ◽  
Xiaoyun Zhou ◽  
Lexi Ding ◽  
Dan Liu ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Dna Methyltransferase ◽  
Cell Model ◽  
Underlying Mechanism ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Retinal Tissue ◽  
Specific Pcr ◽  
Gene And Protein Expression ◽  
Retinal Capillary

Abstract Background Peroxisome proliferator-activated receptor alpha (PPARα) is associated with diabetic retinopathy (DR), and the underlying mechanism is still unclear. Aim of this work was to investigate the mechanism of PPARα in DR. Methods Human retinal capillary pericytes (HRCPs) were treated with high glucose (HG) to induce DR cell model. DR mouse model was established by streptozotocin injection, and then received 5-Aza-2-deoxycytidine (DAC; DNA methyltransferase inhibitor) treatment. Hematoxylin–eosin staining was performed to assess retinal tissue damage. PPARα methylation was examined by Methylation-Specific PCR. Flow cytometry and DCFH-DA fluorescent probe was used to estimate apoptosis and reactive oxygen species (ROS). The interaction between DNA methyltransferase-1 (DNMT1) and PPARα promoter was examined by Chromatin Immunoprecipitation. Quantitative real-time PCR and western blot were performed to assess gene and protein expression. Results HG treatment enhanced the methylation levels of PPARα, and repressed PPARα expression in HRCPs. The levels of apoptotic cells and ROS were significantly increased in HRCPs in the presence of HG. Moreover, DNMT1 was highly expressed in HG-treated HRCPs, and DNMT1 interacted with PPARα promoter. PPARα overexpression suppressed apoptosis and ROS levels of HRCPs, which was rescued by DNMT1 up-regulation. In DR mice, DAC treatment inhibited PPARα methylation and reduced damage of retinal tissues. Conclusion DNMT1-mediated PPARα methylation promotes apoptosis and ROS levels of HRCPs and aggravates damage of retinal tissues in DR mice. Thus, this study may highlight novel insights into DR pathogenesis.

scholarly journals Systematic Elucidation of the Mechanism of Genistein against Pulmonary Hypertension via Network Pharmacology Approach

2019 ◽  
Vol 20 (22) ◽  
pp. 5569 ◽  
Author(s):  
Chen ◽  
Chen ◽  
Liu ◽  
Yuan ◽  
Guo ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Ph Effect ◽  
Interaction Network ◽  
Synthesis Process ◽  
Network Pharmacology ◽  
Systematic Research ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Protein Interaction ◽  
And Cluster Analysis

: Numerous studies have shown that genistein has a good therapeutic effect on pulmonary hypertension (PH). However, there has been no systematic research performed yet to elucidate its exact mechanism of action in relation to PH. In this study, a systemic pharmacology approach was employed to analyze the anti-PH effect of genistein. Firstly, the preliminary predicted targets of genistein against PH were obtained through database mining, and then the correlation of these targets with PH was analyzed. After that, the protein-protein interaction network was constructed, and the functional annotation and cluster analysis were performed to obtain the core targets and key pathways involved in exerting the anti-PH effect of genistein. Finally, the mechanism was further analyzed via molecular docking of genistein with peroxisome proliferator-activated receptor γ (PPARγ). The results showed that the anti-PH effect of genistein may be closely related to PPARγ, apoptotic signaling pathway, and the nitric oxide synthesis process. This study not only provides new insights into the mechanism of genistein against PH, but also provides novel ideas for network approaches for PH-related research.

scholarly journals Molecular characteristics of primary pulmonary lymphoepithelioma-like carcinoma based on integrated genomic analyses

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Bojiang Chen ◽  
Yu Zhang ◽  
Sisi Dai ◽  
Ping Zhou ◽  
Wenxin Luo ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Disease Free Survival ◽  
The Cancer Genome Atlas ◽  
Molecular Characteristics ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
P53 Expression ◽  
Free Survival ◽  
Genomic Analyses

AbstractPrimary pulmonary lymphoepithelioma-like carcinoma (pLELC) is a rare non-small cell lung cancer (NSCLC) subtype. Clinical features have been described in our previous report, but molecular characteristics remain unclear. Herein, pLELC genomic features were explored. Among 41,574 lung cancers, 128 pLELCs and 162 non-pLELC NSCLCs were enrolled. Programmed cell death ligand 1 (PD-L1) and protein 53 (p53) expression was detected in 47 surgically resected pLELC samples by immunohistochemical assays. Multiomics genomic analyses, including whole-genome sequencing (WGS), RNA whole-transcriptome sequencing (RNA-seq), and Epstein-Barr virus (EBV) integration analyses, were performed on eight frozen pLELC tissues and compared with 50 lung adenocarcinomas (LUADs) and 50 lung squamous cell carcinomas (LUSCs) from The Cancer Genome Atlas (TCGA) and another 26 EBV-positive nasopharynx cancers (EBV+-NPCs). Progression-free survival (PFS) and overall survival (OS) of pLELC patients were better than those of non-pLELC patients. High PD-L1 or p53 expression was associated with extended disease-free survival (DFS). pLELC had 14 frequently mutated genes (FMGs). Somatically mutated genes and enrichment of genetic lesions were found, which differed from observations in LUAD, LUSC, and EBV+-nasopharyngeal carcinoma (NPC). Three tumor-associated genes, zinc finger and BTB domain-containing 16 (ZBTB16), peroxisome proliferator activated receptor gamma (PPARG), and transforming growth factor beta receptor 2 (TGFBR2), were downregulated with copy number variation (CNV) loss. EBV was prone to integrating into intergenic and intronic regions with two upregulated miR-BamH1-A rightward transcripts (BARTs), BART5-3P and BART20-3P. Our findings reveal that pLELC has a distinct genomic signature. Three tumor-associated genes with CNV loss and two miR-BARTs might be involved in pLELC tumorigenesis.

scholarly journals Downregulation of RBP4 indicates a poor prognosis and correlates with immune cell infiltration in hepatocellular carcinoma

2021 ◽  
Author(s):  
Mingxing Li ◽  
Zhihui Wang ◽  
Lixu Zhu ◽  
Yifang Shui ◽  
Shuijun Zhang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Cell ◽  
The Cancer Genome Atlas ◽  
Retinol Binding Protein ◽  
Antibiotic Biosynthesis ◽  
Pathway Enrichment Analysis ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Advanced Tumor ◽  
Tumor Stages

Recent research has indicated that metabolically related genes play crucial roles in the pathogenesis of hepatocellular carcinoma (HCC). We evaluated the associations between novel biomarkers and retinol-binding protein 4 (RBP4) for predicting clinical HCC outcomes, hub-related genes, pathway regulation, and immune cells infiltration. Bioinformatic analyses based on data from The Cancer Genome Atlas were performed using online analysis tools. RBP4 expression was low in HCC and was also downregulated in pan-cancers compared to normal tissues. RBP4 expression was also significantly different based on age (41–60 years old versus 61–80 years old), and low RBP4 expression levels were associated with advanced tumor stages and grades. Higher RBP4 expression was associated with better overall survival time in HCC patients, and we identified a deletion-mutation rate of 1.4% in RBP4. We also identified ten co-expressed genes most related to RBP4 and explored the relationships between six hub genes (APOB, FGA, FGG, SERPINC1, APOA1, and F2) involved in RBP4 regulation. A pathway enrichment analysis for RBP4 indicated complement and coagulation cascades, metabolic pathways, antibiotic biosynthesis pathways, peroxisome proliferator-activated receptor signaling pathways, and pyruvate metabolism pathways. These results suggest that RBP4 may be a novel biomarker for HCC prognosis, and an indicator of low immune response to the disease.

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