Genes directly regulated by NF-κB in human hepatocellular carcinoma HepG2
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE98985 | GEO | 2017/06/05
SECONDARY ACCESSION(S): PRJNA386919
REPOSITORIES: GEO
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Project description:Over activation of NF-κB has close relationship with hepatitis and hepatocellular carcinoma (HCC). In this study, by manipulating NF-κB activity with its recognized activator TNFα and using ChIP-seq and RNA-seq techniques, we identified 699 NF-κB direct target genes (DTGs) in a widely used HCC cell line, HepG2, including 399 activated and 300 repressed genes. In these NF-κB DTGs, 216 genes (126 activated and 90 repressed genes) are among the current HCC gene signature. Functional annotation revealed that NF-κB DTGs in HepG2 cell are mainly related with many typical NF-κB-related biological processes, such as immune system process, response to stress, response to stimulus, defense response and signaling pathways of NF-kappa B. Some NF-κB DTGs are also involved in Hepatitis C and B pathways. The NF-κB DTGs were further confirmed by detecting the NF-κB binding and expression of 14 genes with ChIP-PCR and RT-PCR.
2017-06-05 | GSE98984 | GEO
Project description:Over activation of NF-κB has close relationship with hepatitis and hepatocellular carcinoma (HCC). In this study, by manipulating NF-κB activity with its recognized activator TNFα and using ChIP-seq and RNA-seq techniques, we identified 699 NF-κB direct target genes (DTGs) in a widely used HCC cell line, HepG2, including 399 activated and 300 repressed genes. In these NF-κB DTGs, 216 genes (126 activated and 90 repressed genes) are among the current HCC gene signature. Functional annotation revealed that NF-κB DTGs in HepG2 cell are mainly related with many typical NF-κB-related biological processes, such as immune system process, response to stress, response to stimulus, defense response and signaling pathways of NF-kappa B. Some NF-κB DTGs are also involved in Hepatitis C and B pathways. The NF-κB DTGs were further confirmed by detecting the NF-κB binding and expression of 14 genes with ChIP-PCR and RT-PCR.
2017-06-05 | GSE98983 | GEO
Project description:Genes directly regulated by NF-κB in human hepatocellular carcinoma HepG2
| PRJNA386919 | ENA
Project description:ObjectivesFeline sarcoma-related protein (FER) is known to play a critical regulatory role in several carcinomas. However, the exact biological function of FER in hepatocellular carcinoma (HCC) still needs to be investigated. The primary objective of this research was to investigate the unknown function and molecular mechanisms of FER in HCC.Materials and methodsThe expression level of FER in HCC tissue samples and cells was examined by RT-qPCR, immunohistochemistry and western blot. Cellular and animal experiments were used to explore the effect of FER on the proliferative and metastatic capacities of HCC cells. The crosstalk between FER and NF-κB signaling was explored by western blot. The upstream factors that regulate FER were evaluated through dual-luciferase experiments and western blot assays.ResultsFER was overexpressed in HCC specimens and HCC cell lines. FER expression levels were positively associated with unfavorable clinicopathological characteristics. The higher the expression of FER was, the worse the overall survival of HCC patients was. The results of loss-of-function and gain-of-function experiments indicated that knockdown of FER decreased, while overexpression of FER increased, the proliferation, invasion and metastasis of HCC cells in vitro and in vivo. Mechanistically, we found that FER activated the NF-κB signaling pathway and stimulated epithelial-to-mesenchymal transition (EMT). We also found that FER was directly regulated by miR-206, and the downregulation of miR-206 was associated with proliferation and metastatic progression in HCC.ConclusionsThe present research was the first to reveal that a decrease in miR-206 levels results in an increase in FER expression in HCC, leading to enhanced cell growth and metastatic abilities via activation of the NF-κB signaling pathway.
| S-EPMC8289706 | biostudies-literature
Project description:Persistent activation of NF-κB signaling is closely related to chronic inflammation and tumorigenesis. Commonly, NF-κB signaling is tightly controlled by multiple feedback loops and regulators, such as the deubiquitinases (DUBs). However, in cancer cells, NF-κB may override these feedbacks through special pathways and lead to the sustained activation. In the present study, we demonstrate that in transitional cell carcinoma (TCC) of bladder, miR-130b plays an oncogenesis role, it enhanced proliferation, invasion and migration of TCC cell, and was highly correlated with tumor progression. On the other hand, NF-κB directly regulated the transcription of miR-130b by binding with its promoter region. Importantly, we verify that, through deceasing the expression of Cylindromatosis (CYLD), a K63-specific DUB and endogenous blocker of NF-κB signaling, miR-130b can in return sustain the persistent activation of NF-κB, which may promote the malignant progression of TCC. Thus, the present study uncovers a potential signaling transduction in which NF-κB is continuously activated, and may provide a novel therapeutic approach for the clinical management of TCC.
| S-EPMC5217037 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2014-12-10 | E-GEOD-57958 | biostudies-arrayexpress
Project description:Cell-to-cell heterogeneity is a feature of the tumor necrosis factor (TNF)-stimulated inflammatory response mediated by the transcription factor NF-κB, motivating an exploration of the underlying sources of this noise. Here, we combined single-transcript measurements with computational models to study transcriptional noise at six NF-κB-regulated inflammatory genes. In the basal state, NF-κB-target genes displayed an inverse correlation between mean and noise characteristic of transcriptional bursting. By analyzing transcript distributions with a bursting model, we found that TNF primarily activated transcription by increasing burst size while maintaining burst frequency for gene promoters with relatively high basal histone 3 acetylation (AcH3) that marks open chromatin environments. For promoters with lower basal AcH3 or when AcH3 was decreased with a small molecule drug, the contribution of burst frequency to TNF activation increased. Finally, we used a mathematical model to show that TNF positive feedback amplified gene expression noise resulting from burst size-mediated transcription, leading to a subset of cells with high TNF protein expression. Our results reveal potential sources of noise underlying intercellular heterogeneity in the TNF-mediated inflammatory response.
| S-EPMC8290835 | biostudies-literature
Project description:PurposeTP53 mutation is the most common genetic variation type in Hepatocellular carcinoma (HCC). We aim to illustrate the landscape of genomic alterations and TP53 mutation related and directly regulated lncRNA prognosis markers.Materials and methodsUtilizing the clinical and transcriptome data from The Cancer Genome Atlas (TCGA) website, we present the landscape of genomic alterations and RNA differential expression profiles. By analyzing the ENCODE TP53 ChIP-seq data, we get the TP53 chromatin binding profiles. By Kaplan-Meier (KM) survival analysis and ROC analysis, we identify lncRNA prognosis markers.ResultsTP53 ranks the highest mutation frequency gene and the maximum mutation type of TP53 is Missense Mutation (> 2.5×104). TP53 mutation showed poor clinical outcome among the pathological Stage II and Stage III HCC patients. By differential expression analysis of the TP53 wild type and mutation HCC, we find thousands of misregulated genes, including 699 differential expression lncRNAs (p <0.05, |log2FC| ≥1). Functional enrichment analysis of the misregulated genes shows that TP53 mutation events mainly alter DNA replication, cell cycle and immune response signaling pathways. By estimation of tumor-infiltrating immune cells through CIBERSORT, we find that the TP53 mutation events are significantly correlated with the different proportions of nine immune cells. We then integratively analyze the differential expression lncRNAs in TP53 wild type and mutation groups and the TP53 ChIP-seq binding lncRNAs, and get 112 overlap lncRNAs. By Kaplan-Meier survival analysis and ROC analysis, we identify two lncRNAs (RP4-736L20.3 and SNRK-AS1) that show significant prognosis value. Using the collected HCC samples, we validate the misregulated expression of RP4-736L20.3 and SNRK-AS1.ConclusionThe work presents the landscape of genomic variations and two TP53 mutation related and directly regulated lncRNA prognosis markers of HCC.
| S-EPMC8364375 | biostudies-literature
Project description:Our previous study has found that GSK343 is a potent autophagy inducer. To further investigate the underlying mechanisms, microarray analysis was performed.
2019-04-03 | GSE129203 | GEO
Project description:Quinoline core has been shown to possess a promising role in the development of anticancer agents. However, the correlation between its broad spectrum of bioactivity and the underlying mechanism of actions is poorly understood. The present study, with the use of bioinformatics approaches, reported a series of designed molecules which integrated quinoline core and sulfonyl moiety, with the objective of evaluating the substituent and linker effects on anticancer activities and associated mechanistic targets. We identified potent compounds (1h, 2h, 5 and 8) exhibiting significant anticancer effects towards liver cancer cells (Hep3B) with the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) relative values of cytotoxicity below 0.40, a value in the range of doxorubicin positive control with the value of 0.12. Bulky substituents and the presence of bromine atom, as well as the presence of sulfonamide linkage, are likely the favorable structural components for molecules exerting a strong anticancer effect. To the best of our knowledge, our findings obtained from chemical synthesis, in vitro cytotoxicity, bioinformatics-based molecular docking analysis (similarity ensemble approach, SEA),and electrophoretic mobility shift assay provided the first evidence in correlation to the anticancer activities of the selected compound 5 with the modulation on the binding of transcription factor NF-κB to its target DNA. Accordingly, compound 5 represented a lead structure for the development of quinoline-based NF-κB inhibitors and this work added novel information on the understanding of the mechanism of action for bioactive sulfonyl-containing quinoline compounds against hepatocellular carcinoma.
| S-EPMC6209864 | biostudies-literature