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Epigenome analysis of normal and DDX20 knockdown HepG2 cells

ABSTRACT: MicroRNAs (miRNAs) are small RNAs that regulate the expression of specific target genes. While deregulated miRNA expression levels have been detected in many tumors, whether miRNA functional impairment is also involved in carcinogenesis remains unknown. We investigated whether deregulation of miRNA machinery components and subsequent functional impairment of miRNAs are involved in hepatocarcinogenesis. Among miRNA-containing ribonucleoprotein complex components, reduced expression of DDX20 was frequently observed in human hepatocellular carcinomas, in which enhanced NF-kB activity is closely linked to carcinogenesis. Because DDX20 normally suppresses NF-kB activity by preferentially regulating the function of the NF-kB suppressing miRNA-140, we hypothesized that impairment of miRNA-140 function may be involved in hepatocarcinogenesis. Dnmt1 was identified as a direct target of miRNA-140, and increased Dnmt1 expression in DDX20-deficient cells hypermethylated the promoters of metallothionein genes, resulting in decreased metallothionein expression leading to enhanced NF-kB activity and hepatocarcinogenesis. MiRNA-140 knockout mice were prone to hepatocarcinogenesis and showed phenomena similar to those of DDX20 deficiency, suggesting that miRNA-140 plays a central role in DDX20 deficiency–related pathogenesis. Conclusion: These results indicate that miRNA-140 acts as a liver tumor suppressor, and that impairment of miRNA-140 function due to a deficiency of DDX20, a miRNA machinery component, could lead to hepatocarcinogenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE37633 | GEO | 2012/04/27

SECONDARY ACCESSION(S): PRJNA162415

REPOSITORIES: GEO

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Epigenome analysis of normal and DDX20 knockdown HepG2 cells

Project description:MicroRNAs (miRNAs) are small RNAs that regulate the expression of specific target genes. While deregulated miRNA expression levels have been detected in many tumors, whether miRNA functional impairment is also involved in carcinogenesis remains unknown. We investigated whether deregulation of miRNA machinery components and subsequent functional impairment of miRNAs are involved in hepatocarcinogenesis. Among miRNA-containing ribonucleoprotein complex components, reduced expression of DDX20 was frequently observed in human hepatocellular carcinomas, in which enhanced NF-kB activity is closely linked to carcinogenesis. Because DDX20 normally suppresses NF-kB activity by preferentially regulating the function of the NF-kB suppressing miRNA-140, we hypothesized that impairment of miRNA-140 function may be involved in hepatocarcinogenesis. Dnmt1 was identified as a direct target of miRNA-140, and increased Dnmt1 expression in DDX20-deficient cells hypermethylated the promoters of metallothionein genes, resulting in decreased metallothionein expression leading to enhanced NF-kB activity and hepatocarcinogenesis. MiRNA-140 knockout mice were prone to hepatocarcinogenesis and showed phenomena similar to those of DDX20 deficiency, suggesting that miRNA-140 plays a central role in DDX20 deficiency–related pathogenesis. Conclusion: These results indicate that miRNA-140 acts as a liver tumor suppressor, and that impairment of miRNA-140 function due to a deficiency of DDX20, a miRNA machinery component, could lead to hepatocarcinogenesis. Genome wide DNA methylation profiling of control and DDX20-knockdown HepG2 cells. Bisulphite converted DNA from the 2 samples were hybridised to the Illumina HumanMethylation450 BeadChip.

2012-04-26 | E-GEOD-37633 | biostudies-arrayexpress

DDX20 knockdown effect on hepatocellular carcinoma cells

Project description:Analysis of DDX20 knockdown - hepatocellular carcinoma cells. The expression levels of genes driven by NF-kB and related with carcinogenesis, were significantly enhanced in DDX20-knockdown cells. One condition experiment, HepG2 vs. HepG2-DDX20 knockdown cells

2012-07-14 | E-GEOD-28088 | biostudies-arrayexpress

DDX20 knockdown effect on hepatocellular carcinoma cells

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Sublethal necroptosis signaling promotes inflammation and liver cancer

Project description:We developed a genetic mouse model of chronic necroptosis activation in hepatocytes (in the presence of basal NF-kB activity) that lead to hepatocellular carcinoma. Blocking Necroptosis (RIP3) or NF-kB-(IKKβ) activation in those mice blocked hepatocarcinogenesis.

2023-07-03 | GSE166875 | GEO

A novel YDDX linear motif mediates docking of the IKK kinase to substrates: structural and functional insights

Project description:The inhibitor of kB kinase (IKK) is the master regulator of the nuclear factor kB (NF-kB) pathway, involved in inflammatory, immune and apoptotic responses. In the ‘canonical’ NF-kB pathway, IKK phosphorylates inhibitor of kB (IkB) proteins and this triggers ubiquitin-mediated degradation of IkB, leading to release and nuclear translocation of NF-B transcription factors. The data presented show that the IKK and IKK subunits recognize a YDDX docking site located within the disordered C-terminal region of IkBa. Our results also suggest that IKK contributes to the docking interaction with higher affinity as compared to IKK.

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Polidocanol injury wildtype versus Myd88 KO trachea

Project description:Nf-kB activity is associated with the key pathological features of chronic respiratory diseases including epithelial remodelling, excess mucous production, and submucosal gland hyperplasia. However, the role of Nf-kB activity in airway epithelial differentiation remains controversial. In the present study we demonstrate that Nf-kB adaptor protein Myd88 deficiency promotes increased airway submucosal gland abundance and abnormal epithelial differentiation in proximal adult airways. Abnormal airway differentiation was not developmentally determined, became exacerbated following acute lung injury, and did not involve altered epithelial proliferation or apoptosis. Instead, we demonstrate that tracheal Myd88 deficiency promotes upregulation of a unique gene expression profile that includes activation of alternate, Myd88-independent Nf-kB signalling. Finally, we show that these effects are not intrinsically maintained in vitro using an air-liquid interface epithelial culture. This finding indicates that Myd88 deficiency promotes adult airway remodelling by regulating non-epithelial, non-cell autonomous Nf-kB activity. 20 microarray samples of whole trachea RNA in total: 5 samples wildtype control tissue 5 samples Myd88 KO control tissue 5 samples wildtype 3 day polidocanol injury tissue 5 samples Myd88 KO 3 day polidocanol injury tissue

2011-03-17 | E-GEOD-17268 | biostudies-arrayexpress

Polidocanol injury wildtype versus Myd88 KO trachea

2011-03-17 | GSE17268 | GEO

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2014-10-01 | GSE31064 | GEO

Deficiency in tumor suppressor p53 is required for doxorubicin induced transcriptional upregulation of NF-kB target genes in human breast cancer

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2013-12-31 | E-GEOD-47013 | biostudies-arrayexpress

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