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Regulatory network controlling tumor-promoting inflammation in human cancers [ChIP-seq]

ABSTRACT: Using an inducible, inflammatory model of breast cellular transformation, we describe the transcriptional regulatory network mediated by STAT3, NF-kB, and AP-1 factors on a genomic scale. These regulators form transcriptional complexes that directly regulate the expression of hundreds of genes in oncogenic pathways, such as cell proliferation, metastasis, angiogenesis, apoptosis and metabolism, via a positive feedback loop. This inflammatory feedback loop and associated network, which function to various extents in many types of cancer cells and patient tumors, is the basis for an “inflammation” index that defines cancer types by functional criteria. The inflammation index is negatively correlated with expression of genes involved in DNA metabolism, and transformation is associated with genome instability. Inflammatory tumors are preferentially associated with infiltration immune cells that might be recruited to the site of the tumor via inflammatory molecules produced by the cancer cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE115597 | GEO | 2018/06/11

REPOSITORIES: GEO

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Project description:Inflammasome, activated by pathogen-derived and host-derived danger signals, constitutes a multimolecular signaling complex that serves as a platform for caspase-1 (CASP1) activation and interleukin-1beta (IL1B) maturation. The activation of NLRP3 inflammasome requires two-step signals. The first “priming” signal (Signal 1) enhances gene expression of inflammasome components. The second “activation” signal (Signal 2) promotes the assembly of inflammasome components. Deregulated activation of NLRP3 inflammasome contributes to the pathological processes of Alzheimer’s disease (AD) and multiple sclerosis (MS). However, at present, the precise mechanism regulating NLRP3 inflammasome activation and deactivation remains largely unknown. By genome-wide gene expression profiling, we studied the molecular network of NLRP3 inflammasome activation-responsive genes in a human monocyte cell line THP-1 sequentially given two-step signals. We identified the set of 83 NLRP3 inflammasome activation-responsive genes. Among them, we found the NR4A nuclear receptor family NR4A1, NR4A2, and NR4A3, the EGR family EGR1, EGR2, and EGR3, the IkappaB family NFKBIZ, NFKBID, and NFKBIA as a key group of the genes that possibly constitute a negative feedback loop for shutting down inflammation following NLRP3 inflammasome activation. By molecular network analysis, we identified a complex network of NLRP3 inflammasome activation-responsive genes involved in cellular development and death, and immune and inflammatory responses, where transcription factors AP-1, NR4A, and EGR serve as a hub. Thus, NLRP3 inflammasome activation-responsive genes constitute the molecular network composed of a set of negative feedback regulators for prompt resolution of inflammation. To load the Signal 1 (S1), THP-1 cells were incubated for 3 hours in the culture medium with or without inclusion of 0.2 microgram/ml lipopolysaccharide (LPS). To load the Signal 2 (S2), they were incubated further for 2 hours in the culture medium with inclusion of 10 microM nigericin sodium salt dissolved in ethanol or the equal v/v% concentration of ethanol (vehicle), followed by processing for microarray analysis on Human Gene 1.0 ST Array (Affymetrix).

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Regulatory network controlling tumor-promoting inflammation in human cancers [ChIP-seq]

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