Mus musculus
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ABSTRACT:
PROVIDER: PRJNA269780 | ENA |
REPOSITORIES: ENA
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Project description:Purpose: Chronic pulmonary inflammation in the form of chronic obstructive pulmonary disease (COPD) has been consistently shown to increase the risk of lung cancer. Therefore, identification of chemopreventive agents with anti-inflammatory effects, in addition to antiproliferative and apoptotic activities, is indispensable. Recently, we found that combinations of silibinin (Sil) and indole-3-carbinol (I3C) significantly inhibited lung tumorigenesis induced by 4-(methylnitro-samino)-1-(3-pyridyl)-1-butanone (NNK) and enhanced by chronic treatment with the inflammatory agent lipopolysaccharide (LPS). In this study, we described gene expression profiling of lung tissues using RNA-seq to determine the gene expression signature in inflammation-driven lung tumors and modulation of this signature by the chemopreventive agents Sil and I3C. Methods: Total RNA extracted from lung tissues of control and treated mice were processed for mRNA sequencing, in triplicate, using Illumina HiSeq 2000. The sequence reads that passed quality filters were analyzed for transcript abundance at the gene level using CLC Bio Genomics Workbench and differential gene expression analysis was performed using the built-in Empirical Analysis of Differential Gene Expression (DGE) based on 'Exact Test' method. qRTâPCR validation was performed using SYBR Green assays. Results and conclusions: We found that 330, 2,957, and 1,143 genes were differentially regulated in mice treated with NNK, LPS, and NNK + LPS, respectively. The expression of inflammation-and immunity-related genes was significantly more deregulated in lung tissues of mice treated with LPS alone compared to mice treated with NNK + LPS. Among 1,143 genes differentially regulated in the NNK + LPS group, the expression of 162 genes and associated signaling pathways were significantly modulated by I3C and/or Sil + I3C. These genes include cytokines, chemokines, and genes with a well-established role in inflammation and/or tumorigenesis such as c-ros oncogene 1 (Ros1), the EGFR ligands amphiregulin and epiregulin, Cyp1a1, and the circadian rhythm genes Arntl, and Npas2. To our knowledge, this is the first report that provides insight into genes that are differentially expressed during inflammation-driven lung tumorigenesis and the modulation of these genes by chemopreventive agents. Lung tissue mRNA profiles of mice treated with control vehicle, NNK, LPS, NNK+LPS, or NNK+LPS supplemented with chemopreventive agent(s) were generated by deep sequencing, in triplicate, using Illumina HiSeq 2000.
2016-07-03 | E-GEOD-64027 | biostudies-arrayexpress
Project description:Purpose: Chronic pulmonary inflammation in the form of chronic obstructive pulmonary disease (COPD) has been consistently shown to increase the risk of lung cancer. Therefore, identification of chemopreventive agents with anti-inflammatory effects, in addition to antiproliferative and apoptotic activities, is indispensable. Recently, we found that combinations of silibinin (Sil) and indole-3-carbinol (I3C) significantly inhibited lung tumorigenesis induced by 4-(methylnitro-samino)-1-(3-pyridyl)-1-butanone (NNK) and enhanced by chronic treatment with the inflammatory agent lipopolysaccharide (LPS). In this study, we described gene expression profiling of lung tissues using RNA-seq to determine the gene expression signature in inflammation-driven lung tumors and modulation of this signature by the chemopreventive agents Sil and I3C. Methods: Total RNA extracted from lung tissues of control and treated mice were processed for mRNA sequencing, in triplicate, using Illumina HiSeq 2000. The sequence reads that passed quality filters were analyzed for transcript abundance at the gene level using CLC Bio Genomics Workbench and differential gene expression analysis was performed using the built-in Empirical Analysis of Differential Gene Expression (DGE) based on 'Exact Test' method. qRT–PCR validation was performed using SYBR Green assays. Results and conclusions: We found that 330, 2,957, and 1,143 genes were differentially regulated in mice treated with NNK, LPS, and NNK + LPS, respectively. The expression of inflammation-and immunity-related genes was significantly more deregulated in lung tissues of mice treated with LPS alone compared to mice treated with NNK + LPS. Among 1,143 genes differentially regulated in the NNK + LPS group, the expression of 162 genes and associated signaling pathways were significantly modulated by I3C and/or Sil + I3C. These genes include cytokines, chemokines, and genes with a well-established role in inflammation and/or tumorigenesis such as c-ros oncogene 1 (Ros1), the EGFR ligands amphiregulin and epiregulin, Cyp1a1, and the circadian rhythm genes Arntl, and Npas2. To our knowledge, this is the first report that provides insight into genes that are differentially expressed during inflammation-driven lung tumorigenesis and the modulation of these genes by chemopreventive agents.
2016-01-01 | GSE64027 | GEO
Project description:Chemoprevention is a pragmatic approach to reduce the risk of colorectal cancer, one of the leading causes of cancer-related death in western countries. In this regard, maslinic acid (MA), a pentacyclic triterpene extracted from wax-like coatings of olives, is known to inhibit proliferation and induce apoptosis in colon cancer cell lines without affecting normal intestinal cells. The present study evaluated the chemopreventive efficacy and associated mechanisms of maslinic acid treatment on spontaneous intestinal tumorigenesis in Apc(Min/+) mice. Twenty-two mice were randomized into 2 groups: control group and MA group, fed with a maslinic acid-supplemented diet for six weeks. MA treatment reduced total intestinal polyp formation by 45% (P<0.01). Putative molecular mechanisms associated with suppressing intestinal polyposis in Apc(Min/+) mice were investigated by comparing microarray expression profiles of MA-treated and control mice and by analyzing the serum metabolic profile using NMR techniques. The different expression phenotype induced by MA suggested that it exerts its chemopreventive action mainly by inhibiting cell-survival signaling and inflammation. These changes eventually induce G1-phase cell cycle arrest and apoptosis. Moreover, the metabolic changes induced by MA treatment were associated with a protective profile against intestinal tumorigenesis. These results show the efficacy and underlying mechanisms of MA against intestinal tumor development in the Apc(Min/+) mice model, suggesting its chemopreventive potential against colorectal cancer.
2017-02-09 | MTBLS240 | MetaboLights
Project description:Chronic stimulation of innate immune pathways by microbial agents or damaged tissue is known to promote inflammation-driven tumorigenesis by unclarified mechanisms1-3. Here we demonstrate that mutagenic 7,12-dimethylbenz(a)anthracene (DMBA), etoposide or cisplatin induces nuclear DNA leakage into the cytosol to intrinsically activate STING (Stimulator of Interferon Genes) dependent cytokine production. Inflammatory cytokine levels were subsequently augmented in a STING-dependent extrinsic manner by infiltrating phagocytes purging dying cells. Consequently, STING-/- mice, or wild type mice adoptively transferred with STING-/- bone marrow, were almost completely resistant to DMBA-induced skin carcinogenesis compared to their wild type counterparts. Our data emphasizes, for the first time, a role for STING in the induction of cancer, sheds significant insight into the causes of inflammation-driven carcinogenesis, and may provide therapeutic strategies to help prevent malignant disease Total RNA obtained from DMBA or acetone treated wild type (WT) or STING deficient (SKO) mouse skin or skin tumor was examined for gene expression.
2014-05-31 | E-GEOD-57604 | biostudies-arrayexpress
Project description:Drugs that modify the epigenome are powerful tools for treating cancer, but these drugs often have pleiotropic effects, and identifying patients who will benefit from them remains a major clinical challenge. Here we show that medulloblastomas driven by the transcription factor Gfi1 are exquisitely dependent on the enzyme lysine demethylase 1 (Kdm1a/Lsd1). We demonstrate that Lsd1 physically associates with Gfi1, and that these proteins cooperate to inhibit genes involved in neuronal commitment and differentiation. We also show that Lsd1 is essential for Gfi1-mediated transformation: Gfi1 proteins that cannot recruit Lsd1 are unable to drive tumorigenesis and genetic ablation of Lsd1 markedly impairs tumor growth in vivo. Finally, pharmacological inhibitors of Lsd1 potently inhibit growth of Gfi1-driven tumors. These studies provide important insight into the mechanisms by which Gfi1 contributes to tumorigenesis, and identify Lsd1 inhibitors as promising therapeutic agents for Gfi1-driven medulloblastoma.
2018-12-07 | GSE123409 | GEO
Project description:Chronic stimulation of innate immune pathways by microbial agents or damaged tissue is known to promote inflammation-driven tumorigenesis by unclarified mechanisms1-3. Here we demonstrate that mutagenic 7,12-dimethylbenz(a)anthracene (DMBA), etoposide or cisplatin induces nuclear DNA leakage into the cytosol to intrinsically activate STING (Stimulator of Interferon Genes) dependent cytokine production. Inflammatory cytokine levels were subsequently augmented in a STING-dependent extrinsic manner by infiltrating phagocytes purging dying cells. Consequently, STING-/- mice, or wild type mice adoptively transferred with STING-/- bone marrow, were almost completely resistant to DMBA-induced skin carcinogenesis compared to their wild type counterparts. Our data emphasizes, for the first time, a role for STING in the induction of cancer, sheds significant insight into the causes of inflammation-driven carcinogenesis, and may provide therapeutic strategies to help prevent malignant disease Total RNA obtained from wild type murine embryonic fibroblasts (WT MEFs), STING deficient MEFs (SKO), Trex1 deficient MEFs (TKO), and both STING and Trex1 deficient MEFs (STKO) treated with DMBA and examined cytokine production by these cells.
2014-05-31 | E-GEOD-57603 | biostudies-arrayexpress
Project description:We previously showed that exposure of rats to environmental cigarette smoke (ECS) causes extensive downregulation of microRNA expression in the lung, resulting in overexpression of multiple genes and proteins. In the present study, we evaluated by microarray the expression of 484 microRNAs in the lung of rats receiving orally chemopreventive agents, including N-acetylcysteine, oltipraz, indole-3-carbinol, 5,6-benzoflavone and phenethyl isothiocyanate, or combinations thereof. Scatterplot, hierarchical cluster, and principal component analyses showed that none of the above chemopreventive regimens appreciably affected the baseline microRNA expression, while all of them attenuated ECS-induced alterations but to a variable extent. Thus, mirnome analysis provides a new tool for predicting both safety and efficacy of cancer chemopreventive agents at early carcinogenesis stages. Keywords: cancer chemoprevention, microRNA, environmental cigarete smoke (ECS), 5,6-benzoflavone (BF), Indole 3-carbinol (I3C),N-acetylcysteine (NAC), oltipraz (OPZ), Phenethyl isothiocyanate (PEITC). Adult male Sprague-Dawley rats (Harlan Italy, Correzzana, Milan, Italy), weighing 315-320 g, were divided into 16 groups, each composed of 8 animals. Half of them were exposed to ECS for 28 consecutive days, as previously described (Izzotti et al., 2005), while the remaining rats (Sham-exposed) were kept for the same period of time in filtered air. The rats belonging to 14 groups were treated with chemopreventive agents, starting 3 days before exposure to ECS.
2010-05-16 | E-GEOD-19540 | biostudies-arrayexpress
Project description:Drugs that modify the epigenome are powerful tools for treating cancer, but these drugs often have pleiotropic effects, and identifying patients who will benefit from them remains a major clinical challenge. Here we show that medulloblastomas driven by the transcription factor Gfi1 are exquisitely dependent on the enzyme lysine demethylase 1 (Kdm1a/Lsd1). We demonstrate that Lsd1 physically associates with Gfi1, and that these proteins cooperate to inhibit genes involved in neuronal commitment and differentiation. We also show that Lsd1 is essential for Gfi1-mediated transformation: Gfi1 proteins that cannot recruit Lsd1 are unable to drive tumorigenesis and genetic ablation of Lsd1 markedly impairs tumor growth in vivo. Finally, pharmacological inhibitors of Lsd1 potently inhibit growth of Gfi1-driven tumors. These studies provide important insight into the mechanisms by which Gfi1 contributes to tumorigenesis, and identify Lsd1 inhibitors as promising therapeutic agents for Gfi1-driven medulloblastoma. ChIP-seq data generated for n=2 MG (Myc/Gfi1) murine medulloblastomas. ChIP was independently performed for Gfi1 and Lsd1 on the same chromatin extracts.
2018-12-15 | GSE123870 | GEO
Project description:To date, there is little information on early molecular events in the development of N-nitrosomethylbenzylamine (NMBA) induced esophageal tumorigenesis and of the effects of chemopreventive agents on these events. In this study, we identified genes in rat esophagus that were differentially expressed in response to short–term NMBA-treatment and modulated by co-treatment with phenethylisothiocyanate (PEITC). Rats were fed AIN-76A diet or AIN-76A diet containing PEITC for three weeks. During the third week of dietary treatment, they were administered three s.c. doses of NMBA (0.5 mg/kg b.w.). Rats were sacrificed 24 h after the last treatment, esophagi excised and processed for histological grading, microarray and real-time PCR analysis. Our histopathological data showed that treatment of rats with PEITC had protective effect on NMBA-induced preneoplastic lesions in the rat esophagus. We identified 2261 genes that were differentially expressed in the NMBA-treated vs. control esophagi and 1936 genes in the NMBA+PEITC- vs. NMBA-treated esophagi. The intersection of these two sets resulted in the identification of 1323 genes in NMBA-treated esophagus that were modulated by PEITC to near-normal levels of expression. The measured changes in the expression levels of 10 selected genes were validated using real-time PCR. Principle components analysis (PCA) was applied to all twelve microarrays in the study, which suggested that in terms of global gene expression, PEITC treatment had a genome-wide modulating effect on NMBA-induced gene expression. Samples obtained from animals treated with PEITC alone or co-treated with NMBA were more similar to controls than they were to NMBA treatment alone. Keywords: Toxicogenomics,reference design
2007-07-18 | GSE6917 | GEO
Project description:Epidemiological studies have indicated an association between statin use and reduced incidence of colorectal cancer (CRC), and work in preclinical models has demonstrated a potential chemopreventive effect. Statins are also associated with reduced dysbiosis in the gut microbiome, yet the role of the gut microbiome in the protective effect of statins in CRC is unclear. Here we validated the chemopreventive role of statins by retrospectively analysing a cohort of patients who underwent colonoscopies. This was confirmed in preclinical models and patient cohorts, and we found that reduced tumour burden was partly due to statin modulation of the gut microbiota. Specifically, the gut commensal Lactobacillus reuteri was increased as a result of increased microbial tryptophan availability in the gut after atorvastatin treatment. Our in vivo studies further revealed that L. reuteri administration suppressed colorectal tumorigenesis via the tryptophan catabolite, indole-3-lactic acid (ILA). ILA exerted anti-tumorigenic effects by downregulating the IL-17 signalling pathway. This microbial metabolite inhibited T helper 17 cell differentiation by targeting the nuclear receptor, RAR-related orphan receptor γt (RORγt). Together, our study provides insights into an anti-cancer mechanism driven by statin use and suggests that interventions with L. reuteri or ILA could complement chemoprevention strategies for CRC.
2023-02-17 | GSE201452 | GEO