RNA profiling in lungs of WT and HGF transgenic mice with or without exposure to carcinogen
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE20468 | GEO | 2010/12/31
SECONDARY ACCESSION(S): PRJNA125013
REPOSITORIES: GEO
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Project description:The hepatocyte growth factor (HGF)/c-Met signaling pathway is known to mediate vascularization. We have previously demonstrated that expression of a human HGF transgene in the small airways produced mice (HGF TG) that were more susceptible to the tobacco carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). We also have observed that HGF TG mice display significantly enhanced vascularization in the lungs that increases over time compared to wild-type (WT) littermates. To analyze which genes might contribute to increased vascularization from HGF overexpression in the airways, RNA and protein were isolated from whole lungs of individual HGF TG and WT adult mice. We profiled the mRNA expression of several hundred genes representative of six biological pathways involved in transformation, angiogenesis, and tumorigenesis using two commercial microarrays. Significant changes in expression over a 1.5-fold boundary were also observed in lung tumors derived from NNK-treated HGF TG mice. Lung tumors were induced by exposing mice to four weekly i.p. injections of 3mg NNK (15μg/μl) over 2 weeks. Whole lungs from control untreated animals were dissected after sacrifice at 10, 20, or 40 wks of age, and NNK induced lung tumors were dissected from the animals at 20 or 40 weeks of age. Total RNA was extracted from whole lung or isolated tumors from HGF TG or WT mice using TRIzol reagent and the Array Grade Total RNA Isolation Kit. The cDNA was generated and labeled using the TrueLabeling-AMP Linear RNA Amplication Kit. RNA was analyzed from 28 mice in total. The angiogenesis array was used to analyze 10 samples taken from 40 week old mice (HGF TG untreated [n=4], WT untreated [n=4], HGF TG NNK treated [n=1], WT NNK treated [n=1]) and 6 samples from 20 week old mice (HGF TG untreated [n=2], WT untreated [n=2], HGF TG NNK treated [n=1], WT NNK treated [n=1]). The cancer gene array was used to analyze 8 samples taken from 40 week old mice (HGF TG untreated [n=2], WT untreated [n=2], HGF TG NNK treated [n=2], WT NNK treated [n=2]) and 4 samples from 20 week old mice (HGF TG untreated [n=2], WT untreated [n=2]).
2010-12-31 | E-GEOD-20468 | biostudies-arrayexpress
Project description:Purpose: The goals of this study are to compare transcriptome profiling (RNA-seq) in pancreatic intraepithelial neoplasm (PanIN) cells exposed to tobacco-specific nitrosamine 4-(methyl nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and to examine the upregulated pathways.
2018-09-06 | GSE119517 | GEO
Project description:We developed a two-staged lung cancer mouse model, which mimics the smoking carcinogen-induced, and chronic obstructive pulmonary disease (COPD)-related airway inflammation promoted lung cancers. We used the carcinogen 4-(methylnitrosamino)-1-(3- pyridyl)-1-butanone (NNK) to induce lung cancer and in parallel to repeated Lipopolysaccharide (LPS) installation to induce chronic lung inflammation. To identify genes associated with chronic inflammation promoting lung tumorigenesis, we have performed whole genome microarray expression profiling of mice exposed to Phosphate-Buffered Saline (PBS), NNK, LPS, and combined NNK and LPS.
2020-12-31 | GSE132661 | GEO
Project description:In order to assess the alteration in lncRNA expression in rat lung carcinogenesis induced by NNK, we determined the lncRNA expression profiles in 3 rat lung tumor samples and matched normal lung tissues and 2 blood samples from the control and NNK treatment group in the 95th week using Arraystar Rat lncRNA Microarray. We induced lung cancer using 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in a rat model and determined the lncRNA expression profiles in lung cancer tissues and rat blood samples.
2015-05-19 | E-GEOD-68967 | biostudies-arrayexpress
Project description:This study evaluated transcriptional effects of the lung carcinogen NNK ( 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone) injection and selenocystine consumption on the murine lung. Female A/J mice at 5 weeks of age were obtained from The Jackson Laboratory. Animals were stabilized on an unsupplemented AIN-76 diet for one week prior to being given the selenium supplemented diet. The basal level of selenium in the diet is 0.35 ppm Se, the selenocytine supplemention was at 15 ppm. NNK was administered i.p. as a single 10 uM injection in 0.2 mL saline. With this protocol, 100% of animals reproducibly develop lung tumors after 3 months. Three days after NNK administration, animals were provided AIN-76A diets supplemented with selenocystine at 15 ppm selenium ad libitum for 10 days. Animals were sacrificed thirteen days after NNK administration. Lung tissue was harvested, immediately homogenized in Trizol and frozen. The organic extracted RNAs were run over Qiagen RNeasy columes before quantifying and qualifying them. All samples had RNA quality index's greater than 9.
2012-06-01 | GSE29447 | GEO
Project description:This study evaluated transcriptional effects of the lung carcinogen NNK ( 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone) injection and selenocystine consumption on the murine lung. Female A/J mice at 5 weeks of age were obtained from The Jackson Laboratory. Animals were stabilized on an unsupplemented AIN-76 diet for one week prior to being given the selenium supplemented diet. The basal level of selenium in the diet is 0.35 ppm Se, the selenocytine supplemention was at 15 ppm. NNK was administered i.p. as a single 10 uM injection in 0.2 mL saline. With this protocol, 100% of animals reproducibly develop lung tumors after 3 months. Three days after NNK administration, animals were provided AIN-76A diets supplemented with selenocystine at 15 ppm selenium ad libitum for 10 days. Animals were sacrificed thirteen days after NNK administration. Lung tissue was harvested, immediately homogenized in Trizol and frozen. The organic extracted RNAs were run over Qiagen RNeasy columes before quantifying and qualifying them. All samples had RNA quality index's greater than 9. Four groups of A/J mice were utilized with 4 biological replicates per group. 1) Untreated - controls on the AIN-76 diet (0.35 ppm Se). 2) NNK treated - single injection of NNK, maintained on norma AIN-76 diet, sacraficed after 13 days. 3) SECY - selenocystine supplemented (15 ppm) for 10 days on a AIN-76 diet then sacraficed. 4) NNK plus SECY - single injection of NNK, after 3 days, selenocystine supplemented (15 ppm) diet for 10 days then sacraficed. RNAs from the the four untreated mice were combined to phenotypically anchor the dual color expression profile. mouse lung responses to NNK injection and/or selenocystine dietary supplementation
2012-05-31 | E-GEOD-29447 | biostudies-arrayexpress
Project description:Even though smoking is associated with lung cancer, the exact molecular pathways that link carcinogens with inflammation and oncogenic transformation are not well elucidated. Nicotine-derived nitrosamine ketone, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and Benzo(α)pyrene (BaP) are two major carcinogens in cigarette smoke and have not been tested in models that mimic inhaled exposure for prolonged periods of time. We treated ICR mice with intratracheal delivery of NNK and BaP three times a week for 18 months to mimic chronic smoking exposure. Mice developed epithelial dysplasia followed by lung cancers at increased rates relative to controls. Histology revealed myeloid inflammation in murine lung tissues. Exposure of lung epithelial cells to cigarette smoking condensate led to increased production of pro-inflammatory IL-1. Downstream mediator of IL-1β signaling, Interleukin 1 receptor associated kinase–4 (IRAK4), was overexpressed in murine lung tissues exposed to carcinogens in vivo. Two-thirds of human lung cancer samples also exhibited overactivated IRAK4 expression. IRAK4 was found to localize in microtubules in lung cancer cell lines. Using mass spectrometry on isolated microtubules, we observed that IRAK4 inhibition was associated with decreased phosphorylation of tubular motility proteins including MYH9. Inhibition of IRAK4 resulted in decreased invasion in lung cancer cell lines and reduced growth of lung cancer xenografts. These data demonstrate that smoking associated carcinogens cause myeloid inflammation that can be linked to oncogenic transformation via IRAK4 activation.
2024-10-23 | PXD053181 | Pride
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:To examine effects of environmental risk factors on pancreatic cancer development, we fed control Pdx1-Cre (WT) and Pdx1-Cre; Kras-flox (Kras) mice with a Western alcohol diet containing high-cholesterol and high-saturated fat diet and 3.5% alcohol for 5 months. To enhance alcohol-induced pancreatic injury, we added a low dose of lipopolysaccharide (LPS, 1 μg/ml) to the diet. Mice were also given 7 hourly injections of cerulein (50 μg/kg) 4 times from the 1st to 4th month. To mimic tobacco smoking, we injected tobacco-derived carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK, 100 mg/kg) 4 times from the 1st to 4th month. Pancreas tissues were collected from Pdx1-Cre (n=3, normal) and Pdx1-Cre; Kras-flox (n=6, all) mice. Kras-flox (Kras) mice were also fed a regular chow (n=3, control) or 3.5% alcohol diet (N=3, alcohol) for 5 months. RNA-seq analysis revealed induction of cancer-associated genes by these risk factors in the pancreatic cancer tissues.
2020-10-22 | GSE139357 | GEO
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