Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Characterization of the molecular signature associated with the ablation of integrin Î±6 in IECs in the Î±6ÎIEC-TAM mouse model

ABSTRACT: Transcriptome analysis of mRNAs extracted from the rectal mucosa of WT and Î±6ÎIEC-TAM mice, 15 days after tamoxifen treatment Inflammatory bowel diseases (IBD) in humans are characterized by chronic inflammation and gastrointestinal tissue damage, caused by a combination of genetic and environmental factors. We show that the specific ablation of integrin Î±6 in intestinal epithelial cells (IECs) results in spontaneous colorectal inflammation in mice. In order to characterize the earlier molecular signature involved in the onset of inflammation, we performed Affymetrix microarrays and compare control versus Î±6ÎIEC-TAM transcriptomes after tamoxifen treatment. RNAs were prepared from rectal mucosa of 3 control mice treated with tamoxifen, 4 mutant mice treated with tamoxifen and 4 mutant mice treated with NaCl. The transcriptome analysis was performed using the Affymetrix Mouse Gene 1.0 ST arrays. Images were processed using affymetrix GeneChipÂ® Command ConsoleÂ® Software (AGCC) (version 2.0) and numerical values were generated using Affymetrix Expression Consoleâ¢ Software (version 1.1).

ORGANISM(S): Mus musculus

SUBMITTER: Doulaye Dembele

PROVIDER: E-GEOD-70700 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Inflammatory bowel diseases (IBD) in humans are characterized by chronic inflammation and gastrointestinal tissue damage, caused by a combination of genetic and environmental factors. It has been largely documented that IBD frequently lead to colorectal cancers (CRC). The identification of causative factors of IBD is thus essential to understand CRC progression and develop therapeutical approaches. Models have been described in which molecular alterations are combined with inflammatory treatments in order to recapitulate IBD-associated CRC. Here, we describe a mouse line, Î±6fl/fl Villin-Cre, in which inactivation of the gene encoding the integrin alpha-6 subunit (ITGA6) specifically in the intestinal mucosa results into chronic inflammation and intestinal carcinogenesis. In these mice, the loss of integrin alpha-6 beta-4, a receptor mediating the attachment of epithelial cells to laminins, leads to epithelial detachment, hyperplasia, chronic inflammation, rectal prolapses, and ultimately adenocarcinomas. Alterations of differentiation affecting mucus secreting (goblet) cells as well as changes in expression of essential intestinal transcription factors were detected. Thus alpha-6 beta-4 integrin is a key factor for the maintenance of intestinal integrity and its loss may represent a risk factor for tumor progression associated with IBD. Transcriptome analysis of RNA from normal versus inflamed and carcinomatous rectal mucosa of Î±6 integrin deficient intestinal epithelium mice was performed. RNAs were prepared from 5 adenocarcinomas, which were macrodissected from the rectal prolapses and 4 flanking inflamed rectal mucosa of 53-80 week-old Î±6fl/fl Villin-Cre mice. RNAs from normal rectal mucosa were obtained by rectum scraping from 4 matched control animals. The transcriptome analysis was performed using the Affymetrix Mouse Gene 1.0 ST arrays. Images were processed using affymetrix GeneChipÂ® Command ConsoleÂ® Software (AGCC) (version 2.0) and numerical value were generated using Affymetrix Expression Consoleâ¢ Software (version 1.1).

Project description:Administration of tamoxifen (TAM) as breast cancer adjuvant therapy is associated with a 50% reduction in breast cancer risk and an increase in endometrial cancer risk. To investigate underlying mechanisms, we documented TAM-induced gene expression changes in cultured normal human mammary epithelial cell (NHMEC) strains (numbered 5, 16 and 40) established from tissue taken at reduction mammoplasty from three different individuals. Cells exposed to 0 and 10 uM TAM for 48 hours were evaluated for survival, TAM-DNA adduct formation by TAM-DNA chemiluminescence immunoassay (CIA), and gene expression changes using DNA-oligonucleotide microarray and real time reverse transcriptase-PCR (RT-PCR). At 48 hr, cells exposed to 10 uM TAM were 78% viable, respectively, and there were no measurable TAM-DNA adducts (limit of detection [LOD] = 0.3 adducts/10^8 nucleotides). For microarray analysis, RNA was extracted from cells exposed on three occasions to 10 uM TAM and the corresponding oligonucleotide probes were labeled with fluorescent dyes and hybridized to NCI microarrays (>20,000 human genes). Expression changes of > 3-fold were considered significant, and by these criteria, thirteen genes were up-regulated and one was down-related in NHMEC strain 16, seventeen genes were up-regulated in strain 05, and eleven genes were up-regulated in strain and 40. Elements that were up-regulated in all three cell strains included several interferon-induced genes (IFITM1, IFIT1, IFNA1, MXI and GIP3), and a potassium ion channel (KCNJ1). No significant expression changes were found for genes related to estrogen or xenobiotic metabolism. RT-PCR revealed TAM-induced up-regulation of the five genes of interest, and interferon á (IFNA1), in all three NHMEC strains, with the exception of GIP3 and MX1, which were unchanged in strain 40. The magnitude of TAM-induced up-regulation ranked: strain 16 > strain 05> strain 40. The consistent induction of interferon-related genes in all three NHMEC strains suggests that, in addition to hormonal effects, TAM exposure may enhance immune response, through interferon induction, in normal breast tissue. RNA was extracted from three cell strains (NHMEC 98016, 98040 and 99005) and exposed on three separate occasions to 10 uM TAM. Comparisons were made using 16 arrays with 8 dye swaps for cell strain NHMEC 99005, 9 arrays with 4 dye swaps for NHMEC 98016, and 12 arrays with 6 dye swaps for NHMEC 98040.

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Characterization of the molecular signature associated with the ablation of integrin Î±6 in IECs in the Î±6ÎIEC-TAM mouse model

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Characterization of the molecular signature associated with the ablation of integrin Î±6 in IECs in the Î±6ÎIEC-TAM mouse model