Project description:We used microarrays to decipher the global programme of gene expression in normal colon tissue versus colorectal tumor tissue explants from 6 months old cav1-/+ apcmin/+ mice and identified distinct classes of differentially regulated genes.
Project description:Nonsteroidal anti-inflammatory drugs have been shown to reduce the incidence of gastrointestinal cancers, but the propensity of these drugs to cause ulcers and bleeding limits their use. H2S has been shown to be a powerful cytoprotective and anti-inflammatory substance in the digestive system. This study explored the possibility that a H2S-releasing nonsteroidal anti-inflammatory drug (ATB-346) would be effective in a murine model of hereditary intestinal cancer (APCMin+ mouse) and investigated potential mechanisms of action via transcriptomics analysis. Daily treatment with ATB-346 was significantly more effective at preventing intestinal polyp formation than naproxen. Significant beneficial effects were seen with a treatment period of only 3-7 days, and reversal of existing polyps was observed in the colon. ATB-346, but not naproxen, significantly decreased expression of intestinal cancer-associated signaling molecules (cMyc, β-catenin). Transcriptomic analysis identified 20 genes that were up-regulated in APCMin+ mice, 18 of which were reduced to wild-type levels by one week of treatment with ATB-346. ATB-346 is a novel, gastrointestinal-sparing anti-inflammatory drug that potently and rapidly prevents and reverses the development of pre-cancerous lesions in a mouse model of hereditary intestinal tumorigenesis. These effects may be related to the combined effects of suppression of cyclooxygenase and release of H2S, and correction of most of the APCMin+-associated alterations in the transcriptome. ATB-346 may represent a promising agent for chemoprevention of tumorigenesis in the GI tract and elsewhere. Total RNA obtained from colon of APCMin/+ mice treated for 7 days with vehicle, ATB-346 or naproxen. Tissue collected 7 weeks after the final dose of drug
Project description:Changes in gene expression profile of intestinal (ILEUM) Tumors from APCmin/+/VP16LXRa vs APCmin/+/VP16. The hypothesis tested in the present study was that LXRa overexpression influence cancer growth modulating lipid metabolism in cancer cells. Results provide the information that LXRa induces genes encoding proteins able to regulate cholesterol efflux. Total RNA obtained from Ileum tumors from APCmin/+/VP16LXRa mice was compared to total RNA extracted from APCmin/+/VP16 mice.
Project description:We performed RNAseq on intestinal polyps from diptheria toxin-treated ApcMin;Lgr5DTR mice to investigate the effect of an acute selective pressure on stem cell populations in intestinal lesions. Lgr5+ cells in the ApcMin;Lgr5DTR mice were ablated with a single intraperitoneal dose of diphtheria toxin in saline (50 μg/kg), and samples were collected after 24 hours and after 5 days. Untreated ApcMin mice were used as control. Intestinal polyps were excised and collected for RNA sequencing.
Project description:Changes in gene expression profile of intestinal (COLON) Tumors from APCmin/+/VP16LXRa vs APCmin/+/VP16. The hypothesis tested in the present study was that LXRa overexpression influence cancer growth modulating lipid metabolism in cancer cells. Results provide the information that LXRa induces expression of genes encoding proteins able to regulate cholesterol efflux. Total RNA obtained from colonic tumors from APCmin/+/VP16LXRa mice was compared to total RNA extracted from APCmin/+/VP16 mice.
Project description:APCmin/+ mice develop spontaneous gastrointestinal polyposis due to a dominantly inhereited germline loss-of-function mutation in the tumor suppressor adenomatous polyposis coli (APC). Changes in intestinal immune activity have been documented to occur prior to the development of fulminate polyposis. Such changes are thought to contribute to disease development. We used microarrays to describe the changing intestinal transcriptional landscape in APCmin/+ mice. Whole transcriptome profiling from polypotic and nonpolypotic intestinal sections of APC/min+ mice were examined in the early stages of disease, and compared to normal intestinal sections from littermate matched wildtype B6 mice. Nonpolypotic (wildtype and APCmin/+) and Polypotic (APCmin/+) sections of terminal ileum were identified by visual inspection, and subsequently selected for RNA isolation and hydridzation to Affymetrix Mouse Genome 430A 2.0 Arrays. Interference from bacterial RNA was selected against using a probeset enriched in oligos extending into 3’-poly-A tails.
Project description:The transcription factor Zinc finger protein 148 (Zfp148) interacts physically with the tumor suppressor p53, but the siginficance of this interaction is not known. We recently showed that knockout of Zfp148 in mice leads to ectopic activation of p53 in tissues and cultured fibroblasts, suggesting that Zfp148 represses p53 activity. Here we hypothesized that targeting Zfp148 would unleash p53 activity and protect against cancer development, and test this idea in the APCMin/+ mouse model of intestinal adenomas. Crypt-enriched tissues were isolated by laser microdissection (PALM) from the small intestines (proximal) of Zfp148gt/+APCMin/+ and Zfp148+/+APCMin/+ mice for RNA extraction and hybridization to Affymetrix microarrays.
Project description:Changes in gene expression profile of intestinal (ILEUM) Tumors from APCmin/+/VP16LXRa vs APCmin/+/VP16. The hypothesis tested in the present study was that LXRa overexpression influence cancer growth modulating lipid metabolism in cancer cells. Results provide the information that LXRa induces genes encoding proteins able to regulate cholesterol efflux.
Project description:Changes in gene expression profile of intestinal (COLON) Tumors from APCmin/+/VP16LXRa vs APCmin/+/VP16. The hypothesis tested in the present study was that LXRa overexpression influence cancer growth modulating lipid metabolism in cancer cells. Results provide the information that LXRa induces expression of genes encoding proteins able to regulate cholesterol efflux.
Project description:Setd2 catalyzes trimethylation of lysine 36 on histone H3. H3K36me3 is deposited mainly in the gene body and has recently been demonstrated to play a role in regulating transcriptional elongation and alternative splicing. We conduct deep sequencing in 2-month old control (APCmin) and APCmin; Setd2IEC-/- mice intestinal cells to understand the splicing events regulated by Setd2.