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Gene expression studies in IEC-6 cells induced by non-steroidal anti-inflammatory agents

ABSTRACT: Non-steroidal anti-inflammatory drugs (NSAIDs) are used extensively as therapeutic agents, despite their well-documented gastrointestinal (GI) toxicity. Presently, the mechanisms responsible for NSAID-associated GI damage are incompletely understood. In this study, we used Microarray analysis to generate a novel hypothesis about cellular mechanisms that underlie the GI toxicity of NSAIDs. Monolayers of intestinal epithelial cells (IEC-6) were treated with NSAIDs that either exhibit indomethacin, NS-398) or lack (SC-560) inhibitory effects on intestinal epithelial cell migration. Bioinformatic analysis of array data suggested that NSAIDs with adverse GI effects either decrease the gene expression of the calpains or increase the gene expression of the calpain engodenous inhibitor, calpastatin. Calpains have been shown previously to modulate the migration of a variety of cells in different physiological contexts. Our experimental results suggest that the altered expression of calpain genes may contribute to the adverse effects of NSAIDs on intestinal epithelial restitution. Microarray analysis has generated the novel hypothesis that the GI toxicity of NSAIDs may be attributed in part to drug-induced changes in the expression and activity of calpains. Keywords: dose response

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE7584 | GEO | 2009/03/21

SECONDARY ACCESSION(S): PRJNA100329

REPOSITORIES: GEO

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Project description:The Runx1 transcription factor plays an important role in tissue homeostasis through its effects on stem/progenitor cell populations and differentiation. The effect of Runx1 on epithelial differentiation of the secretory cell lineage of the colon was recently demonstrated. This study aimed to examine the role of Runx1 in tumor development in epithelial cells of the gastrointestinal tract. Conditional knockout mice were generated that lacked Runx1 expression in epithelial cells of the GI tract. These mice were crossed onto the ApcMin background, sacrificed, and their intestinal tumor phenotypes were compared with ApcMin Runx1 wildtype control mice. Apc-wildtype Runx1-mutant mice were also examined for tumor development. Colons from Runx1 knockout and wildtype mice were used for genome-wide mRNA expression analyses followed by gene-specific quantitative RT-PCR of whole colon and colon epithelium, to identify Runx1 target genes. Runx1 deficiency in intestinal epithelial cells significantly enhanced tumorigenesis in ApcMin mice. Notably, epithelial Runx1 deficiency in Apc-wildtype mice was sufficient to cause tumor development. Absence of Runx1 was associated with global changes in expression of genes involved in inflammation and intestinal metabolism, and with gene sets indicative of metastatic phenotype and poor prognosis. Gene-specific analysis of Runx1 deficient colon epithelium revealed increased expression of genes linked to an expansion of the stem/progenitor cell population. These results identify Runx1 as a novel tumor suppressor gene for gastrointestinal tumors and support a role for Runx1 in maintaining the balance between the intestinal stem/progenitor cell population and epithelial differentiation of the GI tract. A total of 8 colon tissue RNA samples were analyzed, comprising 4 colon samples from wild-type mice (Villin-Cre negative / Runx1-floxed) and 4 colon samples from mice that lack epithelial expression of Runx1 (Villin-Cre positive/Runx1-floxed).

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Gene expression studies in IEC-6 cells induced by non-steroidal anti-inflammatory agents

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