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CANDIDATE GENES FOR LIMITING CHOLESTATIC INTESTINAL INJURY IDENTIFIED BY GENE EXPRESSION PROFILING.

ABSTRACT: The lack of bile flow from the liver into the intestine can have devastating complications including hepatic failure, sepsis and even death. This pathologic condition known as cholestasis can result from etiologies as diverse as total parenteral nutrition (TPN), hepatitis and pancreatic cancer. The intestinal injury associated with cholestasis has been shown to result in decreased intestinal resistance, increased bacterial translocation and increased endotoxemia. Anecdotal clinical evidence suggests a genetic predisposition to exaggerated injury. Recent animal research on two different strains of inbred mice demonstrating different rates of bacterial translocation with different mortality rates supports this premise. In this study, a microarray analysis of intestinal tissue following common bile duct ligation (CBDL) performed under general anesthesia on these same two strains of inbred mice was done with the goal of identifying the potential molecular mechanistic pathways responsible. Over 500 genes were increased more than 2.0 fold following CBDL. The most promising candidate genes included MUPs, Serpina1a and LCN-2. RT-PCR validated the microarray results for these candidate genes. In an in vitro experiment using differentiated intestinal epithelial cells, inhibition of MUP-1 by siRNA resulted in increased intestinal epithelial cell permeability. Diverse novel mechanisms involving the growth hormone pathway, the acute phase response and the innate immune response are thus potential avenues for limiting cholestatic intestinal injury. Changes in gene expression were at times found to be not only due to the CBDL but also due to the murine strain. Should further studies in cholestatic patients demonstrate inter-individual variability similar to what we have shown in mice, then a "personalized medicine" approach to cholestatic patients may become possible.

SUBMITTER: Alaish SM

PROVIDER: S-EPMC3808870 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundOne particularly promising component of personalized medicine in cancer treatment is targeted therapy, which aims to maximize therapeutic efficacy while minimizing toxicity. However, the number of approved targeted agents remains limited. Expression microarray data for different types of cancer are resources to identify genes that were upregulated. The genes are candidate targets for cancer-targeting agents for future anticancer research and targeted treatments.Methods and findingsThe gene expression profiles of 48 types of cancer from 2,141 microarrays reported in the Gene Expression Omnibus were analyzed. These data were organized into 78 experimental groups, on which we performed comprehensive analyses using two-tailed Student's t-tests with significance set at P < 0.01 to identify genes that were upregulated compared with normal cells in each cancer type. The resulting list of significantly upregulated genes was cross-referenced with three categories of protein inhibitor targets, categorized by inhibitor type ('Targets of US Food and Drug Administration (FDA)-approved anticancer drugs', 'Targets of FDA-approved nonantineoplastic drugs', or 'Targets of non-FDA-approved chemical agents'). Of the 78 experimental groups studied, 57 (73%) represent cancers that are currently treated with FDA-approved targeted treatment agents. However, the target genes for the indicated therapies are upregulated in only 33 of these groups (57%). Nevertheless, the mRNA expression of the genes targeted by FDA-approved treatment agents is increased in every experimental group, including all of the cancers without FDA-approved targeted treatments. Moreover, many targets of protein inhibitors that have been approved by the FDA as therapies for nonneoplastic diseases, such as 3-hydroxy-3-methylglutaryl-CoA reductase and cyclooxygenase-2 and the targets of many non-FDA-approved chemical agents, such as cyclin-dependent kinase 1 and DNA-dependent protein kinase, are also overexpressed in many types of cancer.ConclusionThis research demonstrates a clinical correlation between bioinformatics data and currently approved treatments and suggests novel uses for known protein inhibitors in future antineoplastic research and targeted therapies.

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CANDIDATE GENES FOR LIMITING CHOLESTATIC INTESTINAL INJURY IDENTIFIED BY GENE EXPRESSION PROFILING.

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