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Epimorphin deletion protects mice from inflammation-induced colon carcinogenesis and alters stem cell niche myofibroblast secretion.

ABSTRACT: Epithelial-mesenchymal interactions regulate normal gut epithelial homeostasis and have a putative role in inflammatory bowel disease and colon cancer pathogenesis. Epimorphin is a mesenchymal and myofibroblast protein with antiproliferative, promorphogenic effects in intestinal epithelium. We previously showed that deletion of epimorphin partially protects mice from acute colitis, associated with an increase in crypt cell proliferation. Here we explored the potential therapeutic utility of modulating epimorphin expression by examining the effects of epimorphin deletion on chronic inflammation-associated colon carcinogenesis using the azoxymethane/dextran sodium sulfate (AOM/DSS) model. We found that mice in which epimorphin expression was absent had a marked reduction in incidence and extent of colonic dysplasia. Furthermore, epimorphin deletion in myofibroblasts altered the morphology and growth of cocultured epithelial cells. Loss of epimorphin affected secretion of soluble mesenchymal regulators of the stem cell niche such as Chordin. Importantly, IL-6 secretion from LPS-treated epimorphin-deficient myofibroblasts was completely inhibited, and stromal IL-6 expression was reduced in vivo. Taken together, these data show that epimorphin deletion inhibits chronic inflammation-associated colon carcinogenesis in mice, likely as a result of increased epithelial repair, decreased myofibroblast IL-6 secretion, and diminished IL-6-induced inflammation. Furthermore, we believe that modulation of epimorphin expression may have therapeutic benefits in appropriate clinical settings.

SUBMITTER: Shaker A

PROVIDER: S-EPMC2877942 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Epimorphin deletion protects mice from inflammation-induced colon carcinogenesis and alters stem cell niche myofibroblast secretion.

Shaker Anisa A Swietlicki Elzbieta A EA Wang Lihua L Jiang Shujun S Onal Birce B Bala Shashi S DeSchryver Katherine K Newberry Rodney R Levin Marc S MS Rubin Deborah C DC

The Journal of clinical investigation 20100510 6

Epithelial-mesenchymal interactions regulate normal gut epithelial homeostasis and have a putative role in inflammatory bowel disease and colon cancer pathogenesis. Epimorphin is a mesenchymal and myofibroblast protein with antiproliferative, promorphogenic effects in intestinal epithelium. We previously showed that deletion of epimorphin partially protects mice from acute colitis, associated with an increase in crypt cell proliferation. Here we explored the potential therapeutic utility of modu ...[more]

PMID: 20458144

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Project description:BACKGROUND & AIMS:Many genetic and environmental factors, including family history, dietary fat, and inflammation, increase risk for colon cancer development. Peroxisome proliferator-activated receptor alpha (PPAR?) is a nuclear receptor that regulates systemic lipid homeostasis. We explored the role of intestinal PPAR? in colon carcinogenesis. METHODS:Colon cancer was induced in mice with intestine-specific disruption of Ppara (Ppara?IE), Pparafl/fl (control), and mice with disruption of Ppara that express human PPARA (human PPARA transgenic mice), by administration of azoxymethane with or without dextran sulfate sodium (DSS). Colons were collected from mice and analyzed by immunoblots, quantitative polymerase chain reaction, and histopathology. Liquid chromatography coupled with mass spectrometry-based metabolomic analyses were performed on urine and colons. We used molecular biology and biochemical approaches to study mechanisms in mouse colons, primary intestinal epithelial cells, and colon cancer cell lines. Gene expression data and clinical features of patients with colorectal tumors were obtained from Oncomine, and human colorectal-tumor specimens and adjacent normal tissues were collected and analyzed by immunohistochemistry. RESULTS:Levels of Ppara messenger RNA were reduced in colon tumors from mice. Ppara?IE mice developed more and larger colon tumors than control mice following administration of azoxymethane, with or without DSS. Metabolomic analyses revealed increases in methylation-related metabolites in urine and colons from Ppara?IE mice, compared with control mice, following administration of azoxymethane, with or without DSS. Levels of DNA methyltransferase 1 (DNMT1) and protein arginine methyltransferase 6 (PRMT6) were increased in colon tumors from Ppara?IE mice, compared with colon tumors from control mice. Depletion of PPAR? reduced the expression of retinoblastoma protein, resulting in increased expression of DNMT1 and PRMT6. DNMT1 and PRMT6 decreased expression of the tumor suppressor genes Cdkn1a (P21) and Cdkn1b (p27) via DNA methylation and histone H3R2 dimethylation-mediated repression of transcription, respectively. Fenofibrate protected human PPARA transgenic mice from azoxymethane and DSS-induced colon cancer. Human colon adenocarcinoma specimens had lower levels of PPARA and retinoblastoma protein and higher levels of DNMT1 and PRMT6 than normal colon tissues. CONCLUSIONS:Loss of PPAR? from the intestine promotes colon carcinogenesis by increasing DNMT1-mediated methylation of P21 and PRMT6-mediated methylation of p27 in mice. Human colorectal tumors have lower levels of PPARA messenger RNA and protein than nontumor tissues. Agents that activate PPAR? might be developed for chemoprevention or treatment of colon cancer.

Dataset Information

Epimorphin deletion protects mice from inflammation-induced colon carcinogenesis and alters stem cell niche myofibroblast secretion.

Publications

Epimorphin deletion protects mice from inflammation-induced colon carcinogenesis and alters stem cell niche myofibroblast secretion.

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