1. Upregulation of DNA methyltransferase-mediated gene silencing, anchorage-independent growth, and migration of colon cancer cells by interleukin-6.
- Author
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Foran E, Garrity-Park MM, Mureau C, Newell J, Smyrk TC, Limburg PJ, and Egan LJ
- Subjects
- Azacitidine analogs & derivatives, Azacitidine pharmacology, Carcinogenicity Tests, Carcinoma enzymology, Carcinoma immunology, Cell Line, Tumor, Cell Movement genetics, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic immunology, Cell Transformation, Neoplastic metabolism, Colitis enzymology, Colitis immunology, Colonic Neoplasms enzymology, Colonic Neoplasms immunology, DNA (Cytosine-5-)-Methyltransferase 1, DNA (Cytosine-5-)-Methyltransferases antagonists & inhibitors, DNA (Cytosine-5-)-Methyltransferases metabolism, DNA Methylation drug effects, DNA Methylation genetics, Decitabine, Down-Regulation drug effects, Down-Regulation genetics, Enzyme Inhibitors, Gene Expression Regulation, Neoplastic drug effects, Gene Expression Regulation, Neoplastic genetics, Genes, Tumor Suppressor drug effects, Genes, Tumor Suppressor physiology, Humans, Immunohistochemistry, Inflammation Mediators metabolism, Inflammation Mediators pharmacology, Interleukin-6 pharmacology, Neoplasm Metastasis genetics, Promoter Regions, Genetic genetics, Up-Regulation physiology, Carcinoma genetics, Colitis genetics, Colonic Neoplasms genetics, DNA (Cytosine-5-)-Methyltransferases genetics, Gene Silencing physiology, Interleukin-6 metabolism
- Abstract
Inflammatory bowel disease is characterized by chronic inflammation which predisposes to colorectal cancer. The mechanisms by which inflammation promotes tumorigenesis are not fully known. We aimed to investigate the links between colonic inflammation and tumorigenesis via epigenetic gene silencing. Colon cancer specimens were assessed for the expression of DNA methyltransferase-1 (DNMT-1) using immunohistochemistry. Colorectal carcinoma cell lines were assessed for DNMT1 expression, methylcytosine content, promoter methylation, gene expression, and tumorigenesis in response to interleukin (IL)-6. DNMT1 was expressed at higher levels in both the peritumoral stroma and tumor in inflammatory bowel disease-associated cancers compared with sporadic colon cancers. IL-6 treatment of colon cancer cells resulted in an increase in DNMT1 expression, independent of de novo gene expression. IL-6 increased the methylation of promoter regions of genes associated with tumor suppression, adhesion, and apoptosis resistance. Expression of a subset of these genes was downregulated by IL-6, an effect that was prevented by preincubation with 5-azadeoxycytidine, a DNMT1 inhibitor. Anchorage-independent growth and migration of colon cancer cells was also increased by IL-6 in a 5-azadeoxycytidine-sensitive manner. Our results indicate that DNMT-mediated gene silencing may play a role in inflammation-associated colon tumorigenesis., ((c) 2010 AACR.)
- Published
- 2010
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