title: Upregulation of DNA methyltransferase-mediated gene silencing, anchorage-independent growth, and migration of colon cancer cells by interleukin-6.
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.
authors.affiliation: Department of Pharmacology and Therapeutics, National University of Ireland, Galway, Ireland.
authors.forename: Eilis
authors.initials: E
authors.lastname: Foran
authors.forename: Megan M
authors.initials: MM
authors.lastname: Garrity-Park
authors.forename: Coralie
authors.initials: C
authors.lastname: Mureau
authors.forename: John
authors.initials: J
authors.lastname: Newell
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Smyrk
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Limburg
authors.forename: Laurence J
authors.initials: LJ
authors.lastname: Egan
mesh_terms: D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D015197:Carcinogenicity Tests; D002277:Carcinoma / Q000201:enzymology / Q000235:genetics* / Q000276:immunology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003092:Colitis / Q000201:enzymology / Q000235:genetics* / Q000276:immunology; D003110:Colonic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000276:immunology; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D000077209:Decitabine; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D020868:Gene Silencing / Q000502:physiology*; D016147:Genes, Tumor Suppressor / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism* / Q000494:pharmacology; D009362:Neoplasm Metastasis / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D015854:Up-Regulation / Q000502:physiology
chemical_list: D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D015850:Interleukin-6; D000077209:Decitabine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; D001374:Azacitidine