Chemopreventive n-3 polyunsaturated fatty acids reprogram genetic signatures during colon cancer initiation and progression in the rat

• Published in: Cancer research (Chicago, Ill.) Vol. 64; no. 18; pp. 6797 - 6804
• Main Authors: DAVIDSON, Laurie A, NGUYEN, Danh V, CHAPKIN, Robert S, HOKANSON, Regina M, CALLAWAY, Evelyn S, ISETT, Robert B, TURNER, Nancy D, DOUGHERTY, Edward R, NAISYIN WANG, LUPTON, Joanne R, CARROLL, Raymond J
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-09-2004
• Subjects: Animals; Anticarcinogenic Agents - pharmacology; Antineoplastic agents; Apoptosis - drug effects; Azoxymethane; Biological and medical sciences; Carcinogens; Cell Differentiation - drug effects; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colonic Neoplasms - prevention & control; Disease Progression; DNA Adducts - antagonists & inhibitors; DNA Adducts - biosynthesis; Down-Regulation - drug effects; Eating - drug effects; Fatty Acids, Omega-3; Fatty Acids, Omega-6 - pharmacology; Fatty Acids, Unsaturated - pharmacology; Fish Oils - pharmacology; Gene Expression Profiling; Gene Expression Regulation, Neoplastic - drug effects; Male; Medical sciences; Oligonucleotide Array Sequence Analysis; Pharmacology. Drug treatments; Polymerase Chain Reaction; Rats; Rats, Sprague-Dawley; Triglycerides - pharmacology; Tumors; Up-Regulation - drug effects; Weight Gain - drug effects; Rat; Rodentia; Polyunsaturated fatty acid; Lipids; Colonic disease; Prevention; Vertebrata; Chemotherapy; Mammalia; Colon cancer; Animal; Tumor progression; Digestive diseases; Intestinal disease; Genetics; Initiation
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-04-1068

The mechanisms by which n-3 polyunsaturated fatty acids (PUFAs) decrease colon tumor formation have not been fully elucidated. Examination of genes up- or down-regulated at various stages of tumor development via the monitoring of gene expression relationships will help to determine the biological processes ultimately responsible for the protective effects of n-3 PUFA. Therefore, using a 3 x 2 x 2 factorial design, we used Codelink DNA microarrays containing approximately 9000 genes to help decipher the global changes in colonocyte gene expression profiles in carcinogen-injected Sprague Dawley rats. Animals were assigned to three dietary treatments differing only in the type of fat (corn oil/n-6 PUFA, fish oil/n-3 PUFA, or olive oil/n-9 monounsaturated fatty acid), two treatments (injection with the carcinogen azoxymethane or with saline), and two time points (12 hours and 10 weeks after first injection). Only the consumption of n-3 PUFA exerted a protective effect at the initiation (DNA adduct formation) and promotional (aberrant crypt foci) stages. Importantly, microarray analysis of colonocyte gene expression profiles discerned fundamental differences among animals treated with n-3 PUFA at both the 12 hours and 10-week time points. Thus, in addition to demonstrating that dietary fat composition alters the molecular portrait of gene expression profiles in the colonic epithelium at both the initiation and promotional stages of tumor development, these findings indicate that the chemopreventive effect of fish oil is due to the direct action of n-3 PUFA and not to a reduction in the content of n-6 PUFA.