Chemopreventive n-3 polyunsaturated fatty acids reprogram genetic signatures during colon cancer initiation and progression in the rat.
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.
Davidson
Laurie A
LA
Faculty of Nutrition, Texas A&M University, College Station, Texas 77843-2471, USA.
Nguyen
Danh V
DV
Hokanson
Regina M
RM
Callaway
Evelyn S
ES
Isett
Robert B
RB
Turner
Nancy D
ND
Dougherty
Edward R
ER
Wang
Naisyin
N
Lupton
Joanne R
JR
Carroll
Raymond J
RJ
Chapkin
Robert S
RS
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001397:Azoxymethane; D002273:Carcinogens; D002454:Cell Differentiation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control*; D018736:DNA Adducts / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018450:Disease Progression; D015536:Down-Regulation / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D015525:Fatty Acids, Omega-3; D043371:Fatty Acids, Omega-6 / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D005395:Fish Oils / Q000494:pharmacology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D051381:Rats; D017207:Rats, Sprague-Dawley; D014280:Triglycerides / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects; D015430:Weight Gain / Q000187:drug effects
D016588:Anticarcinogenic Agents; D002273:Carcinogens; D018736:DNA Adducts; D015525:Fatty Acids, Omega-3; D043371:Fatty Acids, Omega-6; D005231:Fatty Acids, Unsaturated; D005395:Fish Oils; D014280:Triglycerides; C077446:Pikasol; D001397:Azoxymethane