Identification of actively translated mRNA transcripts in a rat model of early-stage colon carcinogenesis.
With respect to functional mapping of gene expression signatures, the steady-state mRNA expression level does not always accurately reflect the status of critical signaling proteins. In these cases, control is exerted at the epigenetic level of recruitment of mRNAs to polysomes, the factories of ribosomes that mediate efficient translation of many cellular messages. However, to date, a genome-wide perspective of the effect of carcinogen and chemoprotective bioactive diets on actively translated (polysomal) mRNA populations has not been done. Therefore, we used an established colon cancer model, i.e., the azoxymethane (AOM)-treated rat, in combination with a chemoprotective diet extensively studied in our laboratory, i.e., n-3 polyunsaturated fatty acids, to characterize the molecular processes underlying the transformation of normal colonic epithelium. The number of genes affected by AOM treatment 10 weeks after carcinogen injection was significantly greater in the polysome RNA fraction compared with the total RNA fraction as determined using a high-density microarray platform. In particular, polysomal loading patterns of mRNAs associated with the Wnt-beta catenin, phospholipase A(2)-eicosanoid and the mitogen-activated protein kinase signaling axes were significantly upregulated at a very early period of tumor development in the colon. These data indicate that translational alterations are far more extensive relative to transcriptional alterations in mediating malignant transformation. In contrast, transcriptional alterations were found to be more extensive relative to translational alterations in mediating the effects of diet. Therefore, during early stage colonic neoplasia, diet and carcinogen seem to predominantly regulate gene expression at multiple levels via unique mechanisms.
Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, Texas 77843-2253, USA.
Laurie A
LA
Davidson
Naisyin
N
Wang
Ivan
I
Ivanov
Jennifer
J
Goldsby
Joanne R
JR
Lupton
Robert S
RS
Chapkin
D000818:Animals; D001397:Azoxymethane / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D015525:Fatty Acids, Omega-3 / Q000008:administration & dosage; D020869:Gene Expression Profiling; D005796:Genes / Q000502:physiology*; D007124:Immunoenzyme Techniques; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D011132:Polyribosomes / Q000235:genetics* / Q000378:metabolism; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D002273:Carcinogens; D015525:Fatty Acids, Omega-3; D012333:RNA, Messenger; D001397:Azoxymethane