title: Cancer-predicting gene expression changes in colonic mucosa of Western diet fed Mlh1+/- mice.
abstract: Colorectal cancer (CRC) is the second most common cause of cancer-related deaths in the Western world and interactions between genetic and environmental factors, including diet, are suggested to play a critical role in its etiology. We conducted a long-term feeding experiment in the mouse to address gene expression and methylation changes arising in histologically normal colonic mucosa as putative cancer-predisposing events available for early detection. The expression of 94 growth-regulatory genes previously linked to human CRC was studied at two time points (5 weeks and 12 months of age) in the heterozygote Mlh1(+/-) mice, an animal model for human Lynch syndrome (LS), and wild type Mlh1(+/+) littermates, fed by either Western-style (WD) or AIN-93G control diet. In mice fed with WD, proximal colon mucosa, the predominant site of cancer formation in LS, exhibited a significant expression decrease in tumor suppressor genes, Dkk1, Hoxd1, Slc5a8, and Socs1, the latter two only in the Mlh1(+/-) mice. Reduced mRNA expression was accompanied by increased promoter methylation of the respective genes. The strongest expression decrease (7.3 fold) together with a significant increase in its promoter methylation was seen in Dkk1, an antagonist of the canonical Wnt signaling pathway. Furthermore, the inactivation of Dkk1 seems to predispose to neoplasias in the proximal colon. This and the fact that Mlh1 which showed only modest methylation was still expressed in both Mlh1(+/-) and Mlh1(+/+) mice indicate that the expression decreases and the inactivation of Dkk1 in particular is a prominent early marker for colon oncogenesis.
authors.affiliation: Department of Biosciences, University of Helsinki, Helsinki, Finland.
authors.forename: Marjaana
authors.initials: M
authors.lastname: Pussila
authors.forename: Laura
authors.initials: L
authors.lastname: Sarantaus
authors.forename: Denis
authors.initials: D
authors.lastname: Dermadi Bebek
authors.forename: Satu
authors.initials: S
authors.lastname: Valo
authors.forename: Nima
authors.initials: N
authors.lastname: Reyhani
authors.forename: Saara
authors.initials: S
authors.lastname: Ollila
authors.forename: Essi
authors.initials: E
authors.lastname: Päivärinta
authors.forename: Päivi
authors.initials: P
authors.lastname: Peltomäki
authors.forename: Marja
authors.initials: M
authors.lastname: Mutanen
authors.forename: Minna
authors.initials: M
authors.lastname: Nyström
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics*; D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics; D003106:Colon / Q000378:metabolism* / Q000473:pathology; D003110:Colonic Neoplasms / Q000175:diagnosis / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis / Q000235:genetics; D019175:DNA Methylation; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D027501:Monocarboxylic Acid Transporters; D009092:Mucous Membrane / Q000378:metabolism* / Q000473:pathology; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics; D013997:Time Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D027682:Cation Transport Proteins; C501127:Dkk1 protein, mouse; D018398:Homeodomain Proteins; C486697:Hoxd1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; C501485:Mlh1 protein, mouse; D027501:Monocarboxylic Acid Transporters; D009687:Nuclear Proteins; C507459:Slc5a8 protein, mouse; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D000070957:MutL Protein Homolog 1