title: Plant stanols induce intestinal tumor formation by up-regulating Wnt and EGFR signaling in Apc Min mice.
abstract: The rate of APC mutations in the intestine increases in middle-age. At the same period of life, plant sterol and stanol enriched functional foods are introduced to diet to lower blood cholesterol. This study examined the effect of plant stanol enriched diet on intestinal adenoma formation in the Apc(Min) mouse. Apc(Min) mice were fed 0.8% plant stanol diet or control diet for nine weeks. Cholesterol, plant sterols and plant stanols were analyzed from the caecum content and the intestinal mucosa. Levels of β-catenin, cyclin D1, epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase 1/2 (ERK1/2) were measured from the intestinal mucosa by Western blotting. Gene expression was determined from the intestinal mucosa using Affymetrix and the data were analyzed for enriched categories and pathways. Plant stanols induced adenoma formation in the small intestine, however, the adenoma size was not affected. We saw increased levels of nuclear β-catenin, phosphorylated β-catenin (Ser675 and Ser552), nuclear cyclin D1, total and phosphorylated EGFR and phosphorylated ERK1/2 in the intestinal mucosa after plant stanol feeding. The Affymetrix data demonstrate that several enzymes of cholesterol synthesis pathway were up-regulated, although the cholesterol level in the intestinal mucosa was not altered. We show that plant stanols induce adenoma formation by activating Wnt and EGFR signaling. EGFR signaling seems to have promoted β-catenin phosphorylation and its translocation into the nucleus, where the expression of cyclin D1 was increased. Up-regulated cholesterol synthesis may partly explain the increased EGFR signaling in the plant stanol-fed mice.
authors.affiliation: Department of Food and Environmental Sciences, Division of Nutrition, P.O. Box 66 (Agnes Sjöbergin katu 2), FIN-00014 University of Helsinki, Finland. maija.marttinen@helsinki.fi
authors.forename: Maija
authors.initials: M
authors.lastname: Marttinen
authors.forename: Essi
authors.initials: E
authors.lastname: Päivärinta
authors.forename: Markus
authors.initials: M
authors.lastname: Storvik
authors.forename: Laura
authors.initials: L
authors.lastname: Huikko
authors.forename: Heli
authors.initials: H
authors.lastname: Luoma-Halkola
authors.forename: Vieno
authors.initials: V
authors.lastname: Piironen
authors.forename: Anne-Maria
authors.initials: AM
authors.lastname: Pajari
authors.forename: Marja
authors.initials: M
authors.lastname: Mutanen
mesh_terms: D000236:Adenoma / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D002432:Cecum / Q000187:drug effects / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D017491:Genes, APC; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D007414:Intestinal Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010840:Phytosterols / Q000009:adverse effects* / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D012855:Sitosterols / Q000494:pharmacology; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000378:metabolism
chemical_list: C530105:Ccnd1 protein, mouse; D010840:Phytosterols; D012855:Sitosterols; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; D051176:beta Catenin; D019938:Cyclin D1; D012694:Serine; C003535:campestanol; D002784:Cholesterol; C021255:stigmastanol; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D048052:Mitogen-Activated Protein Kinase 3