Public PhD defence on 16th of June 2017, at 12 noon
Biocenter 2, Lecture hall 2041
Author: M.Sc. Marjaana Pussila
University of Helsinki, Faculty of Biological and Environmental Sciences, Department of Biosciences, perinnöllisyystiede
Opponent: Professor Theodore Fotsis, MD, PhD
Foundation for Research & Technology-Hellas (FORTH)
Institute of Molecular Biology and Biotechnology (IMBB)
Department of Biomedical Research (Ioannina)
Prof. Theodore Fotsis, M.Sc Marjaana Pussila and Prof. Minna Nyström
Western-style diets (WD) high in fat and scarce in fiber and vitamin D increase risk of colorectal cancer. Here, we performed a long-term diet study in mice to follow tumorigenesis and characterize structural and metabolic changes in colon mucosa associated with WD and predisposition to colorectal cancer. WD increased colon tumor numbers, and mucosa proteomic analysis indicated severe deregulation of intracellular bile acid (BA) homeostasis and activation of cell proliferation. WD also increased crypt depth and colon cell proliferation. Despite increased luminal BA, colonocytes from WD-fed mice exhibited decreased expression of the BA transporters FABP6, OSTβ, and ASBT and decreased concentrations of secondary BA deoxycholic acid and lithocholic acid, indicating reduced activity of the nuclear BA receptor FXR. Overall, our results suggest that WD increases cancer risk by FXR inactivation, leading to BA deregulation and increased colon cell proliferation.
Cancer Res; 77(12); 3352–63. ©2017 AACR.