Consumption of high-fat diet induces tumor progression and epithelial–mesenchymal transition of colorectal cancer in a mouse xenograft model

• Published in: The Journal of nutritional biochemistry Vol. 23; no. 10; pp. 1302 - 1313
• Main Authors: Tang, Feng-Yao, Pai, Man-Hui, Chiang, En-Pei Isabel
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.10.2012; Elsevier
• Subjects: adverse effects; Animals; beta Catenin; beta Catenin - genetics; beta Catenin - metabolism; Biological and medical sciences; Cadherins; Cadherins - genetics; Cadherins - metabolism; Cell Proliferation; Cell Proliferation - drug effects; colon; Colorectal cancer; colorectal neoplasms; Colorectal Neoplasms - pathology; Cyclin D1; Cyclin D1 - genetics; Cyclin D1 - metabolism; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Cyclooxygenase 2; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 - metabolism; Diet, High-Fat; Diet, High-Fat - adverse effects; Disease Models, Animal; drug effects; epidemiological studies; Epithelial-Mesenchymal Transition; Epithelial-Mesenchymal Transition - drug effects; Feeding. Feeding behavior; Female; Fundamental and applied biological sciences. Psychology; gene expression regulation; Gene Expression Regulation, Neoplastic; genetics; High-fat diet; Histone deacetylase; HT29 Cells; Humans; inflammation; metabolism; Mice; Mice, Inbred BALB C; mitogen-activated protein kinase; Mitogen-Activated Protein Kinases; Mitogen-Activated Protein Kinases - genetics; Mitogen-Activated Protein Kinases - metabolism; NF-kappa B; NF-kappa B - genetics; NF-kappa B - metabolism; pathology; phosphatidylinositol 3-kinase; Phosphatidylinositol 3-Kinase - genetics; Phosphatidylinositol 3-Kinase - metabolism; proliferating cell nuclear antigen; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction; TOR Serine-Threonine Kinases; Up-Regulation; Vertebrates: anatomy and physiology, studies on body, several organs or systems; vimentin; Vimentin - genetics; Vimentin - metabolism; Histone deacetylase; Epithelial–mesenchymal transition; Cyclooxygenase-2; High-fat diet; Colorectal cancer; Animal model; Rectal disease; Cyclooxygenase 2; Heterograft; Tumor progression; Intestinal disease; Histone; Enzyme; Rodentia; Malignant tumor; Feeding; Colonic disease; Epithelial-mesenchymal transition; Vertebrata; Mammalia; Diet; Mouse; Food intake; High-fat diet: Histone deacetylase; Fat; Digestive diseases; Oxidoreductases; Cancer
• ISSN: 0955-2863; 1873-4847; 1873-4847
• DOI: 10.1016/j.jnutbio.2011.07.011

Epidemiologic studies suggest that intake of high-fat diet (HFD) promotes colon carcinogenesis. Epithelial–mesenchymal transition (EMT) and inflammation play important roles during tumor progression of colorectal cancer (CRC). Oncogenic pathways such as phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR and mitogen-activated protein kinase (MAPK)/ERK signaling cascades induce EMT and inflammation in cancer. No experimental evidence has been demonstrated regarding HFD-mediated tumor progression including EMT in CRC so far. Our results demonstrated that HFD consumption could induce tumor growth and progression, including EMT and inflammation, in a mouse xenograft tumor model. The molecular mechanisms were through activation of MAPK/ERK and PI3K/Akt/mTOR signaling pathways. HFD induced up-regulation of cyclooxygenase-2, cyclin D1 and proliferating cell nuclear antigen proteins concomitant with increases in expression of nuclear factor-κB p65 (RelA) and β-catenin proteins. Surprisingly, HFD consumption could suppress p21CIP1/WAF1 expression through increases in nuclear histone deacetylase complex (HDAC). Moreover, HFD could mediate the disassembly of E-cadherin adherent complex and the up-regulation of Vimentin and N-cadherin proteins in tumor tissues. Taken together, our novel findings support evidence for HFD-mediated modulation of HDAC activity and activation of oncogenic cascades, which involve EMT and inflammation in CRC, playing important roles in tumor growth and progression in a mouse xenograft model.