Consumption of high-fat diet induces tumor progression and epithelial-mesenchymal transition of colorectal cancer in a mouse xenograft model.
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 p21(CIP1/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.
Department of Nutrition, Biomedical Science Laboratory, China Medical University, Taichung 40402, Taiwan. vincenttang@mail.cmu.edu.tw
Feng-Yao
FY
Tang
Man-Hui
MH
Pai
En-Pei Isabel
EP
Chiang
D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000473:pathology*; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects*; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D015854:Up-Regulation; D014746:Vimentin / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
C495267:CTNNB1 protein, mouse; D015820:Cadherins; C530105:Ccnd1 protein, mouse; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016328:NF-kappa B; D014746:Vimentin; D051176:beta Catenin; D019938:Cyclin D1; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C546843:mTOR protein, mouse; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases