Folate deficient tumor microenvironment promotes epithelial-to-mesenchymal transition and cancer stem-like phenotypes
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Yen-Hao Su1,*, Wen-Chien Huang2,3,*, Tse-Hung Huang4,5, Yan-Jiun Huang6,11, Yu-Kai Sue7, Thanh-Tuan Huynh8, Michael Hsiao9, Tsan-Zon Liu10, Alexander TH Wu11, Chien-Min Lin7,12
1Department of Surgery, Division of General Surgery, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan
2Institute of Traditional Medicine, School of Medicine, National Yang Ming University, Taipei, Taiwan
3Department of Thoracic Surgery, Mackay Memorial Hospital, Taipei, Taiwan
4Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan
5Graduate Institute of Clinical Medicine Sciences, Chang Gung University, Taoyuan, Taiwan
6Department of Surgery, Division of General Surgery, Taipei Medical University Hospital, Taipei, Taiwan
7Department of Neurosurgery, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan
8Center for Molecular Biomedicine, University of Medicine and Pharmacy, HoChiMinh City, Viet Nam
9Genomics Research Center, Academia Sinica, Nankang, Taipei, Taiwan
10Translational Research Laboratory, Cancer Center, Taipei Medical University and Hospital, Taipei, Taiwan
11The Ph.D. Program for Translational Medicine, College of Science and Technology, Taipei Medical University, Taipei, Taiwan
12Department of Neurology, School of Medicine, College of Medicine, Taipei Medical University
*These authors have Contributed equally to this work
Chien-Min Lin, e-mail: [email protected]
Alexander TH Wu, e-mail: [email protected]
Keywords: folate deficiency, oxidative/nitrosative stress, epithelial-mesenchymal transition, cancer stem-like cells, miR-22
Received: September 29, 2015 Accepted: March 28, 2016 Published: April 22, 2016
Clinically, serum level of folate has been negatively correlated to the stage and progression of liver cancer. Nevertheless, the functional consequence of folate deficiency (FD) in malignancy has not been fully investigated. Human hepatocellular carcinoma (HCC) cells (as study model) and other cancer types such as lung and glioma were cultured under folate deficient (FD) and folate complete (FD) conditions. Molecular characterization including intracellular ROS/RNS (reactive oxygen/nitrogen species), viability, colony formation, cancer stem-like cell (CSC) phenotype analyses were performed. In vivo tumorigenesis under FD and FC conditions were also examined. FD induced a significant increase in ROS and RNS, suppressing proliferative ability but inducing metastatic potential. Mesenchymal markers such as Snail, ZEB2, and Vimentin were significantly up-regulated while E-cadherin down-regulated. Importantly, CSC markers such as Oct4, β-catenin, CD133 were induced while PRRX1 decreased under FD condition. Furthermore, FD-conditioned HCC cells showed a decreased miR-22 level, leading to the increased expression of its target genes including HDAC4, ZEB2 and Oct4. Finally, xenograft mouse model demonstrated that FD diet promoted tumorigenesis and metastasis as compared to their FC counterparts. Our data provides rationales for the consideration of folate supplement as a metastasis preventive measure.
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