Folate deficient tumor microenvironment promotes epithelial-to-mesenchymal transition and cancer stem-like phenotypes
| Autor: | Yu Kai Sue, Chien Min Lin, Tsan Zon Liu, Michael Hsiao, Tse-Hung Huang, Wen Chien Huang, Alexander T.H. Wu, Yan Jiun Huang, Thanh Tuan Huynh, Yen-Hao Su |
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| Rok vydání: | 2016 |
| Předmět: |
cancer stem-like cells
0301 basic medicine Oncology Gerontology Time Factors miR-22 Mice SCID Traditional Chinese medicine medicine.disease_cause folate deficiency Metastasis 0302 clinical medicine Mice Inbred NOD Neoplasms Tumor Microenvironment Reactive Nitrogen Species Gene Expression Regulation Neoplastic Phenotype Nitrosative Stress 030220 oncology & carcinogenesis Hepatocellular carcinoma Neoplastic Stem Cells Liver cancer Research Paper oxidative/nitrosative stress Signal Transduction medicine.medical_specialty Epithelial-Mesenchymal Transition Cell Survival Translational research Folic Acid Deficiency 03 medical and health sciences Folic Acid Cell Line Tumor Internal medicine medicine Animals Humans Epithelial–mesenchymal transition Cell Proliferation business.industry Cancer medicine.disease MicroRNAs Oxidative Stress 030104 developmental biology Reactive Oxygen Species business Carcinogenesis |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Yen-Hao Su 1, * , Wen-Chien Huang 2, 3, * , Tse-Hung Huang 4, 5 , Yan-Jiun Huang 6, 11 , Yu-Kai Sue 7 , Thanh-Tuan Huynh 8 , Michael Hsiao 9 , Tsan-Zon Liu 10 , Alexander TH Wu 11 , Chien-Min Lin 7, 12 1 Department of Surgery, Division of General Surgery, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan 2 Institute of Traditional Medicine, School of Medicine, National Yang Ming University, Taipei, Taiwan 3 Department of Thoracic Surgery, Mackay Memorial Hospital, Taipei, Taiwan 4 Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan 5 Graduate Institute of Clinical Medicine Sciences, Chang Gung University, Taoyuan, Taiwan 6 Department of Surgery, Division of General Surgery, Taipei Medical University Hospital, Taipei, Taiwan 7 Department of Neurosurgery, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan 8 Center for Molecular Biomedicine, University of Medicine and Pharmacy, HoChiMinh City, Viet Nam 9 Genomics Research Center, Academia Sinica, Nankang, Taipei, Taiwan 10 Translational Research Laboratory, Cancer Center, Taipei Medical University and Hospital, Taipei, Taiwan 11 The Ph.D. Program for Translational Medicine, College of Science and Technology, Taipei Medical University, Taipei, Taiwan 12 Department of Neurology, School of Medicine, College of Medicine, Taipei Medical University * These authors have Contributed equally to this work Correspondence to: Chien-Min Lin, e-mail: m513092004@s.tmu.edu.tw Alexander TH Wu, e-mail: chaw1211@tmu.edu.tw 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 ABSTRACT 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. |
| Databáze: | OpenAIRE |
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