Research Papers:

Folate deficient tumor microenvironment promotes epithelial-to-mesenchymal transition and cancer stem-like phenotypes

Yen-Hao Su _, Wen-Chien Huang, Tse-Hung Huang, Yan-Jiun Huang, Yu-Kai Sue, Thanh-Tuan Huynh, Michael Hsiao, Tsan-Zon Liu, Alexander TH Wu and Chien-Min Lin

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Oncotarget. 2016; 7:33246-33256. https://doi.org/10.18632/oncotarget.8910

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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

Correspondence to:

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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