Folate deficient tumor microenvironment promotes epithelial-to-mesenchymal transition and cancer stem-like phenotypes.
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.
Department of Surgery, Division of General Surgery, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan.
Yen-Hao
YH
Su
Institute of Traditional Medicine, School of Medicine, National Yang Ming University, Taipei, Taiwan.|Department of Thoracic Surgery, Mackay Memorial Hospital, Taipei, Taiwan.
Wen-Chien
WC
Huang
Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan.|Graduate Institute of Clinical Medicine Sciences, Chang Gung University, Taoyuan, Taiwan.
Tse-Hung
TH
Huang
Department of Surgery, Division of General Surgery, Taipei Medical University Hospital, Taipei, Taiwan.|The Ph.D. Program for Translational Medicine, College of Science and Technology, Taipei Medical University, Taipei, Taiwan.
Yan-Jiun
YJ
Huang
Department of Neurosurgery, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan.
Yu-Kai
YK
Sue
Center for Molecular Biomedicine, University of Medicine and Pharmacy, HoChiMinh City, Vietnam.
Thanh-Tuan
TT
Huynh
Genomics Research Center, Academia Sinica, Nankang, Taipei, Taiwan.
Michael
M
Hsiao
Translational Research Laboratory, Cancer Center, Taipei Medical University and Hospital, Taipei, Taiwan.
Tsan-Zon
TZ
Liu
The Ph.D. Program for Translational Medicine, College of Science and Technology, Taipei Medical University, Taipei, Taiwan.
Alexander Th
AT
Wu
Department of Neurosurgery, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan.|Department of Neurology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Chien-Min
CM
Lin
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D058750:Epithelial-Mesenchymal Transition; D005492:Folic Acid / Q000378:metabolism*; D005494:Folic Acid Deficiency / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D000073039:Nitrosative Stress; D018384:Oxidative Stress; D010641:Phenotype; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D059016:Tumor Microenvironment
C548375:MIRN22 microRNA, human; D035683:MicroRNAs; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D005492:Folic Acid
cancer stem-like cells; epithelial-mesenchymal transition; folate deficiency; miR-22; oxidative/nitrosative stress