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

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

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)33246-33256
Number of pages11
JournalOncotarget
Volume7
Issue number22
DOIs
Publication statusPublished - May 31 2016

Fingerprint

Epithelial-Mesenchymal Transition
Tumor Microenvironment
Folic Acid
Phenotype
Neoplasms
Neoplastic Stem Cells
Hepatocellular Carcinoma
Carcinogenesis
Neoplasm Metastasis
Reactive Nitrogen Species
Catenins
Vimentin
Cadherins
Liver Neoplasms
Heterografts
Glioma
Reactive Oxygen Species
Diet

Keywords

  • Cancer stem-like cells
  • Epithelial-mesenchymal transition
  • Folate deficiency
  • MiR-22
  • Oxidative/nitrosative stress

ASJC Scopus subject areas

  • Oncology

Cite this

Folate deficient tumor microenvironment promotes epithelial-to-mesenchymal transition and cancer stem-like phenotypes. / Su, Yen-Hao; Huang, Wen Chien; Huang, Hung Tse; Huang, Yan Jiun; Sue, Yu-Kai; Huynh, Thanh Tuan; Hsiao, Michael; Liu, Tsan Zon; Wu, TH Alexander; Lin, Chien-Min.

In: Oncotarget, Vol. 7, No. 22, 31.05.2016, p. 33246-33256.

Research output: Contribution to journalArticle

Su, Yen-Hao ; Huang, Wen Chien ; Huang, Hung Tse ; Huang, Yan Jiun ; Sue, Yu-Kai ; Huynh, Thanh Tuan ; Hsiao, Michael ; Liu, Tsan Zon ; Wu, TH Alexander ; Lin, Chien-Min. / Folate deficient tumor microenvironment promotes epithelial-to-mesenchymal transition and cancer stem-like phenotypes. In: Oncotarget. 2016 ; Vol. 7, No. 22. pp. 33246-33256.
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