title: 14-3-3ε overexpression contributes to epithelial-mesenchymal transition of hepatocellular carcinoma.
abstract: BACKGROUND
  14-3-3ε is implicated in regulating tumor progression, including hepatocellular carcinoma (HCC). Our earlier study indicated that elevated 14-3-3ε expression is significantly associated with higher risk of metastasis and lower survival rates of HCC patients. However, the molecular mechanisms of how 14-3-3ε regulates HCC tumor metastasis are still unclear.
  
  
  RESULTS
  In this study, we show that increased 14-3-3ε expression induces HCC cell migration and promotes epithelial-mesenchymal transition (EMT), which is determined by the reduction of E-cadherin expression and induction of N-cadherin and vimentin expression. Knockdown with specific siRNA abolished 14-3-3ε-induced cell migration and EMT. Furthermore, 14-3-3ε selectively induced Zeb-1 and Snail expression, and 14-3-3ε-induced cell migration was abrogated by Zeb-1 or Snail siRNA. In addition, the effect of 14-3-3ε-reduced E-cadherin was specifically restored by Zeb-1 siRNA. Positive 14-3-3ε expression was significantly correlated with negative E-cadherin expression, as determined by immunohistochemistry analysis in HCC tumors. Analysis of 14-3-3ε/E-cadherin expression associated with clinicopathological characteristics revealed that the combination of positive 14-3-3ε and negative E-cadherin expression is significantly correlated with higher incidence of HCC metastasis and poor 5-year overall survival. In contrast, patients with positive 14-3-3ε and positive E-cadherin expression had better prognostic outcomes than did those with negative E-cadherin expression.
  
  
  CONCLUSIONS
  Our findings show for the first time that E-cadherin is one of the downstream targets of 14-3-3ε in modulating HCC tumor progression. Thus, 14-3-3ε may act as an important regulator in modulating tumor metastasis by promoting EMT as well as cell migration, and it may serve as a novel prognostic biomarker or therapeutic target for HCC.
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Tzu-An
authors.initials: TA
authors.lastname: Liu
authors.forename: Yee-Jee
authors.initials: YJ
authors.lastname: Jan
authors.forename: Bor-Sheng
authors.initials: BS
authors.lastname: Ko
authors.forename: Shu-Man
authors.initials: SM
authors.lastname: Liang
authors.forename: Shyh-Chang
authors.initials: SC
authors.lastname: Chen
authors.forename: John
authors.initials: J
authors.lastname: Wang
authors.forename: Chiun
authors.initials: C
authors.lastname: Hsu
authors.forename: Yao-Ming
authors.initials: YM
authors.lastname: Wu
authors.forename: Jun-Yang
authors.initials: JY
authors.lastname: Liou
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D048948:14-3-3 Proteins; D015820:Cadherins; D018398:Homeodomain Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C482983:YWHAE protein, human; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1