14-3-3ε Overexpression Contributes to Epithelial-Mesenchymal Transition of Hepatocellular Carcinoma

Background: 14-3-3 epsilon is implicated in regulating tumor progression, including hepatocellular carcinoma (HCC). Our earlier study indicated that elevated 14-3-3 epsilon expression is significantly associated with higher risk of metastasis and lower survival rates of HCC patients. However, the molecular mechanisms of how 14-3-3 epsilon regulates HCC tumor metastasis are still unclear. Methodology and Principal Findings: In this study, we show that increased 14-3-3 epsilon 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 14-3-3 epsilon-induced cell migration and EMT. Furthermore, 14-3-3 epsilon selectively induced Zeb-1 and Snail expression, and 14-3-3 epsilon-induced cell migration was abrogated by Zeb-1 or Snail siRNA. In addition, the effect of 14-3-3 epsilon-reduced E-cadherin was specifically restored by Zeb-1 siRNA. Positive 14-3-3 epsilon expression was significantly correlated with negative E-cadherin expression, as determined by immunohistochemistry analysis in HCC tumors. Analysis of 14-3-3 epsilon/E-cadherin expression associated with clinicopathological characteristics revealed that the combination of positive 14-3-3 epsilon 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 14-3-3 epsilon and positive E-cadherin expression had better prognostic outcomes than did those with negative E-cadherin expression. Significance: Our findings show for the first time that E-cadherin is one of the downstream targets of 14-3-3 epsilon in modulating HCC tumor progression. Thus, 14-3-3 epsilon 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.