7531

YWHAE

tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, epsilon;YWHAE;tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, epsilon

14-3-3 epsilon|14-3-3 protein epsilon|epididymis luminal protein 2|mitochondrial import stimulation factor L subunit|protein kinase C inhibitor protein-1|tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, epsilon polypeptide|tyrosine

17p13.3

protein-coding

AIMS: The results of our earlier studies suggested that 14-3-3epsilon is involved in cancer cell survival and growth. However, it is not clear whether 14-3-3epsilon plays a role in tumour metastasis and patient outcome. The aim of this study was to determine whether 14-3-3epsilon is a marker for predicting hepatocellular carcinoma (HCC) metastasis and survival. METHODS AND RESULTS: One hundred and fourteen patients with tissue-diagnosed primary HCC were followed for an average of 58.6 months. 14-3-3epsilon in liver tissues was analysed by immunohistochemistry, and quantified by a Quick score system. Correlation of 14-3-3epsilon with patient survival and metastasis was analysed with a Wilcoxon signed rank test, Kaplan-Meier survival curves, and Cox proportional hazard regression. Seventy-one of 114 patients (62.3%) had a significant increase of 14-3-3epsilon expression in HCC tissues, whereas normal tissues expressed weak or undetectable 14-3-3epsilon. Elevated 14-3-3epsilon expression was significantly associated with shortened overall survival and progression-free survival. Furthermore, 14-3-3epsilon overexpression increased the risk of metastasis 4.6-fold. CONCLUSIONS: Overexpression of 14-3-3epsilon in primary HCC tissues predicts a high risk of extrahepatic metastasis and worse survival, and is a potential therapeutic target.

BACKGROUND: 14-3-3epsilon is implicated in regulating tumor progression, including hepatocellular carcinoma (HCC). Our earlier study indicated that elevated 14-3-3epsilon expression is significantly associated with higher risk of metastasis and lower survival rates of HCC patients. However, the molecular mechanisms of how 14-3-3epsilon regulates HCC tumor metastasis are still unclear. METHODOLOGY AND PRINCIPAL FINDINGS: In this study, we show that increased 14-3-3epsilon 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 14-3-3epsilon-induced cell migration and EMT. Furthermore, 14-3-3epsilon selectively induced Zeb-1 and Snail expression, and 14-3-3epsilon-induced cell migration was abrogated by Zeb-1 or Snail siRNA. In addition, the effect of 14-3-3epsilon-reduced E-cadherin was specifically restored by Zeb-1 siRNA. Positive 14-3-3epsilon expression was significantly correlated with negative E-cadherin expression, as determined by immunohistochemistry analysis in HCC tumors. Analysis of 14-3-3epsilon/E-cadherin expression associated with clinicopathological characteristics revealed that the combination of positive 14-3-3epsilon 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 14-3-3epsilon 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 14-3-3epsilon in modulating HCC tumor progression. Thus, 14-3-3epsilon 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.