Abstract
Background14-3-3ε 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.Methodology and Principal FindingsIn 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.SignificanceOur 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.
Highlights
Epithelial-mesenchymal transition (EMT), a developmental process by which epithelial cells reduce cell-cell adhesion and lose apical-basal cell polarity, plays a critical role in the embryogenesis and conversion of early stage tumors into aggressive malignancies [1,2,3]
We previously demonstrated that 14-3-3e expression is increased in primary and metastatic hepatocellular carcinoma (HCC)
Elevated 14-3-3e expression is correlated with higher risk of extrahepatic metastasis and lower survival rates of HCC patients [30]
Summary
Epithelial-mesenchymal transition (EMT), a developmental process by which epithelial cells reduce cell-cell adhesion and lose apical-basal cell polarity, plays a critical role in the embryogenesis and conversion of early stage tumors into aggressive malignancies [1,2,3]. EMT promotes multiple physiological processes that increase the invasiveness and metastasis potentials of human tumors [1,2,3]. Increased Zeb-1, Snail, SIP1, and Twist expressions are reportedly associated with the clinicopathological significances of HCC malignant progression, including cancer invasion and poor patient survival [12,13,14,15,16]. 14-3-3e Promotes EMT and Suppresses E-cadherin multiple cellular processes, including cell cycle regulation, DNA repair, apoptosis, cell adhesion, and motility [17,18]. Enhanced expression of 14-3-3e was suggested to induce and be associated with focal adhesion kinase (FAK) expression via activation of NFkB signaling [35] These results implied that 14-3-3e was involved in the modulation of cell polarization and migration, which may potentially regulate HCC tumor development and metastasis. Our results reveal that E-cadherin is a downstream modulator for 14-3-3e during HCC tumor progression
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