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

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.

14-3-3σ Gene Loss Leads to Activation of the Epithelial to Mesenchymal Transition Due to the Stabilization of c-Jun Protein

“…These properties are accompanied by a decrease in cell-cell adhesion and an increase in invasion and migration, all properties of invasive tumor cells. In contrast, two reports have suggested that other 14-3-3 isoforms, particularly 14-3-3⑀, can form a complex with the EMT transcription factor snail (80) and that 14-3-3⑀ is over-expressed in hepatocellular carcinoma and it contributes to the acquisition of the EMT phenotype (81). Importantly, 14-3-3 did not form a complex with snail (80), which is consistent with our observations that it preserves the epithelial phenotype.…”

“…The two 14-3-3 isoforms affect EMT progression by targeting different components in the EMT pathway, 14-3-3 by inducing c-Jun degradation and therefore preventing expression of slug (this report) and 14-3-3⑀ by forming a complex with the EMT transcription factor snail and stimulating snail-dependent transcription (80). These results are also consistent with the observation that 14-3-3 expression is low in multiple tumor types (16 -24), whereas 14-3-3⑀ expression is associated with the acquisition of EMT in hepatocellular carcinoma (81). Therefore, these are two distinct molecular mechanisms, and they reflect the diversity of mechanisms by which the 14-3-3 protein family regulates cellular pathways.…”

Protein Modifications Regulate the Role of 14-3-3γ Adaptor Protein in cAMP-induced Steroidogenesis in MA-10 Leydig Cells

“…In addition, the outer surfaces of 14-3-3 isoforms are highly variable, and post-translational modifications (PTMs) 3 influence target/isoform specificity (for reviews, see Refs. [13][14][15][16][17][18][19]. Moreover, recent studies have indicated that 14-3-3 monomers are also functional (20); 14-3-3⑀-sv is a monomeric form of 14-3-3⑀ that lacks the exon encoding the N-terminal dimerization domain but remains functional and promotes cell survival similar to intact 14-3-3⑀ (21), and 14-3-3␥ S58N monomers interact with the scaffold protein kinase suppressor of Ras in the same manner as 14-3-3␥ dimers (22).…”

Overexpression of Nuclear Apoptosis-Inducing Factor 1 Altered the Proteomic Profile of Human Gastric Cancer Cell MKN45 and Induced Cell Cycle Arrest at G1/S Phase

“…Moreover, a histopathological study reported that in 114 hepatocellular carcinoma patients, elevated expression of 14-3-3ε was significantly associated with a high risk of metastasis and decreased survival rates [35]. Cellular experiments confirmed that increased 14-3-3ε expression induces hepatocellular carcinoma cell migration and promotes epithelial-mesenchymal transition (EMT) by inducing Zeb-1 and Snail expression [41]. To conclude, 14-3-3ε is a remarkable oncogene that participates in the development of several tumors and plays an important role in apoptosis and metastasis.…”