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

被引:51
作者
Liu, Tzu-An [1 ]
Jan, Yee-Jee [2 ]
Ko, Bor-Sheng [1 ,3 ]
Liang, Shu-Man [1 ]
Chen, Shyh-Chang [2 ]
Wang, John [2 ]
Hsu, Chiun [4 ]
Wu, Yao-Ming [5 ]
Liou, Jun-Yang [1 ,6 ]
机构
[1] Natl Hlth Res Inst, Inst Cellular & Syst Med, Zhunan, Taiwan
[2] Taichung Vet Gen Hosp, Dept Pathol & Lab Med, Taichung, Taiwan
[3] Natl Taiwan Univ Hosp, Dept Internal Med, Taipei 100, Taiwan
[4] Natl Taiwan Univ Hosp, Dept Oncol, Taipei, Taiwan
[5] Natl Taiwan Univ Hosp, Dept Surg, Taipei 100, Taiwan
[6] China Med Univ, Grad Inst Basic Med Sci, Taichung, Taiwan
关键词
ISOFORM-SPECIFIC EXPRESSION; TUMOR PROGRESSION; BREAST-CANCER; 14-3-3; PROTEINS; LUNG-CANCER; E-CADHERIN; EXTRAHEPATIC METASTASIS; DOWN-REGULATION; KAPPA-B; SNAIL;
D O I
10.1371/journal.pone.0057968
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];
摘要
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.
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页数:12
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