The 14-3-3 proteins are highly conserved molecules that are involved in many vital biologic processes and are associated with the progression of cancer. The role of 14-3-3 zeta, a dimeric isoform of 14-3-3, in intrahepatic cholangiocarcinoma (ICC) was investigated in this study. The expression of 14-3-3 zeta in tumour samples from patients with ICC was examined by Western blot and immunohistochemistry, and the correlation between its expression and various clinicopathological features was determined. Then, the capacity for invasion, migration and proliferation as well as the expression of epithelial-mesenchymal transition (EMT)-related markers in ICC cells were assessed after 14-3-3 zeta depletion. Finally, the prognostic significance of 14-3-3 zeta in patients with ICC was further evaluated by Kaplan-Meier and Cox regression analyses. The expression of 14-3-3 zeta was significantly higher in ICC tissues compared to peritumoural tissues. High expression of 14-3-3 zeta positively correlated with lymphatic metastasis and tumour-node-metastasis (TNM) stage. The inhibition of 14-3-3 zeta expression was able to impair the invasion, migration and proliferation of ICC cells in vitro. The expression of 14-3-3 zeta was significantly correlated with the expression of the EMT-related markers snail and E-cadherin in ICC samples. Moreover, the down-regulation of 14-3-3 zeta also decreased the phosphorylation of extracellular signal-regulated kinase (ERK) in ICC cells. Clinically, patients with ICC with high 14-3-3 zeta expression demonstrated a poor prognosis in terms of a short overall survival and a high recurrence rate of the disease. A multivariate analysis revealed that 14-3-3 zeta overexpression was an independent prognostic indicator for patients with ICC. 14-3-3 zeta may enhance the invasive and proliferative capacity of tumour cells and thus prompt the progression of ICC via the activation of ERK signalling and the induction of EMT. The overexpression of 14-3-3 zeta may be used as a prognostic biomarker and therapeutic target in patients with ICC.
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