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Up-regulation of 14-3-3ζ expression in intrahepatic cholangiocarcinoma and its clinical implications

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Tumor Biology

Abstract

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 14-3-3ζ, a dimeric isoform of 14-3-3, in intrahepatic cholangiocarcinoma (ICC) was investigated in this study. The expression of 14-3-3ζ 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 14-3-3ζ depletion. Finally, the prognostic significance of 14-3-3ζ in patients with ICC was further evaluated by Kaplan–Meier and Cox regression analyses. The expression of 14-3-3ζ was significantly higher in ICC tissues compared to peritumoural tissues. High expression of 14-3-3ζ positively correlated with lymphatic metastasis and tumour–node–metastasis (TNM) stage. The inhibition of 14-3-3ζ expression was able to impair the invasion, migration and proliferation of ICC cells in vitro. The expression of 14-3-3ζ was significantly correlated with the expression of the EMT-related markers snail and E-cadherin in ICC samples. Moreover, the down-regulation of 14-3-3ζ also decreased the phosphorylation of extracellular signal-regulated kinase (ERK) in ICC cells. Clinically, patients with ICC with high 14-3-3ζ 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 14-3-3ζ overexpression was an independent prognostic indicator for patients with ICC. 14-3-3ζ 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 14-3-3ζ may be used as a prognostic biomarker and therapeutic target in patients with ICC.

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Acknowledgments

This study was supported by the National Key Sci-Tech Project (2012ZX10002011-002) the National Natural Science Foundation of China (81172023, 81071741 and 81030038), Shanghai Municipal Natural Science Foundation (14ZR1405800) and the Ph.D. Programs Foundation of the Ministry of Education of China (20110072120050).

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Authors and Affiliations

  1. Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China

    Chi Zhang, Zhao-Ru Dong, Guo-Ming Shi, Jia-Bin Cai, Peng-Fei Zhang, Ai-Wu Ke, Jing-Xian Yu, Jian Zhou & Jia Fan

  2. Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, 200032, People’s Republic of China

    Chi Zhang, Zhao-Ru Dong, Guo-Ming Shi, Jia-Bin Cai, Peng-Fei Zhang, Ai-Wu Ke, Jing-Xian Yu, Jian Zhou & Jia Fan

  3. Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical College, Kunming, 650101, People’s Republic of China

    Li-Xin Liu

  4. Cancer Center, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, People’s Republic of China

    Jia Fan

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  1. Chi Zhang
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  2. Li-Xin Liu
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  3. Zhao-Ru Dong
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  9. Jian Zhou
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  10. Jia Fan
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Correspondence to Jia Fan.

Additional information

Chi Zhang and Li-Xin Liu and Zhao-Ru Dong and Guo-Ming Shi contributed equally to this work. None of the material that appears in the article has been previously presented or published in any form.

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Zhang, C., Liu, LX., Dong, ZR. et al. Up-regulation of 14-3-3ζ expression in intrahepatic cholangiocarcinoma and its clinical implications. Tumor Biol. 36, 1781–1789 (2015). https://doi.org/10.1007/s13277-014-2780-5

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  • DOI: https://doi.org/10.1007/s13277-014-2780-5

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