Oncotarget

Research Papers:

This article has been corrected. Correction in: Oncotarget. 2018; 9:35026.

Regulation of Aldo-keto-reductase family 1 B10 by 14-3-3ε and their prognostic impact of hepatocellular carcinoma

Tzu-An Liu _, Yee-Jee Jan, Bor-Sheng Ko, Yi-Ju Wu, Yi-Jhu Lu, Shu-Man Liang, Chia-Chia Liu, Shyh-Chang Chen, John Wang, Song-Kun Shyue and Jun-Yang Liou

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Oncotarget. 2015; 6:38967-38982. https://doi.org/10.18632/oncotarget.5734

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Abstract

Tzu-An Liu1,*, Yee-Jee Jan2,*, Bor-Sheng Ko3,*, Yi-Ju Wu1,4,*, Yi-Jhu Lu1, Shu-Man Liang1, Chia-Chia Liu1, Shyh-Chang Chen2, John Wang2, Song-Kun Shyue5, Jun-Yang Liou1,6

1Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan 350, Taiwan

2Department of Pathology and Laboratory Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan

3Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan

4Institute of Molecular Medicine, National Tsing Hua University, Hsinchu 300, Taiwan

5Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan

6Graduate Institute of Basic Medical Science, China Medical University, Taichung 404, Taiwan

*These authors contributed equally to this work

Correspondence to:

Jun-Yang Liou, e-mail: jliou@nhri.org.tw

Keywords: 14-3-3ε, AKR1B10, β-catenin, hepatocellular carcinoma

Received: May 15, 2015     Accepted: October 09, 2015     Published: October 19, 2015

ABSTRACT

14-3-3ε is overexpressed in hepatocellular carcinoma (HCC) and its expression significantly associates with a poor prognostic outcome. To uncover how 14-3-3ε contributes to the tumor progression of HCC, we investigated the potential downstream targets regulated by 14-3-3ε. We found that 14-3-3ε increases expression and nuclear translocation of β-catenin and that 14-3-3ε-induced cell proliferation is attenuated by β-catenin silencing in HCC cells. Moreover, 14-3-3ε induces aldo-keto reductase family 1 member B10 (AKR1B10) expression through the activation of β-catenin signaling. Knockdown of AKR1B10 by siRNAs abolished 14-3-3ε-induced in vitro cell proliferation, anchorage-independent growth as well as in vivo tumor growth. Furthermore, AKR1B10 silencing increased retinoic acid (RA) levels in the serum of tumor-bearing mice and RA treatment attenuated 14-3-3ε-induced HCC cell proliferation. We further examined 14-3-3ε and AKR1B10 expression and clinicopathological characteristics of HCC tumors. Although the expression of AKR1B10 was significantly correlated with 14-3-3ε, an increase of AKR1B10 expression in 14-3-3ε positive patients paradoxically had better overall survival and disease-free survival rates as well as lower metastatic incidence than those without an AKR1B10 increase. Finally, we found a loss of AKR1B10 expression in cells exhibiting a high capacity of invasiveness. Silencing of AKR1B10 resulted in inducing snail and vimentin expression in HCC cells. These results indicate that AKR1B10 may play a dual role during HCC tumor progression. Our results also indicate that 14-3-3ε regulates AKR1B10 expression by activating β-catenin signaling. A combination of 14-3-3ε with AKR1B10 is a potential therapeutic target and novel prognostic biomarker of HCC.


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