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

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.

• Authors: 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, Jun-Yang Liou
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 36 Pg. 38967-82 (Nov 17 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26516929 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 14-3-3 Proteins

Topics

• 14-3-3 Proteins (genetics, metabolism)
• Carcinoma, Hepatocellular (enzymology, genetics, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation (physiology)
• Female
• Humans
• Liver Neoplasms (enzymology, genetics, metabolism, pathology)
• Male
• Prognosis
• Signal Transduction