14-3-3epsilon is overexpressed in hepatocellular carcinoma (HCC) and its expression significantly associates with a poor prognostic outcome. To uncover how 14-3-3epsilon contributes to the tumor progression of HCC, we investigated the potential downstream targets regulated by 14-3-3epsilon. We found that 14-3-3epsilon increases expression and nuclear translocation of beta-catenin and that 14-3-3epsilon-induced cell proliferation is attenuated by beta-catenin silencing in HCC cells. Moreover, 14-3-3epsilon induces aldo-keto reductase family 1 member B10 (AKR1B10) expression through the activation of beta-catenin signaling. Knockdown of AKR1B10 by siRNAs abolished 14-3-3epsilon-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 14-3-3epsilon-induced HCC cell proliferation. We further examined 14-3-3epsilon and AKR1B10 expression and clinicopathological characteristics of HCC tumors. Although the expression of AKR1B10 was significantly correlated with 14-3-3epsilon, an increase of AKR1B10 expression in 14-3-3epsilon 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 14-3-3epsilon regulates AKR1B10 expression by activating beta-catenin signaling. A combination of 14-3-3epsilon with AKR1B10 is a potential therapeutic target and novel prognostic biomarker of HCC.
