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

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

SUBMITTER: Liu TA 

PROVIDER: S-EPMC4770750 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature