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.
Highlights
The 14-3-3 protein family comprises seven isoforms (β, ε, γ, η, σ, τ/θ, and ζ) in all mammals and is implicated in regulating multiple cellular and physiological functions [1,2,3]. 14-3-3 proteins are involved in regulating tumor progression of various malignancies [4,5,6,7,8,9]
We discovered that aldo-keto reductase family 1 member B10 (AKR1B10) is regulated by 14-3-3ε/β-catenin signaling and that AKR1B10 contributes to 14-3-3ε-induced hepatocellular carcinoma (HCC) cell proliferation and tumor growth
We studied whether 14-3-3ε-induced AKR1B10 expression is involved in regulating HCC cell proliferation and tumor growth
Summary
The 14-3-3 protein family comprises seven isoforms (β, ε, γ, η, σ, τ/θ, and ζ) in all mammals and is implicated in regulating multiple cellular and physiological functions [1,2,3]. 14-3-3 proteins are involved in regulating tumor progression of various malignancies [4,5,6,7,8,9]. Some 14-3-3 isoforms, including 14-3-3β, 14-3-3ε, 14-3-3γ, 14-3-3σ and 14-3-3ζ, are overexpressed and associated with poor prognosis and tumor progression in HCC [10,11,12,13,14,15,16]. The expression of AKR1B10 is increased in primary HCC tumors, several studies indicate that AKR1B10 is paradoxically correlated with the less aggressive and well-differentiated HCC tumors [23, 31,32,33] These results suggest that decreased expression of AKR1B10 is associated with the more advanced and malignant HCC. Silencing of AKR1B10 induces the expression of snail and vimentin in HCC cells This suggests that AKR1B10 may play a dual role during HCC tumor progression. 14-3-3ε and AKR1B10 are potential prognostic markers and therapeutic targets of HCC
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