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.

Prognostic significance of AKR1B10 in patients with resected lung adenocarcinoma

“…The AKR1B10 gene encodes a member of the AKR superfamily . Human AKR1B10 is reported to be overexpressed in several human cancers, including lung and liver cancers . AKR1B10 is often overexpressed in male and smoking NSCLC patients, therefore AKR1B10 has been proposed as a diagnostic marker in smokers with NSCLC .…”

“…Liu et al . reported that increased AKR1B10 is a prognostic factor for better overall survival (OS) and less metastasis in patients with hepatic cellular carcinoma (HCC) . Yoshitake et al .…”

Prognostic value of aldo-keto reductase family 1 member B10 in solid tumors: a systematic review and meta-analysis

“…After full-text review, 12 articles were excluded. Eventually, we identi ed 11 articles published between 2014 and 2019, which were included in the nal analysis [5][6][7][8][9][10][11][12][13][14][15]. The ow diagram of the literature search is shown in Fig1.…”

“…Studies have shown that AKR1B10 is characterized by obvious carcinogenicity and can be used as a tumor marker [4]. Recently, an increasing number of studies showed that abnormal expression of AKR1B10 is signi cantly correlated with the prognosis of certain solid tumors [5][6][7][8][9][10][11][12][13][14][15]. However, the currently available results are inconsistent, and the prognostic value of AKR1B10 remains unclear.…”

Aldo-Keto Reductase Family 1 Member B10 Inhibitors: Potential Drugs for Cancer Treatment

“…AKR1B10 can convert highly reactive carbonyl groups to less toxic hydroxyl groups to protect cells from carbonyl toxic injury, although it also participates in the activation of procarcinogens [40]. AKR1B10 possesses high enzymatic activity to reduce retinaldehyde isomers, especially all-transretinaldehyde, to their corresponding retinols [5,6], resulting presumably in a decrease of the cellular levels of retinoic acid, a signal molecule involved in cell proliferation and differentiation [41][42][43][44]. AKR1B10 has been shown to promote cell growth and survival via modulating lipid synthesis and membrane function by hindering the degradation of acetyl-CoA carboxylase-(ACCA), a rate-limiting enzyme in fatty acid synthesis, through the ubiquitination-proteasome pathway [45,46].…”