title: 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.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan 350, Taiwan.
authors.forename: Tzu-An
authors.initials: TA
authors.lastname: Liu
authors.affiliation: Department of Pathology and Laboratory Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan.
authors.forename: Yee-Jee
authors.initials: YJ
authors.lastname: Jan
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan.
authors.forename: Bor-Sheng
authors.initials: BS
authors.lastname: Ko
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan 350, Taiwan.|Institute of Molecular Medicine, National Tsing Hua University, Hsinchu 300, Taiwan.
authors.forename: Yi-Ju
authors.initials: YJ
authors.lastname: Wu
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan 350, Taiwan.
authors.forename: Yi-Jhu
authors.initials: YJ
authors.lastname: Lu
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan 350, Taiwan.
authors.forename: Shu-Man
authors.initials: SM
authors.lastname: Liang
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan 350, Taiwan.
authors.forename: Chia-Chia
authors.initials: CC
authors.lastname: Liu
authors.affiliation: Department of Pathology and Laboratory Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan.
authors.forename: Shyh-Chang
authors.initials: SC
authors.lastname: Chen
authors.affiliation: Department of Pathology and Laboratory Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan.
authors.forename: John
authors.initials: J
authors.lastname: Wang
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Song-Kun
authors.initials: SK
authors.lastname: Shyue
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan 350, Taiwan.|Graduate Institute of Basic Medical Science, China Medical University, Taichung 404, Taiwan.
authors.forename: Jun-Yang
authors.initials: JY
authors.lastname: Liou
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D011379:Prognosis; D015398:Signal Transduction
chemical_list: D048948:14-3-3 Proteins
keywords: 14-3-3ε; AKR1B10; hepatocellular carcinoma; β-catenin