Wang Yuqin, Fukuda Tomohiko, Isaji Tomoya, Lu Jishun, Im Sanghun, Hang Qinglei, Gu Wei, Hou Sicong, Ohtsubo Kazuaki, Gu Jianguo
*Division of Regulatory Glycobiology, Tohoku Pharmaceutical University, Sendai, Miyagi, Japan; and Department of Analytical Biochemistry, Faculty of Life Sciences, Kumamoto University, Japan.
*Division of Regulatory Glycobiology, Tohoku Pharmaceutical University, Sendai, Miyagi, Japan; and Department of Analytical Biochemistry, Faculty of Life Sciences, Kumamoto University, Japan
FASEB J. 2015 Aug;29(8):3217-27. doi: 10.1096/fj.15-270710. Epub 2015 Apr 14.
Up-regulation of core fucosylation catalyzed by α1,6-fucosyltransferase (Fut8) has been observed in hepatocellular carcinoma (HCC). Here, to explore the role of Fut8 expression in hepatocarcinogensis, we established the chemical-induced HCC models in the male wild-type (WT; Fut8(+/+)), hetero (Fut8(+/-)), and knockout (KO; Fut8(-/-)) mice by use of diethylnitrosamine (DEN) and pentobarbital (PB). In the Fut8(+/+) and Fut8(+/-) mice, multiple large and vascularized nodules were induced with an increased expression of Fut8 after DEN and PB treatment. However, the formation of HCC in Fut8(-/-) mice was suppressed almost completely. This potent inhibitory effect of Fut8 deficiency on tumorigenesis was also confirmed by the abolished tumor formation of Fut8 KO human hepatoma cell line cells by use of a xenograft tumor model. Furthermore, loss of the Fut8 gene resulted in attenuated responses to epidermal growth factor (EGF) and hepatocyte growth factor (HGF) in the HepG2 cell line, which provides the possible mechanisms for the contribution of Fut8 to hepatocarcinogensis. Taken together, our study clearly demonstrated that core fucosylation acts as a critical functional modulator in the liver and implicated Fut8 as a prognostic marker, as well as a novel, therapeutic target for HCC.
在肝细胞癌（HCC）中已观察到由α1,6-岩藻糖基转移酶（Fut8）催化的核心岩藻糖基化上调。在此，为了探究Fut8表达在肝癌发生中的作用，我们通过使用二乙基亚硝胺（DEN）和戊巴比妥（PB）在雄性野生型（WT；Fut8(+/+)）、杂合子（Fut8(+/-)）和敲除（KO；Fut8(-/-)）小鼠中建立了化学诱导的HCC模型。在Fut8(+/+)和Fut8(+/-)小鼠中，DEN和PB处理后诱导出多个大的、有血管的结节，且Fut8表达增加。然而，Fut8(-/-)小鼠中HCC的形成几乎完全受到抑制。通过使用异种移植肿瘤模型，Fut8基因敲除的人肝癌细胞系细胞无法形成肿瘤，这也证实了Fut8缺陷对肿瘤发生的这种强大抑制作用。此外，Fut8基因的缺失导致HepG2细胞系对表皮生长因子（EGF）和肝细胞生长因子（HGF）的反应减弱，这为Fut8在肝癌发生中的作用提供了可能的机制。综上所述，我们的研究清楚地表明核心岩藻糖基化在肝脏中起关键的功能调节作用，并表明Fut8作为一种预后标志物以及HCC的新型治疗靶点。
