Loss of α1,6-fucosyltransferase inhibits chemical-induced hepatocellular carcinoma and tumorigenesis by down-regulating several cell signaling pathways
Loss of α1,6-fucosyltransferase inhibits chemical-induced hepatocellular carcinoma and tumorigenesis by down-regulating several cell signaling pathways
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DOI：
10.1096/fj.15-270710
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发表时间：
2015-08-01
期刊：
影响因子：
4.8
通讯作者：
Gu, Jianguo
中科院分区：
文献类型：
--
作者：
Wang, Yuqin;Fukuda, Tomohiko;Gu, Jianguo
在肝细胞癌（HCC）中观察到α 1，6-岩藻糖基转移酶（Fut 8）催化的核心岩藻糖基化上调。为了探讨Fut 8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; Fut 8（+/+））、异源（Fut 8（+/-））和敲除（KO; Fut 8（-/-））小鼠中建立了化学诱导的HCC模型。在Fut 8（+/+）和Fut 8（+/-）小鼠中，在DEN和PB处理后，诱导了多个大的和血管化的结节，并且Fut 8的表达增加。然而，在Fut 8（-/-）小鼠中HCC的形成几乎被完全抑制。Fut 8缺陷对肿瘤发生的这种有效抑制作用也通过使用异种移植肿瘤模型消除Fut 8 KO人肝癌细胞系细胞的肿瘤形成来证实。此外，Fut 8基因的缺失导致HepG 2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Fut 8参与肝癌发生提供了可能的机制。总之，我们的研究清楚地表明，核心岩藻糖基化在肝脏中起着关键的功能调节剂的作用，并涉及Fut 8作为预后标志物，以及HCC的新的治疗靶点。
Up-regulation of core fucosylation catalyzed by alpha 1,6-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 wildtype (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.