Mucin Glycosylating Enzyme GALNT2 Regulates the Malignant Character of Hepatocellular Carcinoma by Modifying the EGF Receptor
Mucin Glycosylating Enzyme GALNT2 Regulates the Malignant Character of Hepatocellular Carcinoma by Modifying the EGF Receptor
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DOI：
10.1158/0008-5472.can-11-1161
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发表时间：
2011-12-01
期刊：
影响因子：
11.2
通讯作者：
Huang, Min-Chuan
中科院分区：
文献类型：
--
作者：
Wu, Yao-Ming;Liu, Chiung-Hui;Huang, Min-Chuan
细胞外糖基化是恶性特征的关键决定因素。在这里，我们报告说，N-乙酰氨基半乳糖转移酶2（GALNT 2），酶介导的粘蛋白O型糖基化的初始步骤，是一个关键的调解人的恶性性质，在肝细胞癌（HCC）的行为，通过修改的活性表皮生长因子受体（EGFR）。GALNT 2 mRNA和蛋白在HCC肿瘤中频繁下调，这些事件与血管浸润和复发相关。GALNT 2在HCC细胞中的恢复表达抑制EGF诱导的细胞生长、迁移和体内体外侵袭。机制研究显示，GALNT 2改变了与EGFR连接的O-聚糖的状态，改变了EGF结合后的EGFR反应。用厄洛替尼抑制EGFR活性降低了HCC细胞中siRNA介导的GALNT 2敲低引起的恶性特征，确立了EGFR在介导GALNT 2表达效应中的关键作用。总而言之，我们的结果表明GALNT 2失调导致了肝癌细胞的恶性行为，并且它们为O-糖基化在EGFR活性和肝癌发病机制中的重要性提供了新的见解。Cancer Res; 71（23）; 7270-9. (C)2011年AACR。
Extracellular glycosylation is a critical determinant of malignant character. Here, we report that N-acetylgalactosaminyltransferase 2 (GALNT2), the enzyme that mediates the initial step of mucin type-O glycosylation, is a critical mediator of malignant character in hepatocellular carcinoma (HCC) that acts by modifying the activity of the epidermal growth factor receptor (EGFR). GALNT2 mRNA and protein were downregulated frequently in HCC tumors where these events were associated with vascular invasion and recurrence. Restoring GALNT2 expression in HCC cells suppressed EGF-induced cell growth, migration, and invasion in vitro and in vivo. Mechanistic investigations revealed that the status of the O-glycans attached to the EGFR was altered by GALNT2, changing EGFR responses after EGF binding. Inhibiting EGFR activity with erlotinib decreased the malignant characters caused by siRNA-mediated knockdown of GALNT2 in HCC cells, establishing the critical role of EGFR in mediating the effects of GALNT2 expression. Taken together, our results suggest that GALNT2 dysregulation contributes to the malignant behavior of HCC cells, and they provide novel insights into the significance of O-glycosylation in EGFR activity and HCC pathogenesis. Cancer Res; 71(23); 7270-9. (C) 2011 AACR.