Histidine-rich glycoprotein function in hepatocellular carcinoma depends on its N-glycosylation status, and it regulates cell proliferation by inhibiting Erk1/2 phosphorylation.
Histidine-rich glycoprotein function in hepatocellular carcinoma depends on its N-glycosylation status, and it regulates cell proliferation by inhibiting Erk1/2 phosphorylation.
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DOI：
10.18632/oncotarget.4997
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发表时间：
2015-10-06
期刊：
影响因子：
--
通讯作者：
Liu Y
中科院分区：
文献类型：
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作者：
Zhang Q;Jiang K;Li Y;Gao D;Sun L;Zhang S;Liu T;Guo K;Liu Y
肝细胞癌（HCC）是癌症死亡的第三大常见原因。通过iTRAQ标记和2DLC-ESI-MS/MS分析，筛选出WB F344肝卵圆样细胞肿瘤转化动态阶段（WB、WB 7和WB 11）中显著下调的富组氨酸糖蛋白（HRG）。HRG在肝癌组织中的表达明显降低。HRG在Huh 7和MHCC-97 H肝癌细胞系中的过表达导致细胞增殖、集落形成能力和肿瘤生长的降低，以及细胞凋亡的增加。HRG可通过降低Erk 1/2磷酸化水平，通过FGF-Erk 1/2信号通路抑制细胞增殖。另一方面，HRG的功能表达也依赖于其N-末端的糖基化状态，特别是在糖基化位点Asn 125。HRG的糖基化可能在HRG与硫酸肝素结合bFGF和激活FGF受体的相互作用中起关键的竞争作用。这些发现为深入了解HRG在HCC中的分子机制提供了新的见解。
Hepatocellular carcinoma (HCC) is the third most common cause of cancer mortality. Significantly downregulated histidine-rich glycoprotein (HRG) during the dynamic stages (WB, WB7, and WB11) of neoplastic transformation of WB F344 hepatic oval-like cells was screened out by iTRAQ labeling followed by 2DLC-ESI-MS/MS analysis. HRG expression was significantly lower in HCC tissues. HRG overexpression in Huh7 and MHCC-97H hepatoma cell lines led to decreased cell proliferation, colony-forming ability, and tumor growth, and increased cell apoptosis. HRG could inhibit cell proliferation via the FGF-Erk1/2 signaling pathway by reducing Erk1/2 phosphorylation. On the other hand, the functional expression of HRG was also dependent on the glycosylation status at its N-terminal, especially at the glycosylation site Asn 125. The glycosylation of HRG may play a key competitive role in the interaction between HRG and heparin sulfate for binding bFGF and activating the FGF receptor. These findings provide novel insights into the molecular mechanism of HRG in HCC.