Abstract
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.
Highlights
Hepatocellular carcinoma (HCC) is the main subtype among all primary liver cancers, accounting for 70–85% of the known liver cancers worldwide [1]
We showed that histidine-rich glycoprotein (HRG) was downregulated in the process of neoplastic transformation of Hepatic oval cells (HOCs) (WB-F344 cells)
We validated that HRG was downregulated in a transformation model by western blot analysis and quantitative real-time PCR (Fig. 1B and 1C), as well as in 31 paired human HCC tissues and tumor surrounding liver tissues by western blotting
Summary
Hepatocellular carcinoma (HCC) is the main subtype among all primary liver cancers, accounting for 70–85% of the known liver cancers worldwide [1]. By quantitative proteomic analysis, we identified and validated the differential expression of HRG in neoplastic transformation of WB-F344 cells. Overexpressed HRG inhibited HCC cell proliferation through the FGF-Erk1/2 pathway, and the glycosylated status of N-terminal domains of HRG was essential for its protein function.
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