Abstract
BackgroundWe previously reported increased levels of protein-linked fucosylation with the development of liver cancer and identified many of the proteins containing the altered glycan structures. One such protein is alpha-1-antitrypsin (A1AT). To advance these studies, we performed N-linked glycan analysis on the five major isoforms of A1AT and completed a comprehensive study of the glycosylation of A1AT found in healthy controls, patients with hepatitis C- (HCV) induced liver cirrhosis, and in patients infected with HCV with a diagnosis of hepatocellular carcinoma (HCC).Methodology/Principal FindingsPatients with liver cirrhosis and liver cancer had increased levels of triantennary glycan-containing outer arm (α-1,3) fucosylation. Increases in core (α-1,6) fucosylation were observed only on A1AT from patients with cancer. We performed a lectin fluorophore-linked immunosorbent assay using Aleuria Aurantia lectin (AAL), specific for core and outer arm fucosylation in over 400 patients with liver disease. AAL-reactive A1AT was able to detect HCC with a sensitivity of 70% and a specificity of 86%, which was greater than that observed with the current marker of HCC, alpha-fetoprotein. Glycosylation analysis of the false positives was performed; results indicated that these patients had increases in outer arm fucosylation but not in core fucosylation, suggesting that core fucosylation is cancer specific.Conclusions/SignificanceThis report details the stepwise change in the glycosylation of A1AT with the progression from liver cirrhosis to cancer and identifies core fucosylation on A1AT as an HCC specific modification.
Highlights
Infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) is the major etiology of hepatocellular cancer (HCC) [1,2,3,4]
Using fucose-specific lectins to identify the proteins that become fucosylated in patients with liver disease, we identified more than 100 glycoproteins from patients with hepatocellular carcinoma (HCC) and/or cirrhosis that contained increased fucosylation [19]
The A1AT concentrations in each patient group were comparable (Figures 1E–1G) and fell within normal serum concentrations. This result was confirmed by analyzing A1AT an Enzyme-linked immunosorbent assay (ELISA), whereby the A1AT levels were 3.2 mg/mL in the composite from the healthy patients, 3.3 mg/mL in the composite from the cirrhotic patients, and 3.3 mg/mL in the composite from the HCC patients
Summary
Infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) is the major etiology of hepatocellular cancer (HCC) [1,2,3,4]. We previously reported increased levels of protein-linked fucosylation with the development of liver cancer and identified many of the proteins containing the altered glycan structures. To advance these studies, we performed N-linked glycan analysis on the five major isoforms of A1AT and completed a comprehensive study of the glycosylation of A1AT found in healthy controls, patients with hepatitis C- (HCV) induced liver cirrhosis, and in patients infected with HCV with a diagnosis of hepatocellular carcinoma (HCC)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
