Linkage Specific Fucosylation of Alpha-1-Antitrypsin in Liver Cirrhosis and Cancer Patients: Implications for a Biomarker of Hepatocellular Carcinoma |
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Authors: | Mary Ann Comunale Lucy Rodemich-Betesh Julie Hafner Mengjun Wang Pamela Norton Adrian M Di Bisceglie Timothy Block Anand Mehta |
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Institution: | 1. Department of Microbiology and Immunology, Drexel Institute for Biotechnology and Virus Research, Drexel University College of Medicine, Doylestown, Pennsylvania, United States of America.; 2. Division of Gastroenterology and Hepatology, Saint Louis VA Medical Center, Saint Louis University School of Medicine, St Louis, Missouri, United States of America.;Yonsei University, Republic of Korea |
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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. |
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