Linkage specific fucosylation of alpha-1-antitrypsin in liver cirrhosis and cancer patients: implications for a biomarker of hepatocellular carcinoma.

Abstract

BACKGROUND:

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. 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 FINDINGS:

Patients with liver cirrhosis and liver cancer had increased levels of triantennary glycan-containing outer arm (alpha-1,3) fucosylation. Increases in core (alpha-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/SIGNIFICANCE:

This 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.

• Authors: Mary Ann Comunale, Lucy Rodemich-Betesh, Julie Hafner, Mengjun Wang, Pamela Norton, Adrian M Di Bisceglie, Timothy Block, Anand Mehta
• Journal: PloS one (PLoS One) Vol. 5 Issue 8 Pg. e12419 (Aug 25 2010) ISSN: 1932-6203 [Electronic] United States
• PMID: 20811639 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• Lectins
• Protein Isoforms
• SERPINA1 protein, human
• alpha 1-Antitrypsin
• lectin, Aleuria aurantia
• Fucose

Topics

• Biomarkers (metabolism)
• Carcinoma, Hepatocellular (diagnosis, metabolism)
• Case-Control Studies
• Cohort Studies
• Disease Progression
• False Positive Reactions
• Fucose (metabolism)
• Glycosylation
• Humans
• Lectins (metabolism)
• Liver Cirrhosis (metabolism, pathology)
• Liver Neoplasms (diagnosis, metabolism)
• Protein Isoforms (chemistry, metabolism)
• Sensitivity and Specificity
• alpha 1-Antitrypsin (chemistry, metabolism)