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


RESULTS
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
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.
Comunale
Mary Ann
MA
Department of Microbiology and Immunology, Drexel Institute for Biotechnology and Virus Research, Drexel University College of Medicine, Doylestown, Pennsylvania, United States of America.
Rodemich-Betesh
Lucy
L
Hafner
Julie
J
Wang
Mengjun
M
Norton
Pamela
P
Di Bisceglie
Adrian M
AM
Block
Timothy
T
Mehta
Anand
A
D015415:Biomarkers / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis / Q000378:metabolism*; D016022:Case-Control Studies; D015331:Cohort Studies; D018450:Disease Progression; D005189:False Positive Reactions; D005643:Fucose / Q000378:metabolism*; D006031:Glycosylation; D006801:Humans; D037102:Lectins / Q000378:metabolism; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology; D008113:Liver Neoplasms / Q000175:diagnosis / Q000378:metabolism*; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D012680:Sensitivity and Specificity; D000515:alpha 1-Antitrypsin / Q000737:chemistry / Q000378:metabolism*
D015415:Biomarkers; D037102:Lectins; D020033:Protein Isoforms; C043392:SERPINA1 protein, human; D000515:alpha 1-Antitrypsin; C064549:lectin, Aleuria aurantia; D005643:Fucose
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