Quantitative and qualitative alterations of heparan sulfate in fibrogenic liver diseases and hepatocellular cancer.
Heparan sulfate (HS), due to its ability to interact with a multitude of HS-binding factors, is involved in a variety of physiological and pathological processes. Remarkably diverse fine structure of HS, shaped by non-exhaustive enzymatic modifications, influences the interaction of HS with its partners. Here we characterized the HS profile of normal human and rat liver, as well as alterations of HS related to liver fibrogenesis and carcinogenesis, by using sulfation-specific antibodies. The HS immunopattern was compared with the immunolocalization of selected HS proteoglycans. HS samples from normal liver and hepatocellular carcinoma (HCC) were subjected to disaccharide analysis. Expression changes of nine HS-modifying enzymes in human fibrogenic diseases and HCC were measured by quantitative RT-PCR. Increased abundance and altered immunolocalization of HS was paralleled by elevated mRNA levels of HS-modifying enzymes in the diseased liver. The strong immunoreactivity of the normal liver for 3-O-sulfated epitope further increased with disease, along with upregulation of 3-OST-1. Modest 6-O-undersulfation of HCC HS is probably explained by Sulf overexpression. Our results may prompt further investigation of the role of highly 3-O-sulfated and partially 6-O-desulfated HS in pathological processes such as hepatitis virus entry and aberrant growth factor signaling in fibrogenic liver diseases and HCC.
Tátrai
Péter
P
Second Department of Pathology, Semmelweis University, 93 Ulloi út H-1091 Budapest, Hungary. peter.tatrai@biomembrane.hu
Egedi
Krisztina
K
Somorácz
Aron
A
van Kuppevelt
Toin H
TH
Ten Dam
Gerdy
G
Lyon
Malcolm
M
Deakin
Jon A
JA
Kiss
András
A
Schaff
Zsuzsa
Z
Kovalszky
Ilona
I
D018171:Agrin / Q000096:biosynthesis; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D002908:Chronic Disease; D004187:Disaccharides / Q000378:metabolism; D020518:Focal Nodular Hyperplasia / Q000378:metabolism; D005966:Glucuronidase / Q000096:biosynthesis / Q000235:genetics; D053673:Glypicans / Q000096:biosynthesis; D019812:Heparan Sulfate Proteoglycans / Q000096:biosynthesis; D006497:Heparan Sulfate / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism*; D008297:Male; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015238:Sulfotransferases / Q000096:biosynthesis / Q000235:genetics; D053668:Syndecan-1 / Q000096:biosynthesis; D000099175:Heparanase
D018171:Agrin; D004187:Disaccharides; D005966:Glucuronidase; D053673:Glypicans; D019812:Heparan Sulfate Proteoglycans; D006497:Heparan Sulfate; D012333:RNA, Messenger; D015238:Sulfotransferases; D053668:Syndecan-1; D000099175:Heparanase; C071927:perlecan