Quantitative and Qualitative Alterations of Heparan Sulfate in Fibrogenic Liver Diseases and Hepatocellular Cancer

Abstract

S U M M A R Y 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 HSmodifying 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. (J Histochem Cytochem 58:429-441, 2010)

Role of 6-O-Sulfated Heparan Sulfate in Chronic Renal Fibrosis

“…The expression of HS epitopes targeted by HS3A8 and RB4EA12 were significantly increased. Increased expression of RB4EA12 has been observed in human fibrogenic diseases including liver cirrhosis and focal nodular hyperplasia (28). Thus increased expression of HS3A8 and RB4EA12 is consistent with the suggested role of 6-O-sulfation changes in HS regulation during fibrogenic renal disease.…”

“…SULF knock-out mice show increased expression of 6-O-sulfate groups and simultaneous increased binding of RB4EA12 antibody (27). Interestingly, increased binding of HS4C3 and RB4EA12 has been noticed in human chronic liver disease (28). These observations strongly suggest a possible role for HS 6-O-sulfation in the etiology and development of chronic diseases.…”

Nutrigenomics of hepatic steatosis in a feline model: effect of monosodium glutamate, fructose, and Trans-fat feeding

“…The increase in HGF was accompanied by elevations in urokinase plasminogen activator (uPA) and proliferating cell nuclear antigen (PCNA), suggestive of an upregulation of genes involved in cellular regeneration in these felines. Moreover, the livers of these animals also exhibited increased expression of genes that have been shown to be upregulated in human hepatocellular carcinoma, including RelA (Tai et al 2000), glypican 3 (Wang et al 2010), and perlecan (Tátrai et al 2010).…”

SULF1/SULF2 reactivation during liver damage and tumour growth

“…Viral uptake thus is particularly relevant to liver that is prone to many viral infections including hepatitis that often precedes the development of hepatocellular carcinoma. Virus entry into hepatocytes is a multi-step process in which many factors are involved including HSPGs whose sulfation levels play a critical role in this process (Tátrai P1 et al 2010;Xu Y et al 2015). Interactions between HSPGs and its ligands are fine-tuned by the sulfation pattern of its heparan sulfate (Ashikari-Hada S et al 2004).…”