Abstract:Liver diseases such as liver cirrhosis, primary and metastatic liver cancers are still a major medical challenge. Syndecan-1 is one of the most important proteoglycans in the liver. Syndecan-1 is normally expressed on the surfaces of hepatocytes and cholangiocytes. Due to liver diseases the amount of syndecan-1 increases in the liver. Despite the emerging data of the biological function of syndecan-1, the clinical usefulness of this proteoglycan is still unknown. In our study we correlated syndecan-1 expressio… Show more
“…Liver cirrhosis is characterized by increased amounts of syndecan-1, and shed syndecan-1 has been experimentally shown to protect against fibrotic remodeling [ 56 ]. The significance of quantitative changes of syndecan-1 in liver cancer is still not clearly understood [ 57 ]. In the present study, we made an effort to investigate the importance of syndecan-1 in HCC, where loss of syndecan-1 was frequently observed and associated with poor prognosis.…”
Syndecan-1 is a transmembrane heparan sulfate proteoglycan which is indispensable in the structural and functional integrity of epithelia. Normal hepatocytes display strong cell surface expression of syndecan-1; however, upon malignant transformation, they may lose it from their cell surfaces. In this study, we demonstrate that re-expression of full-length or ectodomain-deleted syndecan-1 in hepatocellular carcinoma cells downregulates phosphorylation of ERK1/2 and p38, with the truncated form exerting an even stronger effect than the full-length protein. Furthermore, overexpression of syndecan-1 in hepatoma cells is associated with a shift of heparan sulfate structure toward a highly sulfated type specific for normal liver. As a result, cell proliferation and proteolytic shedding of syndecan-1 from the cell surface are restrained, which facilitates redifferentiation of hepatoma cells to a more hepatocyte-like phenotype. Our results highlight the importance of syndecan-1 in the formation and maintenance of differentiated epithelial characteristics in hepatocytes partly via the HGF/ERK/Ets-1 signal transduction pathway. Downregulation of Ets-1 expression alone, however, was not sufficient to replicate the phenotype of syndecan-1 overexpressing cells, indicating the need for additional molecular mechanisms. Accordingly, a reporter gene assay revealed the inhibition of Ets-1 as well as AP-1 transcription factor-induced promoter activation, presumably an effect of the heparan sulfate switch.
“…Liver cirrhosis is characterized by increased amounts of syndecan-1, and shed syndecan-1 has been experimentally shown to protect against fibrotic remodeling [ 56 ]. The significance of quantitative changes of syndecan-1 in liver cancer is still not clearly understood [ 57 ]. In the present study, we made an effort to investigate the importance of syndecan-1 in HCC, where loss of syndecan-1 was frequently observed and associated with poor prognosis.…”
Syndecan-1 is a transmembrane heparan sulfate proteoglycan which is indispensable in the structural and functional integrity of epithelia. Normal hepatocytes display strong cell surface expression of syndecan-1; however, upon malignant transformation, they may lose it from their cell surfaces. In this study, we demonstrate that re-expression of full-length or ectodomain-deleted syndecan-1 in hepatocellular carcinoma cells downregulates phosphorylation of ERK1/2 and p38, with the truncated form exerting an even stronger effect than the full-length protein. Furthermore, overexpression of syndecan-1 in hepatoma cells is associated with a shift of heparan sulfate structure toward a highly sulfated type specific for normal liver. As a result, cell proliferation and proteolytic shedding of syndecan-1 from the cell surface are restrained, which facilitates redifferentiation of hepatoma cells to a more hepatocyte-like phenotype. Our results highlight the importance of syndecan-1 in the formation and maintenance of differentiated epithelial characteristics in hepatocytes partly via the HGF/ERK/Ets-1 signal transduction pathway. Downregulation of Ets-1 expression alone, however, was not sufficient to replicate the phenotype of syndecan-1 overexpressing cells, indicating the need for additional molecular mechanisms. Accordingly, a reporter gene assay revealed the inhibition of Ets-1 as well as AP-1 transcription factor-induced promoter activation, presumably an effect of the heparan sulfate switch.
“…Specifically, in intermediate and advanced stages of fibrosis, the staining intensity was significantly more robust than in early stages and the staining was gradually extended to almost the entire cell membrane, creating a honeycomb-like pattern. There are few reports in the international literature that describe in detail changes in the immunostaining pattern of syndecan-1 in liver disease compared to normal liver tissue (37,38). Syndecans have mainly heparan sulphate (HS) and some chondroitin sulphate GAG side chains on their extracellular domain, which consist of repeating disaccharide units that are attached to serine residues in the proteoglycan core proteins (11).…”
Section: Discussionmentioning
confidence: 99%
“…In our study, no correlation of syndecan-1 expression with patient age and sex nor with the etiology of liver fibrosis was demonstrated. However, syndecan-1 overexpression in hepatitis virus C-infected liver tissue has been described, suggesting syndecan-1 as a major receptor for hepatitis virus C internalization into hepatocytes (23,24,38).…”
“…Cell adhesion to ECM is mediated by ECM receptors namely integrins, discoidin domain and syndecans. Syndecan-1 is normally expressed on the surface of hepatocytes and cholangiocytes, which increases in liver diseases and representing a good molecular marker for liver fibrosis induced by hepatitis C infection (15).…”
Section: Dysregulation Of Extracellular Matrix Synthesis: Key To Fibrmentioning
Liver fibrosis is one of the leading complications of a variety of chronic liver disorders, including the nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, liver cirrhosis and liver failure. The progression of liver fibrosis is driven by chronic inflammation, which activates the secretory fibroblasts to the myofibroblast phenotype. These specialized liver cells are called as hepatic stellate cells (HSCs).The excessive extracellular matrix (ECM) secretion creates a large number of complications. Fibrosis is the result of imbalance between the matrix synthesizing and matrix degrading factors. The major ECM proteins include the matrix metalloproteinases (MMPs), tissue inhibitor of metalloproteinases (TIMPs), lysyl oxidases (LOX), lysyl oxidase-like (LOXLs) enzymes, tenascins and others. These ECM proteins present novel avenues for the therapeutics of liver fibrosis. The current review highlights the major role played by these critical matrix proteins in liver fibrosis. Further, some of the targeted formulations used against these proteins are discussed and suggestions are provided to select the course of research for successful clinical translation of basic research findings for the amelioration of liver fibrosis.
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