Syndecan-1 Promotes Hepatocyte-Like Differentiation of Hepatoma Cells Targeting Ets-1 and AP-1

Péter Hollósi,Bálint Péterfia,Tibor Szarvas,Ilona Kovalszky,Lóránd Váncza,Péter Tátrai,Enikő Tátrai,Katalin Dobos,Sándor Paku,Katalin Karászi,László Szilák

doi:10.3390/biom10101356

Abstract

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.

Highlights

Liver cancer is the sixth most commonly diagnosed cancer (782,000 cases/year) and the second most common cause of cancer death (745,000 deaths/year) worldwide [1]
While syndecan-1 is known to play a key role in the normal function of the liver, its participation in the development and progression of Hepatocellular carcinoma (HCC) is not clarified
Two HCC cell lines with decreased syndecan-1 expression were transfected with the full-length or truncated forms

Summary

Introduction

Liver cancer is the sixth most commonly diagnosed cancer (782,000 cases/year) and the second most common cause of cancer death (745,000 deaths/year) worldwide [1]. This excessively high mortality to incidence ratio reflects the poor prognosis of liver cancer and underlines the importance of a better understanding of its pathogenesis and biological behavior. Syndecan-1 (sdc-1, SDC1) is the prototype member of the syndecan family of membrane-bound proteoglycans, featuring heparan sulfate (HS) and chondroitin sulfate chains on its core protein [5,6] It is predominantly expressed on the basolateral surface of epithelial cells [7]. Cell surface syndecan-1 expression is markedly reduced in HCCs with no underlying cirrhosis, especially in those with poor differentiation and high metastatic potential [9,10,13,14]

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