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Open AccessArticle

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

1
First Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, H-1085 Budapest, Hungary
2
Tumor Progression Research Group of Joint Research Organization of Hungarian Academy of Sciences and Semmelweis University, Széchenyi István tér 9, H-1051 Budapest, Hungary
3
Faculty of Information Technology and Bionics, Pázmány Péter Catholic University, Práter u. 50/A, H-1083 Budapest, Hungary
4
Department of Experimental Pharmacology, National Institute of Oncology, Ráth György utca 7-9, H-1122 Budapest, Hungary
5
Solvo Biotechnology, Irinyi József utca 4-20, H-1117 Budapest, Hungary
6
Department of Urology, Semmelweis University, Üllői út 78/B, H-1082 Budapest, Hungary
7
Department of Urology, West German Cancer Center, University of Duisburg-Essen, University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany
8
Szilak Laboratories Bioinformatics and Molecule-Design Ltd., Gem utca 14, H-6723 Szeged, Hungary
*
Author to whom correspondence should be addressed.
These authors contributed equally to this paper.
Biomolecules 2020, 10(10), 1356; https://doi.org/10.3390/biom10101356
Received: 29 July 2020 / Revised: 18 September 2020 / Accepted: 21 September 2020 / Published: 23 September 2020
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. View Full-Text
Keywords: syndecan-1; liver cancer; epithelium; differentiation; shedding; heparan sulfate; Ets-1; AP-1; MMP-7 syndecan-1; liver cancer; epithelium; differentiation; shedding; heparan sulfate; Ets-1; AP-1; MMP-7
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Hollósi, P.; Váncza, L.; Karászi, K.; Dobos, K.; Péterfia, B.; Tátrai, E.; Tátrai, P.; Szarvas, T.; Paku, S.; Szilák, L.; Kovalszky, I. Syndecan-1 Promotes Hepatocyte-Like Differentiation of Hepatoma Cells Targeting Ets-1 and AP-1. Biomolecules 2020, 10, 1356.

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