Syndecan-1 alters heparan sulfate composition and signaling pathways in malignant mesothelioma

Our plain-English summary of Syndecan-1 alters heparan sulfate composition and signaling pathways in malignant mesothelioma, by G. Heidari-Hamedani, R.R. Vivès, A. Seffouh, et al (Cellular Signalling, 2015).

The study

• Authors: G. Heidari-Hamedani, R.R. Vivès, A. Seffouh, N.A. Afratis, A. Oosterhof, T.H. van Kuppevelt, N.K. Karamanos, M. Metintas, A. Hjerpe, K. Dobra, T. Szatmári
• Journal: Cellular Signalling
• Published: 2015;27(10):2054-67
• Cited by: 20 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Syndecan-1 is a proteoglycan that acts as co-receptor through its heparan sulfate (HS) chains and plays important roles in cancer. HS chains are highly variable in length and sulfation pattern. This variability is enhanced by the SULF1/2 enzymes, which remove 6-O-sulfates from HS. We used malignant mesothelioma, an aggressive tumor with poor prognosis, as a model and demonstrated that syndecan-1 over-expression down-regulates SULF1 and alters the HS biosynthetic machinery. Biochemical characterization revealed a 2.7-fold reduction in HS content upon syndecan-1 over-expression, but an overall increase in sulfation. Consistent with low SULF1 levels, trisulfated disaccharides increased 2.5-fold. ERK1/2 activity was enhanced 6-fold. Counteracting ERK activation, Akt, WNK1, and c-Jun were inhibited. The net effect of these changes manifested in G1 cell cycle arrest. Studies of pleural effusions showed that SULF1 levels are lower in pleural malignancies compared to benign conditions and inversely correlate with the amounts of syndecan-1, suggesting important roles for syndecan-1 and SULF1 in malignant mesothelioma.

Copyright © 2015. Published by Elsevier Inc.

In plain English

This laboratory study used a human malignant mesothelioma cell line (STAV-AB). The authors made the cells produce extra syndecan-1, a cell-surface molecule, and compared them with control cells. It did not study asbestos exposure. In cells with extra syndecan-1, RNA for the enzyme SULF1 fell more than 50-fold and SULF1 protein fell 1.8-fold. The amount of heparan sulfate, a sugar chain carried by such molecules, fell 2.5 to 2.7-fold, while its overall sulfation rose about 20%. Active (phosphorylated) ERK1/2 rose 6.1-fold, measured by flow cytometry after growth-factor (FGF2) stimulation. Akt and c-Jun activity fell, and more cells were in the G0/G1 phase of the cell cycle (66.5% versus 61.3% of control cells). In fluid from around the lungs (pleural effusions), SULF1 was lower in malignant than benign effusions and lower in mesothelioma than adenocarcinoma. A negative correlation between SULF1 and soluble syndecan-1 in 13 mesothelioma patients was not statistically significant, and neither was a survival difference by SULF1 level. The authors suggested SULF1 may have a role as a diagnostic marker in pleural malignancies.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) cell-line experiment comparing syndecan-1 over-expressing mesothelioma cells with mock-transfected control cells, plus measurement of soluble SDC1 and SULF1 in stored pleural effusion samples
• Who was studied: Human malignant mesothelioma cells with epithelioid morphology (STAV-AB cell line). Also 66 pleural effusions (17 adenocarcinomas, 37 malignant mesotheliomas, 12 benign): 42 collected at Karolinska University Hospital, Huddinge, Sweden, 2007 to 2013, and 24 mesothelioma effusions collected at Eskisehir Osmangazi University, Turkey, 2002 to 2004
• Exposure: No asbestos or fiber exposure was studied. The experimental factor was stable over-expression of the human syndecan-1 (SDC1) gene in mesothelioma cells. Some experiments also added recombinant SULF1 enzyme.
• Main results:
  • In SDC1 over-expressing cells, SULF1 was down-regulated more than 50-fold at the RNA level and 1.8-fold at the protein level compared with control
  • SDC1 over-expression lowered the amount of heparan sulfate 2.5 to 2.7-fold in both medium and cell samples, but overall sulfation of the chains was about 20% higher
  • The trisulfated disaccharide that is the main SULF substrate increased about 2.5-fold in SDC1 over-expressing cells
  • EGFR activity was 1.8 plus or minus 0.3 fold higher in SDC1 over-expressing cells (phospho-kinase array), but this was not statistically significant
  • After FGF2 stimulation, flow cytometry showed total ERK1/2 elevated 1.74-fold and phospho-ERK1/2 elevated 6.1-fold in SDC1 over-expressing cells compared with control cells
  • Total and phospho-Akt were reduced (0.48 and 0.5-fold), and c-Jun activity was reduced (0.74 plus or minus 0.07 fold) in SDC1 over-expressing cells
  • In G0/G1 phase, SDC1 over-expressing cells had a larger percentage than mock-transfected cells: 66.5% (plus or minus 2.3) versus 61.3% (plus or minus 0.7). Figure 11 gives these as mean percentage plus or minus SD.
  • SULF1 levels were lower in malignant pleural effusions (49.3 plus or minus 3.3; n = 56) than in benign effusions (118.5 plus or minus 8.7; n = 10), with p less than 0.0001
  • Within malignant effusions, SULF1 was lower in mesothelioma (39.9 plus or minus 2.8; n = 39) than in adenocarcinoma (69.3 plus or minus 5.3; n = 17), with p less than 0.0001
  • In paired mesothelioma effusions (n = 13), SULF1 and soluble SDC1 showed an inverse correlation that was not statistically significant (r = -0.43; p = 0.13)
  • Mesothelioma patients with SULF1 above 36.57 ng/mL had a median survival of 10 months, compared with 6 months for those below it. The difference was not statistically significant (hazard ratio 0.76; 95% CI 0.37 to 1.6; p = 0.47).
  • Above a cut-off of 235 ng/mL, soluble SDC1 correlated with the proportion of tumor cells in malignant effusions (r = 0.8; p = 0.006). SULF1 did not correlate with tumor burden.
• The authors' conclusion: The authors concluded that SDC1 modifies the fine structure and sulfation pattern of proteoglycans, mainly through down-regulation of SULF1, and acts through the PI3K and MAPK signaling pathways in mesothelioma cells, leading to G1 cell cycle arrest. They suggested a potential role for SULF1 as a diagnostic marker in pleural malignancies.
• Limitations the authors state:
  • The authors stated that testing SULF1 as a prognostic marker needs a larger clinical sample
  • Survival times were available only for a subset of patients
  • Because little material could be recovered, heparan sulfate extracts from three independent cultures were pooled for analysis
  • For the capillary electrophoresis check, the small sample allowed only a few types of sulfated disaccharides to be detected

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Prognosis, Pleural Effusion.

Related studies

• Novel genes and pathways modulated by syndecan-1: implications for the proliferation and cell-cycle regulation of malignant mesothelioma cells — T. Szatmári, F. Mundt, et al. (2012)
• Oxidative stress alters syndecan-1 distribution in lungs with pulmonary fibrosis — C.R. Kliment, J.M. Englert, et al. (2009)
• Extracellular superoxide dismutase protects against matrix degradation of heparan sulfate in the lung — C.R. Kliment, J.M. Tobolewski, et al. (2008)
• Diagnostic and prognostic value of soluble syndecan-1 in pleural malignancies — F. Mundt, G. Heidari-Hamedani, et al. (2014)
• Effect of syndecan-1 overexpression on mesenchymal tumour cell proliferation with focus on different functional domains — F. Zong, E. Fthenou, et al. (2010)
• Assessment of signaling pathway inhibitors and identification of predictive biomarkers in malignant pleural mesothelioma — R. Tranchant, L. Quetel, et al. (2018)

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