Background

Syndecan-1 is a proteoglycan involved in many cellular processes such as cell proliferation, adhesion and migration, thus playing an important role in cancer development. Its core protein has cytoplasmic, transmembrane and extracellular domains which may all participate in signal transduction. Human malignant mesothelioma and fibrosarcoma are aggressive mesenchymal tumours; their low endogenous syndecan-1 correlate to a more malignant phonotype. We aimed to explore the role of syndecan-1 in mesenchymal tumours, focusing on its nuclear translocation and structure-function relationship.

Method

Two mesenchymal tumour cell lines were transfected to stably overexpress full-length syndecan-1 or truncated variants: the 78 lacking the extracellular domain except DRKE sequence proposed to be essential for oligomerization; the 77 lacking the whole extracellular domain; and the RMKKK being a potential nuclear localization signal. Subcellular localization was monitored by Confocal microscopy. Spatial interaction between syndecan-1 and ligands was characterized by immunocytochemistry and Co-Immunoprecipitation. Effects of syndecan-1 on cellular behaviour were evaluated by various bioassays. Furthermore, a gene microarray was performed to analyze the global gene expression pattern influenced by syndecan-1.

Results

Syndecan-1 and FGF-2 share a tubulin-mediated transport route and co-localize with heparanase in the nucleus. We were the first to prove that the RMKKK sequence is sufficient for syndecan-1 nuclear translocation and thus serves as a nuclear localization signal. Both full-length and truncated syndecan-1 constructs decrease mesenchymal tumour cell proliferation, migration and motility, but enhances cell adhesion. Distinct protein domains have differential effects. Many genes are differentially regulated by syndecan-1 and a number of genes are actually involved in cell adhesion and migration.

Conclusion

Our results address the importance of nuclear translocation, and the functional protein domains, thereby providing new insights into the role of syndecan-1 in tumour progression. A better understanding of the mechanisms behind these functions could make this family of proteoglycans a novel target for cancer therapy.