The Cell Surface Heparan Sulfate Proteoglycan Syndecan-3 Promotes Ovarian Cancer Pathogenesis

Abstract

Syndecans are transmembrane heparan sulfate proteoglycans that integrate signaling at the cell surface. By interacting with cytokines, signaling receptors, proteases, and extracellular matrix proteins, syndecans regulate cell proliferation, metastasis, angiogenesis, and inflammation. We analyzed public gene expression datasets to evaluate the dysregulation and potential prognostic impact of Syndecan-3 in ovarian cancer. Moreover, we performed functional in vitro analysis in syndecan-3-siRNA-treated SKOV3 and CAOV3 ovarian cancer cells. In silico analysis of public gene array datasets revealed that syndecan-3 mRNA expression was significantly increased 5.8-fold in ovarian cancer tissues (n = 744) and 3.4-fold in metastases (n = 44) compared with control tissue (n = 46), as independently confirmed in an RNAseq dataset on ovarian serous cystadenocarcinoma tissue (n = 374, controls: n = 133, 3.5-fold increase tumor vs. normal). Syndecan-3 siRNA knockdown impaired 3D spheroid growth and colony formation as stemness-related readouts in SKOV3 and CAOV3 cells. In SKOV3, but not in CAOV3 cells, syndecan-3 depletion reduced cell viability both under basal conditions and under chemotherapy with cisplatin, or cisplatin and paclitaxel. While analysis of the SIOVDB database did not reveal differences in Syndecan-3 expression between patients, sensitive, resistant or refractory to chemotherapy, KM Plotter analysis of 1435 ovarian cancer patients revealed that high syndecan-3 expression was associated with reduced survival in patients treated with taxol and platin. At the molecular level, a reduction in Stat3 activation and changes in the expression of Wnt and notch signaling constituents were observed. Our study suggests that up-regulation of syndecan-3 promotes the pathogenesis of ovarian cancer by modulating stemness-associated pathways.

Identification of novel myeloid-derived cell states with implication in cancer outcome

“…Analysis of transcriptome-wide gene expression in ovarian cancer showed that ApoE is upregulated in most high-grade serous carcinomas compared to low-grade serous carcinomas (68) . On the other hand, syndecans (Sdc) are transmembrane heparan sulfate proteoglycans (69) expressed in TAM, cancer cells, and endothelial cells, and their expression is positively correlated with a macrophage gene signature across several TCGA cancer types (70) . The studies regarding the role of SDC3 and apoE in cancer development are sparse.…”

Heparan sulfate modifications of betaglycan promote TIMP3-dependent ectodomain shedding to fine-tune TGF-β signaling

“…It is unclear if the CS modifications have alternate roles when on BG, such as mediating association with ECM components as has been reported for other PGs such as NG2 68 . Other cell surface heparan sulfate proteoglycans (HSPG), such as syndecans, perlecans, and glypicans have been shown to promote cancer pathogenesis (including ovarian) and expression changes of such HSPGs have been correlated with poorer patient outcomes [69][70][71] . Additionally, aberrant regulation of heparan sulfate sulfotransferases, responsible for enzymatic modification of HS on all HS proteoglycans, has been known to affect several pathophysiological processes from inflammation, to organ development and cancer 50,72 suggesting that shifting the balance to a more HS-modified BG could be common in pathologies.…”

Role of Syndecans in Ovarian Cancer: New Diagnostic and Prognostic Biomarkers and Potential Therapeutic Targets

“…Hillemeyer L et al [ 49 ] utilized in silico analysis using the online tool TNMplot to reveal a significant upregulation of syndecan-3 mRNA in tumor tissue and metastases compared with normal tissue. At the functional level, syndecan-3 depletion impaired 3D spheroid growth and colony formation as stemness-related readouts in SKOV3 and CAOV3 cells.…”