Hypoxia Promotes Syndecan-3 Expression in the Tumor Microenvironment

Abstract

The syndecan (Sdc) family is comprised of four members of cell surface molecules (Sdc-1 to 4) with different biological functions. Syndecan-3 (Sdc-3) is known to be mainly expressed in the brain and nervous tissue and plays a key role in development, cell adhesion, and migration. Recent studies point to important roles for Sdc-3 in inflammatory disease, but the patterns of expression and significance of Sdc-3 in cancer remains unexplored. Here we show that Sdc-3 expression is upregulated on several cancer types, especially in solid tumors that are known to be hypoxic. The Cancer Genome Atlas program (TCGA) data demonstrated that Sdc-3 expression in the tumor microenvironment positively correlates with a hypoxia gene signature. To confirm a potential cause-effect, we performed experiments with tumor cell lines showing increased expression upon in vitro exposure to 1% oxygen or dimethyloxalylglycine, an inhibitor of prolyl hydroxylases, indicating that Sdc-3 expression is promoted by hypoxia inducible factors (HIFs). HIF-1α was responsible for this upregulation as confirmed by CRISPR-engineered tumor cells. Using single-cell RNA sequencing data of melanoma patients, we show that Sdc-3 is expressed on tumor associated macrophages, cancer cells, and endothelial cells. Syndecan-3 expression positively correlated with a macrophage gene signature across several TCGA cancer types. In vitro experiments demonstrated that hypoxia (1% oxygen) or treatment with IFN-γ stimulate Sdc-3 expression on RAW-264.7 derived macrophages, linking Sdc-3 expression to a proinflammatory response. Syndecan-3 expression correlates with a better patient overall survival in hypoxic melanoma tumors.

Hypoxia and Extracellular Acidification as Drivers of Melanoma Progression and Drug Resistance

“…for the ECM organization, are involved in the dysregulation of the TME. CAFs exhibited an elevated level of syndecan-4, while high expression of syndecan-3 was detected in melanoma cells, epithelial cells, and tumor-associated macrophages, which also correlated with hypoxia gene signature [ 91 ]. Finally, hypoxia is known to upregulate LOX (lysyl oxidase), one of the enzymes responsible for collagen crosslinking.…”

Regulatory T-cells-related signature for identifying a prognostic subtype of hepatocellular carcinoma with an exhausted tumor microenvironment

“…A vital member of the SDC family, syndecan 3 (SDC3) is essential for cell adhesion, migration, and development. SDC3 expression is boosted by hypoxia in the tumor microenvironment, which influences pro-inflammatory reactions and the overall survival of melanoma patients ( 65 ). Additionally, SDC3 was linked to more dangerous tumors and a worse prognosis in prostate cancer ( 66 ).…”

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

“…Also in melanoma, Sdc3 expression is induced by hypoxia-inducible factors such as HIF1α. Interestingly, cells of the tumor microenvironment such as macrophages and endothelial cells express Sdc3 [ 32 ]. In pancreatic ductal carcinoma, Sdc3 expression correlates with primary tumor size in a mouse model [ 33 ].…”