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Hypoxia Promotes Syndecan-3 Expression in the Tumor Microenvironment
Endika Prieto-Fernández1, Leire Egia-Mendikute1, Alexandre Bosch1
1Cancer Immunology and Immunotherapy Lab, Centre for Cooperative Research in Biosciences CIC bioGUNE, Basque Research and Technology Alliance, Derio, Spain.
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.
Insights
Syndecan-3 (Sdc-3) expression increases in hypoxic tumors, promoted by hypoxia-inducible factors (HIFs). This upregulation in cancer cells and macrophages correlates with better survival in melanoma patients.
Area of Science:
- Cell biology
- Oncology
- Molecular biology
Background:
- Syndecan-3 (Sdc-3) is a cell surface molecule crucial for development and cell adhesion.
- While Sdc-3's role in inflammation is known, its significance in cancer is unexplored.
- Sdc-3 expression patterns and functions in various cancer types require investigation.
Purpose of the Study:
- To investigate the expression patterns and significance of Syndecan-3 (Sdc-3) in cancer.
- To determine the relationship between Sdc-3 expression, tumor hypoxia, and the tumor microenvironment.
- To explore the impact of Sdc-3 expression on patient survival in hypoxic tumors.
Main Methods:
- Analysis of Cancer Genome Atlas (TCGA) data for Sdc-3 expression and hypoxia correlation.
- In vitro experiments exposing tumor cell lines to hypoxia (1% oxygen) and dimethyloxalylglycine.
- CRISPR engineering to confirm HIF-1α's role in Sdc-3 upregulation.
- Single-cell RNA sequencing analysis of melanoma patient data.
- In vitro experiments with macrophages (RAW-264.7) under hypoxia and IFN-γ stimulation.
Main Results:
- Sdc-3 expression is upregulated in multiple cancer types, particularly in solid tumors with hypoxia.
- TCGA data shows a positive correlation between Sdc-3 expression and hypoxia gene signatures.
- Hypoxia and HIFs, specifically HIF-1α, were confirmed to promote Sdc-3 expression.
- Sdc-3 is expressed on cancer cells, macrophages, and endothelial cells in melanoma.
- Sdc-3 expression correlates positively with macrophage signatures and better overall survival in hypoxic melanoma.
Conclusions:
- Hypoxia is a key regulator of Syndecan-3 (Sdc-3) expression in cancer via HIFs.
- Sdc-3 is implicated in the tumor microenvironment, involving cancer cells and tumor-associated macrophages.
- Sdc-3 expression may serve as a predictive biomarker for improved patient survival in hypoxic melanoma.
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