BGN/TLR4/NF-B Mediates Epigenetic Silencing of Immunosuppressive Siglec Ligands in Colon Cancer Cells

Area of Science:

• Immunology
• Oncology
• Glycobiology

Background:

• Toll-like receptor (TLR) signaling is crucial in intestinal inflammation via the NF-B pathway.
• Increased TLR2 and TLR4 expression is observed in colorectal cancer (CRC).
• Specific glycans, disialyl Lewis^a and sialyl 6-sulfo Lewis^x, are reduced in CRC and act as Siglec-7 ligands.

Purpose of the Study:

• To investigate the role of TLR4 in CRC and its impact on specific glycan expression.
• To identify ligands involved in TLR4-mediated CRC progression.
• To elucidate the mechanism linking BGN, TLR4, NF-B, and glycan expression in CRC.

Main Methods:

• Gene expression analysis using GENT2 datasets.
• RNA interference (shRNA) to suppress TLR4 and BGN expression.
• Analysis of glycan expression, Siglec-7 binding, NF-B activity, and epigenetic markers (H3K27me3).

Main Results:

• TLR4, but not TLR2, suppression restored normal glycan expression and Siglec-7 binding.
• BGN was identified as a TLR4 ligand highly expressed in cancers, epigenetically silencing Siglec-7 ligands.
• BGN suppression reduced NF-B activity and H3K27me3, restoring normal glycans and Siglec-7 binding.
• A positive feedback loop involving TLR4, NF-B, and BGN was identified, promoting carcinogenesis.

Conclusions:

• The BGN/TLR4/NF-B pathway promotes CRC by reducing immunosuppressive glycan ligands.
• Targeting this pathway may offer a novel therapeutic strategy for colorectal cancer.