Overexpression of Basonuclin Zinc Finger Protein 2 in stromal cell is related to mesenchymal phenotype and immunosuppression of mucinous colorectal adenocarcinoma.

BACKGROUND

Mucinous carcinoma (MC) is a distinct histologic subtype of colorectal cancer (CRC) that is less studied and associated with poor prognosis. This study aimed to identify MC-specific therapeutic targets and biomarkers to improve the prognosis of this aggressive disease.

METHODS

CRC samples from The Cancer Genome Atlas (TCGA) were categorized into MC and non-MC (NMC) groups based on histologic type. A multi-scale embedded gene co-expression network analysis (MEGENA) was constructed to identify gene modules associated with the MC group. The potential functions of Basonuclin Zinc Finger Protein 2 (BNC2) were further analyzed using the Biomarker Exploration for Solid Tumors (BEST) database. In vivo and in vitro experiments were conducted to validate the predicted results.

RESULTS

We identified the stromal component-related gene, BNC2, in the MC population. This gene is associated with a shorter progression-free interval (PFI) in CRC patients. BNC2 promotes FAP (encoding Fibroblast Activation Protein Alpha) transcription in cancer-associated fibroblasts (CAFs) and is involved in angiogenesis through two pathways. Additionally, BNC2 enhances tumor cell invasiveness in a CAF-dependent manner. Patients with high BNC2 expression benefited less from immunotherapy compared to those with low BNC2 expression.

CONCLUSIONS

Our study highlights the clinical importance of BNC2 in MC, and targeting BNC2 on stromal cells (fibroblasts and endothelial cells) may be an effective strategy for treating MC.