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

ABSTRACT

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.