Prognostic significance and pathological correlation analysis of DKK4 in colorectal cancer

Colorectal cancer (CRC) is a highly prevalent and lethal digestive system malignancy worldwide, which mostly develops through a multi-step progression from normal mucosa to adenoma and finally invasive carcinoma. Lack of specific biomarkers for precancerous lesions limits early screening and intervention efficacy. This study aimed to investigate the differential expression of Dickkopf-related protein 4 (DKK4) in CRC and its correlation with clinicopathological features, and to construct a DKK4-based risk prediction model for CRC.

Bioinformatics analysis was performed to predict the biological functions and immunoregulatory roles of DKK4. A risk prediction model was established using least absolute shrinkage and selection operator (LASSO) regression. The correlation between DKK4 expression and pathological features in colorectal adenomas (CRAs) and carcinomas was analyzed through hematoxylin and eosin (H&E) staining and immunohistochemistry (IHC).

DKK4 was lowly expressed in normal colorectal mucosal tissues, significantly upregulated in CRAs with low-grade intraepithelial neoplasia (LGIN) and high-grade intraepithelial neoplasia (HGIN) with the peak expression in HGIN tissues, and notably downregulated in invasive CRC tissues compared with adenomas (P<0.05). Its expression correlated with tumor mutation burden (P=0.008) and was functionally enriched in the Wnt signaling pathway. DKK4 showed differential expression in CD4+ T cells, macrophages (P<0.05) and modulated immune-related genes, including: Immunostimulatory genes (CD80, ENTPD1, IFNA2, IFNG, PRF1), Immunosuppressive genes (ARG1, CD274, EDNRB, VEGFB) (P<0.05). The LASSO-derived risk model (λ=0.00413) demonstrated predictive performance with areas under the curve (AUCs) in Training set: 0.676 (1-year), 0.695 (3-year), 0.657 (5-year) and Validation set: 0.634 (1-year), 0.596 (3-year), 0.561 (5-year). IHC revealed higher DKK4 was predominantly localized in colorectal glandular cells, and its stage-specific expression pattern was closely associated with glandular structural atypia and adenoma-carcinoma transition.

The DKK4-based risk prediction model shows moderate predictive value for 1-3-year short-term survival in CRC patients. DKK4 exhibits a stage-specific expression pattern during colorectal tumorigenesis and primarily acts in the precancerous stage of adenoma-carcinoma transition, which makes it a potential specific biomarker for CRC precancerous lesion screening, providing a new molecular target for early CRC screening and intervention.