SERPING1 facilitates colorectal liver metastasis by modulating epithelial-mesenchymal transition and tumor microenvironment remodeling.

BACKGROUND

Colorectal liver metastasis (CRLM) remains the primary cause of mortality in patients with colorectal cancer (CRC). Despite its clinical significance, the complex molecular networks and microenvironmental dynamics driving CRLM remain incompletely understood. Identifying robust prognostic biomarkers and elucidating their underlying mechanisms are of critical importance for advancing targeted interventions.

METHODS

We integrated Weighted gene co-expression network analysis (WGCNA) with differential expression profiling to identify the CRLM-associated hub genes. The clinical relevance and spatial expression of the identified target, SERPING1, were validated in human CRC and CRLM tissue cohorts. In vitro functional assays (siRNA knockdown) and transcriptomic enrichment analyses were performed to evaluate the impact of SERPING1 on malignant epithelial phenotypes. Finally, Single-cell RNA sequencing (scRNA-seq) and immune infiltration algorithms were utilized to delineate its distribution within the tumor microenvironment (TME).

RESULTS

SERPING1 was identified as a critical prognostic hub gene, with its elevated expression significantly correlating with poor patient survival and exhibiting a stepwise upregulation along the primary-to-metastasis axis in clinical tissues. In vitro, silencing SERPING1 attenuated the proliferative, migratory, and invasive capacities of CRC cells. This was accompanied by a molecular shift away from the epithelial-mesenchymal transition (EMT) program, supported by the enrichment of classical pro-metastatic cascades. Crucially, scRNA-seq and microenvironmental analysis revealed that in vivo, SERPING1 is predominantly enriched within cancer-associated fibroblasts (CAFs), establishing a strong correlation with stromal infiltration.

CONCLUSIONS

These findings suggest that SERPING1 serves as a crucial molecular nexus in CRLM, potentially facilitating disease dissemination by supporting malignant EMT phenotypes and participating in stromal TME remodeling. Consequently, SERPING1 represents a promising biomarker and a potential therapeutic target for mitigating CRLM.