Colorectal cancer (CRC) is a formidable health challenge, ranking as the third most common cancer globally and the second leading cause of cancer-related deaths. The 5-year survival rate for advanced CRC patients is distressingly low, with recurrence and metastasis being the primary culprits. Perineural invasion (PNI), a process where cancer cells infiltrate nerve bundles, is a critical factor in this grim prognosis. It is associated with an elevated risk of disease recurrence and lymph node metastasis in CRC patients.
PNI is a complex process, encompassing several critical stages, from cancer cell survival to nerve regeneration and invasion. Despite its growing recognition, the specific driving genes and molecular pathways remain elusive.
Enter Cardiotrophin-like cytokine factor 1 (CLCF1), a member of the interleukin-6 (IL-6) family. CLCF1 functions as a potent neurotrophic factor, B-cell stimulator, and neuroendocrine regulator. Previous studies have hinted at its role in promoting axon growth and regulating sorafenib resistance and glycolysis in hepatocellular carcinoma (HCC) cells. However, its impact on the biological behavior of CRC has been unexplored until now.
In this study, we delved into the mRNA expression profiles and clinical data of CRC patients from a public database. We identified a prognostic signature using differentially expressed immune-related genes (DEIRGs) within the Cancer Genome Atlas (TCGA) cohort. Our findings revealed that CLCF1 is not only a novel biomarker implicated in PNI of CRC but also influences the biological phenotypes of CRC cells.
We found that PNI is a significant prognostic factor in CRC, with a higher prevalence in advanced stages. It is associated with elevated serum carcinoembryonic antigen levels and poorer overall survival. We developed a seven-gene signature associated with PNI, which was validated through an internal validation cohort. Functional enrichment analysis shed light on potential mechanisms, highlighting the involvement of genes in cell activation, differentiation, and proliferation, immune processes, and cytokine signaling pathways.
The study also explored the immune microenvironment, revealing that high-risk CRC patients exhibited elevated proportions of certain immune cells and increased expression of immunosuppressive molecules. A nomogram was constructed to predict survival outcomes, incorporating variables such as age, gender, stage, and risk scores.
Furthermore, we conducted expression and survival analyses, identifying CLCF1 as a potentially crucial player in the PNI of CRC. In vitro experiments confirmed that CLCF1 promotes proliferation, invasion, migration, and other malignant biological behaviors of tumor cells.
This study offers novel insights and potential targets for the diagnosis and treatment of colorectal cancer. While there are limitations, such as the lack of external dataset validation and potential selection bias, the findings provide a solid foundation for further research and clinical applications. The role of CLCF1 in CRC and its potential as a therapeutic target warrant further exploration.
