Analysis of Formimidoyltransferase Cyclodeaminase as a Potential Prognostic Biomarker and Therapeutic Target in Colorectal Cancer

Abstract Background/Aim: Formimidoyltransferase cyclodeaminase (FTCD) is a folate-metabolizing enzyme involved in histidine catabolism and intracellular folate homeostasis. Although FTCD has been implicated in cancer progression and epithelial–mesenchymal transition (EMT) in several malignancies, its oncological role in colorectal cancer (CRC) remains unclear. This study investigated the biological and clinical significance of FTCD in CRC. Materials and Methods: FTCD expression was evaluated in CRC cell lines and clinical specimens from 301 patients with resectable stage II/III CRC who underwent curative resection. Functional analyses, including proliferation, invasion, migration, and subcutaneous xenograft assays, were performed using small interfering RNA-mediated FTCD knockdown. Associations between FTCD expression and clinicopathological factors, recurrence patterns, disease-free survival (DFS), and overall survival (OS) were analyzed. External validation was performed using Kaplan–Meier Plotter and The Cancer Genome Atlas (TCGA) cohorts. Results: FTCD knockdown significantly suppressed proliferation, invasion, and migration in CaR-1 and COL-3-JCK cells and reduced tumor growth in vivo. FTCD expression positively correlated with multiple EMT-related genes, particularly COL1A2, SPARC, FZD7, and BMP7. High FTCD expression was significantly associated with deeper tumor invasion and left-sided tumors. Patients with high FTCD expression showed significantly worse DFS [hazard ratio (HR)=2.00, p=0.012] and OS (HR=2.96, p=0.009). In multivariate analysis, high FTCD expression remained an independent prognostic factor for OS (HR=2.47, p=0.030), but not for DFS. Peritoneal and bone recurrences were more frequent in the high FTCD group. External validation cohorts showed similar prognostic trends. Conclusion: FTCD may serve as a useful prognostic biomarker associated with aggressive tumor behavior and poor survival outcomes and may be a potential therapeutic target requiring further validation in CRC.