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

<h3>Abstract</h3> <h3>Background/Aim:</h3> Formimidoyltransferase cyclodeaminase (<i>FTCD</i>) is a folate-metabolizing enzyme involved in histidine catabolism and intracellular folate homeostasis. Although <i>FTCD</i> 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 <i>FTCD</i> in CRC. <h3>Materials and Methods:</h3> <i>FTCD</i> 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 <i>FTCD</i> knockdown. Associations between <i>FTCD</i> 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. <h3>Results:</h3> <i>FTCD</i> knockdown significantly suppressed proliferation, invasion, and migration in CaR-1 and COL-3-JCK cells and reduced tumor growth <i>in vivo. FTCD</i> expression positively correlated with multiple EMT-related genes, particularly <i>COL1A2, SPARC, FZD7</i>, and <i>BMP7</i>. High <i>FTCD</i> expression was significantly associated with deeper tumor invasion and left-sided tumors. Patients with high <i>FTCD</i> expression showed significantly worse DFS [hazard ratio (HR)=2.00, <i>p</i>=0.012] and OS (HR=2.96, <i>p</i>=0.009). In multivariate analysis, high <i>FTCD</i> expression remained an independent prognostic factor for OS (HR=2.47, <i>p</i>=0.030), but not for DFS. Peritoneal and bone recurrences were more frequent in the high <i>FTCD</i> group. External validation cohorts showed similar prognostic trends. <h3>Conclusion:</h3> <i>FTCD</i> 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.