The TCN1 Paradox: Unraveling the Dual Role of Transcobalamin I in Colorectal Cancer-From Metabolic Regulation to Oncogenic Signaling.

BACKGROUND: Colorectal cancer (CRC) remains a leading cause of cancer mortality. While genetic drivers are well-characterized, epigenetic alterations-particularly DNA methylation-are increasingly recognized as critical contributors. The vitamin B12 transporter Transcobalamin I (TCN1) has recently emerged as an epigenetically regulated gene with context-dependent oncogenic functions. MAIN BODY: This review synthesized current evidence positioning TCN1 at the intersection of metabolic regulation and oncogenic signaling. We critically evaluated TCN1's consistent overexpression in CRC, its regulation by promoter methylation, and its functional interactions with the Wnt/β-catenin and Notch pathways via Integrin Beta 4 (ITGB4). Notably, we identified and explored the "TCN1 paradox"-the tissue-specific prognostic disparities observed across gastrointestinal cancers-and proposed mechanistic hypotheses to explain this divergence. We also assessed TCN1's clinical potential as a liquid biopsy biomarker, discussing analytical challenges and benchmarking requirements against established tests like SEPT9 methylation. CONCLUSION: TCN1 represents a promising multi-functional biomarker in CRC, linking one-carbon metabolism to tumor progression. However, significant knowledge gaps remain regarding its precise molecular mechanisms. We outline a translational roadmap prioritizing in vivo validation, prospective clinical cohorts, and therapeutic vulnerability screening to determine whether TCN1 can transition from a biological player to a clinical tool.