Clinical and Functional Characterization of CD-NTase Enzymes in Esophageal Squamous Cell Carcinoma.

Purpose: The cGAS/DncV-like nucleotidyltransferase (CD-NTase) enzyme family plays a critical role in tumor development, but its clinical significance and biological function in esophageal squamous cell carcinoma (ESCC) remain unclear. Methods: We analyzed 352 ESCC cases, including 260 from public datasets (TCGA, GSE53624, and GSE53622) and 92 from our clinical cohort. Candidate CD-NTase enzymes were validated through in vivo and in vitro experiments. Results: Analysis of 11 CD-NTase enzymes identified MB21D2 as the only significant prognostic factor in three clinical cohorts. Patients with low MB21D2 expression demonstrated markedly worse overall survival (OS). Multivariate analysis indicated that low MB21D2 was an independent prognostic factor (HR = 2.5, P =0.04; HR = 1.33, P =0.02; HR = 2.5, P =0.02). Furthermore, biological functional experiments showed that knockdown MB21D2 promotes proliferation, migration, and invasion in ESCC cells. While overexpression MB21D2 has the opposite effect. RNA-seq and western blotting analysis revealed that knockdown of MB21D2 activates markers associated with the Wnt/β-catenin signaling pathway, thereby promoting ESCC progression. Conclusion: MB21D2 serves as a critical prognostic and functional factor in ESCC progression, offering a potential therapeutic target for improving patient outcomes.