Abstract
Gastric cancer (GC) remains one of the leading causes of cancer-related mortality worldwide, with high molecular heterogeneity contributing to its poor prognosis. Among potential biomarkers, THY1 is associated with aggressive tumor behavior and poor patient outcomes. However, the transcriptional mechanisms governing THY1 expression in GC remain largely unexplored. This study aimed to systematically investigate the upstream regulatory landscape of THY1 and its role in tumor progression. By integrating multicohort transcriptomic data (n = 945), we inferred consensus transcriptional regulatory networks (TRNs) and identified six putative transcription factors (PRRX1, TWIST1, SNAI2, MEIS3, VENTX, and EGR2) as robust regulators of THY1. The functional enrichment analysis revealed that these regulators are involved in the epithelial-mesenchymal transition (EMT) and extracellular matrix remodeling, key processes associated with tumor invasion and metastasis. Experimental validation using chromatin immunoprecipitation (ChIP) assays indicated the direct and differential binding of TWIST1 and SNAI2 to the THY1 promoter, supporting their roles as key regulators of THY1 expression in GC. Our findings provide a mechanistic link between THY1 expression and EMT transcriptional programs, offering insights into its association with a poor prognosis. By integrating bioinformatic predictions with experimental demonstration, this study not only improves our understanding of THY1 regulation but also provides a framework for dissecting the transcriptional networks governing aggressive tumor phenotypes. These results contribute to a broader understanding of GC progression and may inform future therapeutic strategies targeting EMT-related pathways in THY1 (high) GC.