NFYA Activates REG1A Expression to Promote Malignant Progression and Chemosensitivity in Rectal Cancer

Objective This study aimed to investigate the molecular mechanisms of rectal cancer (RC) progression and provide new insights for itstreatment. Methods The Cancer Genome Atlas (TCGA), Gene Expression Profiling Interactive Analysis (GEPIA), Tumor Immune Estimation Resource(TIMER) databases, and the UALCAN platform were used to predict gene expression and correlations. The JASPAR database wasused to predict transcription factors. Quantitative polymerase chain reaction (qPCR) and western blot (WB) were performedto detect gene and protein expression. Cell viability was measured using the cell counting kit-8 (CCK-8). Transcription factor-promoterinteractions were examined through chromatin immunoprecipitation (ChIP) and the dual-luciferase reporter assay (DLR assay).Transcription factor-gene interactions were validated in vivo. The stats and ggplot2 packages in R were used for analysis and visualization. Results Regenerating islet-derived protein 1 alpha (REG1A) was significantly associated with RC malignant progression and was the most markedly upregulated. REG1A expression was elevated in RC patient tissues and cells. REG1A knockdown reduced RC cell survival and increased phosphorylated H2A histone family member X (γH2AX) levels under X-ray or 5-Fluorouracil (5FU). Nuclear transcription factor Y subunit alpha (NFYA) was correlated withREG1A, and NFYA knockdown decreased REG1A expression and cell survival while increasing γH2AX; REG1A reversed these effects. In vivo, NFYA knockdown reduced tumor volume, weight, and REG1A levels. Conclusion NFYA promoted REG1A expression, and the NFYA-REG1A axis enhanced RC resistance to RT and CT and malignant progression.