Integrative Analysis of ATP2B4 Expression and Its Clinical and Molecular Associations in Colorectal Cancer

Plasma membrane Ca²⁺-ATPase isoform 4 (PMCA4), encoded by the ATP2B4 gene, is a key regulator of intracellular Ca²⁺ homeostasis and has recently emerged as a context-dependent modulator of cancer progression. However, its clinicopathological significance in colorectal cancer (CRC) remains incompletely characterized. Here, we performed an integrated bioinformatic analysis using multiple publicly available datasets to evaluate ATP2B4 expression at the transcript and protein levels, its association with patient survival and clinicopathological characteristics, and its molecular context in CRC. ATP2B4 expression was additionally evaluated in independent CRC datasets to assess the reproducibility of the observed expression and prognostic associations. Transcriptomic and proteomic analyses demonstrated significantly reduced expression in tumor tissues compared with normal colorectal tissues. Survival analysis using the KM-Plotter dataset showed associations between higher ATP2B4 expression and poorer overall survival; however, this prognostic association was not reproduced in the independent cohort using a median-based cutoff. Further analyses showed that ATP2B4 expression was associated with tumor purity, stromal content, and molecular subtype, indicating that bulk-tumor expression patterns are influenced by tumor composition and molecular context. Co-expression and functional enrichment analyses indicated positive associations with cell adhesion and extracellular matrix organization, whereas tumors with low expression were enriched for mitochondrial and oxidative phosphorylation pathways. Collectively, these findings demonstrate reproducible downregulation of ATP2B4 in CRC while showing that its prognostic and molecular associations are context dependent and should be interpreted in relation to tumor composition and molecular subtype.