Multi-omics Analyses Reveal Function of Apolipoprotein E in Alternative Splicing and Tumor Immune Microenvironment in Kidney Renal Clear Cell Carcinoma via Pan-cancer Analysis

Apolipoprotein E (APOE) regulates lipid metabolism, associated with the development of various cancers. However, its precise prognostic significance and functions in alternative splicing and the tumor immune microenvironment remain unclear. In this study, we extracted APOE expression in pan-cancer from TCGA and analyzed mRNA transcriptome, cell lines, and protein levels. Furthermore, we analyzed the alternative splicing expression of the APOE gene transcript with prognostic profiles using the OncoSplicing database. We obtained 73 common APOE genes to perform functional enrichment analysis, assess the correlation between genes and immune cells using TIMER, EPIC, and ssGSEA methods, and examine the prognostic significance using the UALCAN database. Finally, single-cell data was employed to assess the correlation between APOE genes and cell functions. Our findings revealed that APOE expression varies across different tumor types and cancer cell lines. The alternative splicing analysis demonstrated that APOE transcript expression levels have prognostic value in cancers such as LGG, KIRC, and KIRP. Functional enrichment analysis indicated significant associations between APOE and various immune cells, such as macrophages, CD8 T cells, and NK cells, with significant implications for prognosis. Moreover, single-cell data indicated that APOE was primarily expressed in renal epithelial cells among stromal cells and in macrophages among immune cells, significantly negatively correlated with five functional states. Our study represents the first comprehensive exploration of APOE’s function in pan-cancers and identifies APOE as a potential biomarker in cancer pathogenesis, prognosis, and immune therapeutic target.