A Multi-Omics Analysis of the Prognostic Biomarker GDF15 Associated with Immune Infiltration and Regulated Mitochondrial-Dependent Apoptosis in Colorectal Cancer

Abstract Background: Growth differentiation factor 15 (GDF15), also known as NSAID activated gene-1 (NAG-1), is associated with a large number of biological processes and diseases, including cancer. However, the correlation between the use of GDF15 and the development and immune infiltration of colorectal cancer (CRC) has rarely been studied. Methods: The expression level of GDF15 in pan-cancer was examined using the TIMER 2.0 and TCGA databases. Using the TCGA database and GEPIA, the potential utility of GDF15 as a diagnostic and prognostic biomarker in pan-cancer was assessed. Analysis of the relationship between GDF15 and immune infiltration in CRC was performed using the ESTIMATE method. To examine the level of GDF15 expression in CRC tissues and CRC cell lines, Western blot analysis and qRT‒PCR were carried out. The ability of CRC cells to proliferate, migrate, and invade was examined using colony formation, Transwell assays, and EdU tests. To examine how GDF15 affects the cell cycle and apoptosis, flow cytometry and JC-1 assays were employed. Results: Both CRC and most malignancies had high overexpression of GDF15. In most malignancies, higher expression levels of GDF15 were linked to worse overall survival (OS) and disease-free survival (DSS), according to Kaplan‒Meier survival analyses. The expression of GDF15 was also found to be negatively connected with tumor immune infiltration, as well as with CD4+ T cells, CD8+ T cells, and neutrophil infiltration, in the majority of malignancies. According to the in vitro research, DGF15 levels were higher in CRC tissues and cell lines. Additionally, GDF15 knockdown markedly reduced CRC cell motility, proliferation, and G0/G1 arrest. Most importantly, we also observed that downregulation of GDF15 can promote mitochondrial-related apoptosis in CRC cells. Conclusions: In multiple human cancers, particularly in CRC, GDF15 overexpression predicts progression and a poor prognosis. GDF15 may also be an entirely novel diagnostic marker and offer a possible immune treatment target for tumor immunotherapy.