A pan-cancer bioinformatic analysis of DENND3 expression, prognosis and tumor immune microenvironment associations

Although DENND3 has been recognized as a gene associated with cancer, comprehensive pan-cancer studies examining its immunological activity and prognostic significance are still lacking. Our objective was to investigate the biological roles and molecular pathways governing its activity in diverse malignancies. Pan-cancer bulk sequencing data and online web tools were utilized to examine the associations of DENND3 with survival outcomes, genomic instability, cancer stem cell features, DNA repair mechanisms, and immune cell infiltration. Single-cell analysis datasets and the SpatialDB repository were applied to confirm the link between DENND3 levels and M2 macrophage presence. We employed the cMap web tool to identify compounds targeting DENND3 and utilized PDB along with Autodock Vina for 3D modeling and molecular docking of DENND3. DENND3 is significantly dysregulated across various cancer types, providing notable diagnostic and prognostic value in the majority of cases studied. Individuals diagnosed with melanoma, lung, and kidney malignancies displaying elevated DENND3 expression demonstrate shorter survival periods. Research observations indicate associations between DENND3 expression patterns and multiple factors including genomic instability, methylation status, DNA repair mechanisms, stemness characteristics, and TME metrics across cancer variants. Additionally, evidence suggests a positive link between the CD276 immune checkpoint and DENND3. We observed correlations between DENND3 expression and M2 macrophage-related signatures and demonstrated its association with other immune cells. Elevated DENND3 levels correlate with reduced infiltration of memory B cell, monocyte, neutrophil, M1 macrophage, CD8 + T cell, and CD4 + T cell infiltration, but elevated infiltration of Tregs cells. Additionally, they show a positive correlation with antigen-presenting molecules and diverse immunological suppressor molecules. Finally, we identify sitagliptin as a potential suppressor of DENND3-driven oncogenic activities. This study identifies DENND3 expression as a promising biomarker linked to DNA repair, useful for predicting prognosis in various human cancers, and highlights its promise for creating in silico candidate compounds requiring further experimental validation or strengthening immune-based treatments.