Prognostic relevance of MDK and TIMP1 with immune infiltration in lung adenocarcinoma

Background LUAD is a prevalent and deadly lung cancer type. MDK and TIMP1 expression shows variations in different cancers. The specific contributions of these proteins to LUAD progression and tumor immunity, however, are not well delineated. Methods We leveraged RNA-seq data from TCGA and applied ggpubr R package to discern the expression disparity of MDK and TIMP1 in normal versus LUAD tissues. MDK and TIMP1 levels were further validated by qRT-PCR and western blot. Subsequently, LUAD patients were stratified into high and low expression groups based on MDK and TIMP1 expression, and the impact of their expression on overall survival (OS), disease-free interval (DFI), progression-free interval (PFI), and disease-specific survival (DSS) was analyzed. Kaplan-Meier survival curves and receiver operation characteristic curves were plotted. We also explored KEGG and GO annotations for 50 genes exhibiting expression profiles akin to MDK and TIMP1, and constructed a gene-gene interaction network using GeneMANIA. The enrichment of DEGs in the KEGG and GO pathways was scrutinized in both high and low expression groups of MDK and TIMP1. Furthermore, we investigated the mutational landscape of MDK and TIMP1 within LUAD and assessed correlation between their expression and infiltration of immune cells. Results MDK and TIMP1 were found to be markedly overexpressed in LUAD. LUAD patients with diminished expression of MDK and TIMP1 have extended OS, DFI, DSS, and PFI. Area under the curve values for MDK and TIMP1 were 0.943 and 0.875, respectively. Regression analysis identified TIMP1 as a risk factor influencing the OS of LUAD patients. Genes with similar expression profiles to MDK were notably enriched in the Proteasome pathway and peptidase activator activity, while those exhibit similar expression patterns to TIMP1 were predominantly involved in endopeptidase activity and the Cytoskeleton in muscle cells pathway. Functional predictions for the genes MDK and TIMP1 showed a parallel, particularly in their regulation of peptidase activity. Mutations in MDK and TIMP1 are not determinants of survival in LUAD patients. There was a negative correlation between MDK and TIMP1 expression and tumor purity. The tumor immune dysfunction and exclusion score was elevated in the group with high TIMP1 expression. The IPS_ctla_pos and IPS_pd1_pos scores are statistically significant in the high TIMP1 expression group. Infiltration of immune cells and immune-related functions is more substantial in MDK low expression and TIMP1 high expression groups. Conclusion A strong correlation exists between MDK and TIMP1 with both the prognosis and progression of LUAD, and the extent of immune cell infiltration, indicating that targeting these genes and their related pathways in immunotherapy could be of clinical value.