Prognostic Significance of Elevated UCHL1, SNRNP200, and PAK4 Expression in High-Grade Clear Cell Renal Cell Carcinoma: Insights from LC-MS/MS Analysis and Immunohistochemical Validation

Simple Summary This study explored the protein expression levels of UCHL1, SNRNP200, and PAK4 in clear cell renal cell carcinoma (CCRCC) using advanced proteomic techniques. We found that UCHL1 and SNRNP200 are significantly upregulated, and PAK4 is downregulated in high-grade CCRCC, and all are involved in critical cellular pathways linked to cancer progression and poor clinical outcomes. Specifically, UCHL1 is implicated in the Akt signaling pathway, SNRNP200 plays a role in RNA splicing and cell cycle regulation, and PAK4 is associated with cell proliferation and invasion. The enhanced expression of UCHL1 and SNRNP200, and decreased expression of PAK4 correlate with shorter progression-free survival in CCRCC patients, suggesting their potential as prognostic markers and targets for therapeutic intervention. This research contributes to the understanding of CCRCC's molecular dynamics and opens new avenues for targeted treatments.Abstract Recent advancements in proteomics have enhanced our understanding of clear cell renal cell carcinoma (CCRCC). Utilizing a combination of liquid chromatography-tandem mass spectrometry (LC-MS/MS) followed by immunohistochemical validation, we investigated the expression levels of UCHL1, PAK4, and SNRNP200 in high-grade CCRCC samples. Our analysis also integrated Reactome pathway enrichment to elucidate the roles of these proteins in cancer-related pathways. Our results revealed significant upregulation of UCHL1 and SNRNP200 and downregulation of PAK4 in high-grade CCRCC tissues compared to non-cancerous tissues. UCHL1, a member of the ubiquitin carboxy-terminal hydrolase family, showed variable expression across different tissues and was notably involved in the Akt signaling pathway, which plays a critical role in cellular survival in various cancers. SNRNP200, a key component of the RNA splicing machinery, was found to be essential for proper cell cycle progression and possibly linked to autosomal dominant retinitis pigmentosa. PAK4's role was noted as critical in RCC cell proliferation and invasion and its expression correlated significantly with poor progression-free survival in CCRCC. Additionally, the expression patterns of these proteins suggested potential as prognostic markers for aggressive disease phenotypes. This study confirms the upregulation of UCHL1, SNRNP200, and PAK4 as significant factors in the progression of high-grade CCRCC, linking their enhanced expression to poor clinical outcomes. These findings propose these proteins as potential prognostic markers and therapeutic targets in CCRCC, offering novel insights into the molecular landscape of this malignancy and highlighting the importance of targeted therapeutic interventions.