PCSK9 expression and cancer survival: a prognostic biomarker at the intersection of oncology and geroscience

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is primarily recognized for its role in cholesterol metabolism; however, emerging evidence suggests it plays a broader role in the regulation of cellular aging mechanisms and the pathogenesis of age-related diseases. Given that cancer is an age-related disease, PCSK9 has garnered attention for its potential impact on tumor progression and patient survival. In this study, we conducted a comprehensive analysis of PCSK9 expression across multiple tumor types, assessing its prognostic significance using RNA sequencing data from The Cancer Genome Atlas (TCGA) and gene expression microarray data from the Gene Expression Omnibus (GEO). Cox proportional hazards regression models and Kaplan-Meier survival analyses were employed to evaluate overall survival (OS) associations. Our findings reveal that elevated PCSK9 expression is associated with improved OS in breast and ovarian cancers, particularly in Luminal B breast cancer subtypes. Conversely, high PCSK9 expression correlates with worse OS in bladder cancer, renal clear cell carcinoma, melanoma, and pancreatic cancer. Notably, while PCSK9 expression is significantly upregulated in melanoma and bladder tumors, it is downregulated in renal clear cell carcinoma, yet relatively higher expression among renal tumors still predicts poorer survival. No significant associations between PCSK9 expression and OS were observed in colon, liver, gastric, lung, prostate, head and neck cancers, or low-grade gliomas in the available datasets.In conclusion, our study identifies PCSK9 as a prognostic biomarker with distinct, tumor-specific survival implications. Its dual role-associating with improved survival in some cancers while correlating with worse outcomes in others-suggests that PCSK9 may influence cancer progression through context-dependent mechanisms. Future research should focus on elucidating the mechanistic underpinnings of these associations and exploring the diagnostic and therapeutic potential of targeting PCSK9 in oncology.