| Summary: | Prostate cancer (PCa) is the second most common cancer in men. Diagnosis and risk assessment are widely based on serum Prostate Specific Antigen (PSA) and biopsy, which might not represent the exact degree of PCa risk. Towards the discovery of biomarkers for better patient stratification, we performed proteomic analysis of Formalin Fixed Paraffin Embedded (FFPE) prostate tissue specimens using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Comparative analysis of 86 PCa samples among grade groups 1–5 identified 301 significantly altered proteins. Additional analysis based on biochemical recurrence (BCR; BCR+ <i>n</i> = 14, BCR- <i>n</i> = 51) revealed 197 significantly altered proteins that indicate disease persistence. Filtering the overlapping proteins of these analyses, seven proteins (<i>NPM1</i>, <i>UQCRH</i>, <i>HSPA9</i>, <i>MRPL3</i>, <i>VCAN</i>, <i>SERBP1</i>, <i>HSPE1</i>) had increased expression in advanced grades and in BCR+/BCR- and may play a critical role in PCa aggressiveness. Notably, all seven proteins were significantly associated with progression in Prostate Cancer Transcriptome Atles (PCTA) and <i>NPM1NPM1</i>, <i>UQCRH</i>, and <i>VCAN</i> were further validated in The Cancer Genome Atlas (TCGA), where they were upregulated in BCR+/BCR-. <i>UQCRH</i> levels were also associated with poorer 5-year survival. Our study provides valuable insights into the key regulators of PCa progression and aggressiveness. The seven selected proteins could be used for the development of risk assessment tools.
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