ABSTRACT
Prostate cancer (PCa) has a broad spectrum of clinical behavior; hence, biomarkers are urgently needed for risk stratification. Here, we aim to find potential biomarkers for risk stratification, by utilizing a gene co-expression network of transcriptomics data in addition to laser-microdissected proteomics from human and murine prostate FFPE samples. We show up-regulation of oxidative phosphorylation (OXPHOS) in PCa on the transcriptomic level and up-regulation of the TCA cycle/OXPHOS on the proteomic level, which is inversely correlated to STAT3 expression. We hereby identify gene expression of pyruvate dehydrogenase kinase 4 (PDK4), a key regulator of the TCA cycle, as a promising independent prognostic marker in PCa. PDK4 predicts disease recurrence independent of diagnostic risk factors such as grading, staging, and PSA level. Therefore, low PDK4 is a promising marker for PCa with dismal prognosis.
Subject(s)
Gene Expression Profiling/methods , Neoplasm Recurrence, Local/genetics , Neoplasms, Experimental/pathology , Prostatic Neoplasms/genetics , Proteomics/methods , Pyruvate Dehydrogenase Acetyl-Transferring Kinase/genetics , STAT3 Transcription Factor/genetics , Animals , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Gene Expression Regulation, Neoplastic , Humans , Laser Capture Microdissection , Male , Mice , Neoplasm Grading , Neoplasm Recurrence, Local/metabolism , Neoplasm Recurrence, Local/pathology , Neoplasms, Experimental/genetics , Neoplasms, Experimental/metabolism , Oxidative Phosphorylation , Prognosis , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Pyruvate Dehydrogenase Acetyl-Transferring Kinase/metabolism , STAT3 Transcription Factor/metabolism , Systems Biology , Young AdultABSTRACT
We aimed to identify novel markers for aggressive prostate cancer in a STAT3-low proteomics-derived dataset of mitochondrial proteins by immunohistochemical analysis and correlation with transcriptomic data and biochemical recurrence in a STAT3 independent PCa cohort. Formalin-fixed paraffin-embedded tissue (FFPE) sample selection for proteomic analysis and tissue-microarray (TMA) generation was conducted from a cohort of PCa patients. Retrospective data analysis was performed with the same cohort. 153 proteins differentially expressed between STAT3-low and STAT3-high samples were identified. Out of these, 46 proteins were associated with mitochondrial processes including oxidative phosphorylation (OXPHOS), and 45 proteins were upregulated, including NDUFS1/ATP5O. In a STAT3 independent PCa cohort, high expression of NDUFS1/ATP5O was confirmed by immunocytochemistry (IHC) and was significantly associated with earlier biochemical recurrence (BCR). mRNA expression levels for these two genes were significantly higher in intra-epithelial neoplasia and in PCa compared to benign prostate glands. NDUFS1/ATP5O levels are increased both at the mRNA and protein level in aggressive PCa. Our results provide evidence that NDUFS1/ATP5O could be used to identify high-risk PCa patients.