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.
Highlights
Prostate cancer (PCa) is the second most frequent cancer and the fifth leading cause of death from cancer in men worldwide (Bray et al, 2018)
We show that low pyruvate dehydrogenase kinase 4 (PDK4) expression is significantly associated with a higher risk of Biochemical recurrence (BCR) and that PDK4 predicts disease recurrence independent of International Society of Urological Pathology (ISUP) grading in low-/intermediate-risk primary tumors
In order to assess biological processes associated with signal transducer and activator of transcription 3 (STAT3) expression in primary PCa, we employed two different approaches of analyzing the TCGA PRAD RNA-Seq data of 498 patients (Fig 1A)
Summary
Prostate cancer (PCa) is the second most frequent cancer and the fifth leading cause of death from cancer in men worldwide (Bray et al, 2018). In 2005, the GSC was modified by the International Society of Urological Pathology (ISUP) (Epstein et al, 2005), resulting in the ISUP grade, which ranges from I to V (National Collaborating Centre for Cancer (UK), 2014). PCa shows a wide variety in clinical behavior, ranging from harmless, indolent tumors to aggressive metastatic disease (Epstein & Lotan, 2014; Sathianathen et al, 2018). Treatment following biopsy of the prostate is individualized and based on four main criteria: the amount of tumor in the biopsy, the histological GSC/ISUP grading, clinical staging, and—to a lesser extent— the level of prostate-specific antigen (PSA) in the serum (National Collaborating Centre for Cancer (UK), 2014). There is a significant risk of over- and under-treatment (Sathianathen et al, 2018), and additional biomarkers for risk stratification are urgently needed
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