Overexpression of Pyruvate Dehydrogenase Kinase-3 Predicts Poor Prognosis in Urothelial Carcinoma
Open Access
- 13 September 2021
- journal article
- research article
- Published by Frontiers Media SA in Frontiers in Oncology
Abstract
Background The mitochondrial pyruvate dehydrogenase complex (PDC) link glycolysis to the tricarboxylic acid cycle by decarboxylating pyruvate to acetyl coenzyme A irreversibly. Cancer cells are characterized by a shift in cellular metabolism from mitochondrial respiration to glycolysis. PDC activity inhibition mediated by phosphorylation via pyruvate dehydrogenase kinase (PDK) has been linked to cancer. However, the clinical significance of PDKs in urothelial cancer prognosis is not clear. We investigated the role and prognostic value of PDK3 expression in patients with upper urinary tract urothelial carcinoma (UTUC) and urinary bladder urothelial carcinoma (UBUC). Patients and Methods We retrospectively analyzed clinical data and pathological features. Formalin-fixed urothelial carcinoma (UC) tissues were collected and embedded in paraffin. The correlation of PDK3 expression with clinical characteristics, pathological findings and patient outcomes, including metastasis-free survival (MFS) and disease-specific survival (DSS) were analyzed by Pearson’s chi-square test, Kaplan–Meier analysis, and the multivariate Cox proportional hazards model. Results Data from 295 patients with UBUC and 340 patients with UTUC were evaluated. High PDK3 expression significantly correlated with several pathologic variables such as high T stage, lymph node metastases, high tumor grade, vascular invasion, and high mitotic rate (all P < 0.001). High PDK3 expression was associated with poor disease-specific survival (DSS) (P < 0.0001) and metastatic free survival (MFS) (P < 0.0001) in a Kaplan–Meier analysis. Additionally, multivariate analysis demonstrated increased PDK3 expression is a significant predictive risk factor for DSS [hazard ratio (HR) in UBUC, 2.79, P = 0.009; in UTUC, 2.561, P = 0.03] and MFS (HR in UBUC, 1.907, P = 0.024; in UTUC, 1.793, P = 0.044). The gene co-expression analysis showed abundant PDK3 co-upregulated genes were involved in the processes of DNA replication and repair through the Gene Ontology classification system. Conclusion High PDK3 expression has been linked to negative pathologic characteristics and poor oncological outcomes, suggesting that it could be used as a predictive biomarker for UC. PDK3 mRNA levels and its co-upregulated genes were strongly associated with DNA replication and repair. These results suggest that PDK3 may play a key role in tumor proliferation and development.This publication has 50 references indexed in Scilit:
- Epidemiology and Risk Factors of Urothelial Bladder CancerEuropean Urology, 2012
- Randomized Phase II/III Trial Assessing Gemcitabine/Carboplatin and Methotrexate/Carboplatin/Vinblastine in Patients With Advanced Urothelial Cancer Who Are Unfit for Cisplatin-Based Chemotherapy: EORTC Study 30986Journal of Clinical Oncology, 2012
- Long-term Cancer-specific Survival in Patients with High-risk, Non–muscle-invasive Bladder Cancer and Tumour Progression: A Systematic ReviewEuropean Urology, 2011
- Overexpression of Pyruvate Dehydrogenase Kinase 3 Increases Drug Resistance and Early Recurrence in Colon CancerThe American Journal of Pathology, 2011
- Outcomes of radical nephroureterectomy: A series from the Upper Tract Urothelial Carcinoma CollaborationCancer, 2009
- Significant Predictive Factors for Prognosis of Primary Upper Urinary Tract Cancer after Radical Nephroureterectomy in Taiwanese PatientsEuropean Urology, 2008
- DNA repair pathways as targets for cancer therapyNature Reviews Cancer, 2008
- Isolation of the Cdc45/Mcm2–7/GINS (CMG) complex, a candidate for the eukaryotic DNA replication fork helicaseProceedings of the National Academy of Sciences of the United States of America, 2006
- Peptide Elongation Factor eEF1A-2/S1 Expression in Cultured Differentiated Myotubes and Its Protective Effect against Caspase- 3-mediated ApoptosisOnline Journal of Public Health Informatics, 2002
- Purification and characterization of CAF-I, a human cell factor required for chromatin assembly during DNA replication in vitroCell, 1989