Integrated multi-omics characterization reveals a distinctive metabolic signature and the role of NDUFA4L2 in promoting angiogenesis, chemoresistance, and mitochondrial dysfunction in clear cell renal cell carcinoma.

An altered metabolism is involved in the development of clear cell - renal cell carcinoma (ccRCC), and in this tumor many altered genes play a fundamental role in controlling cell metabolic activities. We delineated a large-scale metabolomic profile of human ccRCC, and integrated it with transcriptomic data to connect the variations in cancer metabolism with gene expression changes. Moreover, to better analyze the specific contribution of metabolic gene alterations potentially associated with tumorigenesis and tumor progression, we evaluated the transcription profile of primary renal tumor cells. Untargeted metabolomic analysis revealed a signature of an increased glucose uptake and utilization in ccRCC. In addition, metabolites related to pentose phosphate pathway were also altered in the tumor samples in association with changes in Krebs cycle intermediates and related metabolites. We identified NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 4-like 2 (NDUFA4L2) as the most highly expressed gene in renal cancer cells and evaluated its role in sustaining angiogenesis, chemoresistance, and mitochondrial dysfunction. Finally, we showed that silencing of NDUFA4L2 affects cell viability, increases mitochondrial mass, and induces ROS generation in hypoxia.

Aging. 2018 Dec 11 [Epub]

Giuseppe Lucarelli, Monica Rutigliano, Fabio Sallustio, Domenico Ribatti, Andrea Giglio, Martina Lepore Signorile, Valentina Grossi, Paola Sanese, Anna Napoli, Eugenio Maiorano, Cristina Bianchi, Roberto A Perego, Matteo Ferro, Elena Ranieri, Grazia Serino, Lauren N Bell, Pasquale Ditonno, Cristiano Simone, Michele Battaglia

Department of Emergency and Organ Transplantation- Urology, Andrology and Kidney Transplantation Unit, University of Bari, Bari, Italy., Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari, Bari, Italy., Department of Biomedical Sciences and Human Oncology, Medical Genetics, University of Bari, Bari, Italy., Department of Emergency and Organ Transplantation, Pathology Unit, University of Bari, Bari, Italy., Department of Health Sciences, School of Medicine and Surgery, University of Milano Bicocca, Milan, Italy., Division of Urology, European Institute of Oncology, Milan, Italy., Department of Medical and Surgical Sciences, Molecular Medicine Center, Section of Clinical Pathology, University of Foggia, Foggia, Italy., National Institute of Gastroenterology, 'S de Bellis', Castellana Grotte, Bari, Italy., Metabolon, Inc., Research Triangle Park, Morrisville, NC 27560, USA.