title: Altered metabolic pathways in clear cell renal cell carcinoma: A meta-analysis and validation study focused on the deregulated genes and their associated networks.
abstract: Clear cell renal cell carcinoma (ccRCC) is the predominant subtype of renal cell carcinoma (RCC). It is one of the most therapy-resistant carcinomas, responding very poorly or not at all to radiotherapy, hormonal therapy and chemotherapy. A more comprehensive understanding of the deregulated pathways in ccRCC can lead to the development of new therapies and prognostic markers. We performed a meta- analysis of 5 publicly available gene expression datasets and identified a list of co- deregulated genes, for which we performed extensive bioinformatic analysis coupled with experimental validation on the mRNA level. Gene ontology enrichment showed that many proteins are involved in response to hypoxia/oxygen levels and positive regulation of the VEGFR signaling pathway. KEGG analysis revealed that metabolic pathways are mostly altered in ccRCC. Similarly, Ingenuity Pathway Analysis showed that the antigen presentation, inositol metabolism, pentose phosphate, glycolysis/gluconeogenesis and fructose/mannose metabolism pathways are altered in the disease. Cellular growth, proliferation and carbohydrate metabolism, were among the top molecular and cellular functions of the co-deregulated genes. qRT-PCR validated the deregulated expression of several genes in Caki-2 and ACHN cell lines and in a cohort of ccRCC tissues. NNMT and NR3C1 increased expression was evident in ccRCC biopsies from patients using immunohistochemistry. ROC curves evaluated the diagnostic performance of the top deregulated genes in each dataset. We show that metabolic pathways are mostly deregulated in ccRCC and we highlight those being most responsible in its formation. We suggest that these genes are candidate predictive markers of the disease.
authors.affiliation: Molecular Medicine Research Center and Laboratory of Molecular and Medical Genetics, Department of Biological Sciences, University of Cyprus, Nicosia, Cyprus.
authors.forename: Apostolos
authors.initials: A
authors.lastname: Zaravinos
authors.affiliation: Molecular Medicine Research Center and Laboratory of Molecular and Medical Genetics, Department of Biological Sciences, University of Cyprus, Nicosia, Cyprus.
authors.forename: Myrtani
authors.initials: M
authors.lastname: Pieri
authors.affiliation: Department of Urology, Asklipieio General Hospital, Athens, Greece.
authors.forename: Nikos
authors.initials: N
authors.lastname: Mourmouras
authors.affiliation: Department of Nephrology, Nicosia General Hospital, Nicosia, Cyprus.
authors.forename: Natassa
authors.initials: N
authors.lastname: Anastasiadou
authors.affiliation: Department of Nephrology, Nicosia General Hospital, Nicosia, Cyprus.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Zouvani
authors.affiliation: Department of Urology, Asklipieio General Hospital, Athens, Greece.
authors.forename: Dimitris
authors.initials: D
authors.lastname: Delakas
authors.affiliation: Molecular Medicine Research Center and Laboratory of Molecular and Medical Genetics, Department of Biological Sciences, University of Cyprus, Nicosia, Cyprus.
authors.forename: Constantinos
authors.initials: C
authors.lastname: Deltas
keywords: clear-cell renal cell carcinoma; gene expression; gene networks; metabolic pathways; oncomine; pathway analysis