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

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

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)3957-3985
Number of pages29
JournalAging
Volume10
Issue number12
DOIs
Publication statusPublished - Dec 11 2018

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Renal Cell Carcinoma
Metabolomics
Neoplasms
Genes
Electron Transport Complex I
Pentose Phosphate Pathway
Citric Acid Cycle
Cell Survival
Carcinogenesis
Kidney
Gene Expression
Glucose

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

In: Aging, Vol. 10, No. 12, 11.12.2018, p. 3957-3985.

Research output: Contribution to journalArticle

Lucarelli, G, Rutigliano, M, Sallustio, F, Ribatti, D, Giglio, A, Lepore Signorile, M, Grossi, V, Sanese, P, Napoli, A, Maiorano, E, Bianchi, C, Perego, RA, Ferro, M, Ranieri, E, Serino, G, Bell, LN, Ditonno, P, Simone, C & Battaglia, M 2018, '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', Aging, vol. 10, no. 12, pp. 3957-3985. https://doi.org/10.18632/aging.101685
Lucarelli, Giuseppe ; Rutigliano, Monica ; Sallustio, Fabio ; Ribatti, Domenico ; Giglio, Andrea ; Lepore Signorile, Martina ; Grossi, Valentina ; Sanese, Paola ; Napoli, Anna ; Maiorano, Eugenio ; Bianchi, Cristina ; Perego, Roberto A ; Ferro, Matteo ; Ranieri, Elena ; Serino, Grazia ; Bell, Lauren N ; Ditonno, Pasquale ; Simone, Cristiano ; Battaglia, Michele. / 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. In: Aging. 2018 ; Vol. 10, No. 12. pp. 3957-3985.
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abstract = "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.",
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AU - Sallustio, Fabio

AU - Ribatti, Domenico

AU - Giglio, Andrea

AU - Lepore Signorile, Martina

AU - Grossi, Valentina

AU - Sanese, Paola

AU - Napoli, Anna

AU - Maiorano, Eugenio

AU - Bianchi, Cristina

AU - Perego, Roberto A

AU - Ferro, Matteo

AU - Ranieri, Elena

AU - Serino, Grazia

AU - Bell, Lauren N

AU - Ditonno, Pasquale

AU - Simone, Cristiano

AU - Battaglia, Michele

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AB - 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.

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