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 language | English |
|---|---|
| Pages (from-to) | 3957-3985 |
| Number of pages | 29 |
| Journal | Aging |
| Volume | 10 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - Dec 11 2018 |
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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 journal › Article
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TY - JOUR
T1 - 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
AU - Lucarelli, Giuseppe
AU - Rutigliano, Monica
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
PY - 2018/12/11
Y1 - 2018/12/11
N2 - 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.
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.
U2 - 10.18632/aging.101685
DO - 10.18632/aging.101685
M3 - Article
C2 - 30538212
VL - 10
SP - 3957
EP - 3985
JO - Aging
JF - Aging
SN - 1945-4589
IS - 12
ER -