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Chromosome 3p loss of heterozygosity is associated with a unique metabolic network in clear cell renal carcinoma

Francesco Gatto (Institutionen för kemi- och bioteknik, Systembiologi) ; Intawat Nookaew (Institutionen för kemi- och bioteknik, Systembiologi) ; Jens B. Nielsen (Institutionen för kemi- och bioteknik, Systembiologi)
Proceedings of the National Academy of Sciences of the United States of America (0027-8424). Vol. 111 (2014), 9, p. E866-E875.
[Artikel, refereegranskad vetenskaplig]

Several common oncogenic pathways have been implicated in the emergence of renowned metabolic features in cancer, which in turn are deemed essential for cancer proliferation and survival. However, the extent to which different cancers coordinate their metabolism to meet these requirements is largely unexplored. Here we show that even in the heterogeneity of metabolic regulation a distinct signature encompassed most cancers. On the other hand, clear cell renal cell carcinoma (ccRCC) strongly deviated in terms of metabolic gene expression changes, showing widespread down-regulation. We observed a metabolic shift that associates differential regulation of enzymes in one-carbon metabolism with high tumor stage and poor clinical outcome. A significant yet limited set of metabolic genes that explained the partial divergence of ccRCC metabolism correlated with loss of von Hippel-Lindau tumor suppressor (VHL) and a potential activation of signal transducer and activator of transcription 1. Further network-dependent analyses revealed unique defects in nucleotide, one-carbon, and glycerophospholipid metabolism at the transcript and protein level, which contrasts findings in other tumors. Notably, this behavior is recapitulated by recurrent loss of heterozygosity in multiple metabolic genes adjacent to VHL. This study therefore shows how loss of heterozygosity, hallmarked by VHL deletion in ccRCC, may uniquely shape tumor metabolism.

Nyckelord: cancer metabolism, systems biology, genome-scale metabolic modeling, renal cancer, NOVO PYRIMIDINE SYNTHESIS, GENE-EXPRESSION, DRUG TARGETS, CANCER, HYPOXIA, VHL, HETEROGENEITY, GROWTH, MODEL, SET

Denna post skapades 2014-05-05. Senast ändrad 2015-11-26.
CPL Pubid: 197568


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Institutioner (Chalmers)

Institutionen för kemi- och bioteknik, Systembiologi (2008-2014)


Cancer och onkologi

Chalmers infrastruktur

C3SE/SNIC (Chalmers Centre for Computational Science and Engineering)

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