title: Hypoxia induces copper stable isotope fractionation in hepatocellular carcinoma, in a HIF-independent manner.
abstract: Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer, with increasing incidence worldwide. The unrestrained proliferation of tumour cells leads to tumour hypoxia which in turn promotes cancer aggressiveness. While changes in the concentration of copper (Cu) have long been observed upon cancerization, we have recently reported that the isotopic composition of copper is also altered in several types of cancer. In particular, we showed that in hepatocellular carcinoma, tumour tissue contains heavier copper compared to the surrounding parenchyma. However, the reasons behind such isotopic signature remained elusive. Here we show that hypoxia causes heavy copper enrichment in several human cell lines. We also demonstrate that this effect of hypoxia is pH, HIF-1 and -2 independent. Our data identify a previously unrecognized cellular process associated with hypoxia, and suggests that in vivo tumour hypoxia determines copper isotope fractionation in HCC and other solid cancers.
authors: Univ Lyon, ENS de Lyon, Université Lyon 1, CNRS, UMR 5276 LGL-TPE, F-69342, Lyon, France. victor.bondanese@ens-lyon.fr albarede@ens-lyon.fr.
authors: Victor P
authors: 0000-0002-2216-6162
authors: VP
authors: Bondanese
authors: Univ Lyon, ENS de Lyon, Université Lyon 1, CNRS, UMR 5276 LGL-TPE, F-69342, Lyon, France. victor.bondanese@ens-lyon.fr albarede@ens-lyon.fr.
authors: Aline
authors: A
authors: Lamboux
authors: Univ Lyon, ENS de Lyon, Université Lyon 1, CNRS, UMR 5276 LGL-TPE, F-69342, Lyon, France. victor.bondanese@ens-lyon.fr albarede@ens-lyon.fr.
authors: Melanie
authors: M
authors: Simon
authors: Institute for Biology and Chemistry of Proteins, CNRS, UMR 5305 Laboratory of Tissue Biology and Therapeutic Engineering, Université Claude Bernard-Lyon 1 and University of Lyon, France.
authors: Jérôme E
authors: JE
authors: Lafont
authors: Univ Lyon, ENS de Lyon, Université Lyon 1, CNRS, UMR 5276 LGL-TPE, F-69342, Lyon, France. victor.bondanese@ens-lyon.fr albarede@ens-lyon.fr.
authors: Emmanuelle
authors: E
authors: Albalat
authors: Univ Lyon, ENS de Lyon, Université Lyon 1, CNRS, UMR 5276 LGL-TPE, F-69342, Lyon, France. victor.bondanese@ens-lyon.fr albarede@ens-lyon.fr.
authors: Sylvain
authors: S
authors: Pichat
authors: Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Université Lyon 1, CNRS, Ecole Normale Supérieure de Lyon, 69007 Lyon, France.
authors: Jean-Marc
authors: JM
authors: Vanacker
authors: Univ Lyon, ENS de Lyon, Université Lyon 1, CNRS, UMR 5276 LGL-TPE, F-69342, Lyon, France. victor.bondanese@ens-lyon.fr albarede@ens-lyon.fr.
authors: Philippe
authors: P
authors: Telouk
authors: Univ Lyon, ENS de Lyon, Université Lyon 1, CNRS, UMR 5276 LGL-TPE, F-69342, Lyon, France. victor.bondanese@ens-lyon.fr albarede@ens-lyon.fr.
authors: Vincent
authors: V
authors: Balter
authors: Univ Lyon, ENS de Lyon, Université Lyon 1, CNRS, UMR 5276 LGL-TPE, F-69342, Lyon, France. victor.bondanese@ens-lyon.fr albarede@ens-lyon.fr.
authors: Philippe
authors: P
authors: Oger
authors: Univ Lyon, ENS de Lyon, Université Lyon 1, CNRS, UMR 5276 LGL-TPE, F-69342, Lyon, France. victor.bondanese@ens-lyon.fr albarede@ens-lyon.fr.
authors: Francis
authors: F
authors: Albarède
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D002458:Cell Fractionation; D002470:Cell Survival; D003300:Copper / Q000378:metabolism*; D003301:Copper Radioisotopes / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D003300:Copper; D003301:Copper Radioisotopes; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000099162:Endothelial PAS Domain-Containing Protein 1